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Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti-programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.

Objectives: We sought to assess the expression of human leukocyte antigen (HLA) proteins and β2-microglobulin (B2M) in tumor cells and the relationship with immune microenvironment and outcome in colorectal cancer (CRC)., Methods: A total of 953 CRC cases were evaluated by immunohistochemistry for HLA class I, HLA class II, and B2M. The expression level of these biomarkers was correlated with clinicopathologic information, BRAF V600E and mismatch repair (MMR) proteins, and the quantitated expression levels of immune cells (CD8 and CD163) and immune regulatory proteins (FoxP3, programmed cell death 1 ligand 1 [PD-L1], and LAG3)., Results: We found that B2M-low tumors were statistically correlated with aggressive histologic features, including higher stage, higher grade, extramural venous invasion, perineural invasion, and distant metastasis. Expression of B2M was positively correlated (R2 = 0.3) and significantly associated with MMR-deficient tumors (P < .001); B2M-low tumors were also associated with an "immune cold"' microenvironment, including a reduced number of immune cells (CD8 and CD163), reduced expression of immune regulatory proteins by immune cells (PD-L1, FoxP3, and LAG3), and reduced tumor cell expression of PD-L1. These B2M-low tumors correlated with lower disease-specific survival (P = .018), a finding that maintained significance only for the proficient MMR cohort (P = .037)., Conclusions: Our findings suggest that B2M expression may support predictive models for both outcome and checkpoint inhibitor therapy treatment response for colorectal adenocarcinoma., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The microsatellite stable (MSS) colon cancer (CC) has long been considered resistant to immunotherapy. Cuproptosis, as a novel form of cell death, may interact with tumor immunity. This project focused on the impact of cuproptosis on the cytotoxicity of CD8 + T in MSS CC, aiming to provide effective clues for improving the treatment strategy of MSS CC. The study developed an MSS CC cuproptosis model using 50 nM elesclomol and 1 μM CuCl 2 . Cuproptotic SW480 cells were directly co-cultured with CD8 + T cells. Cuproptosis levels were assessed via intracellular copper ion detection, Western blot, and confocal laser scanning microscopy. CCK-8, Hochest/PI staining, CFSE cell proliferation assay, LDH cytotoxicity detection, and ELISA were used to evaluate CD8 + T cell immune activity and cytotoxicity. Transcriptome sequencing and bioinformatics analysis identified regulated signals in cuproptotic SW480 cells. A rescue experiment utilized a WNT pathway activator (BML-284). PD-L1 expression in cells/membranes was analyzed using qRT-PCR, Western blot, and flow cytometry. NSG mice were immunoreconstituted, and the effects of cuproptosis on immune infiltration and cancer progression in MSS CC mice were assessed using ELISA and immunohistochemistry (IHC). Treatment with 50 nM elesclomol and 1 μM CuCl 2 significantly increased cuproptosis in SW480 cells. Co-culture with CD8 + T cells enhanced their cytotoxicity. Sequencing revealed cuproptosis-mediated modulation of immune and inflammatory pathways, including WNT signaling. Rescue experiments showed downregulation of WNT signaling in cuproptotic SW480 cells. Indirectly, CD8 + T cell immune function was enhanced by reducing PD-L1 expression. In mice, cuproptosis resulted in increased infiltration of CD8 + T cells in tumor tissue, leading to delayed cancer progression compared to the control group. Cuproptosis in MSS CC cells enhances the cytotoxicity of CD8 + T cells, which may be achieved through downregulation of the WNT signaling pathway and decreased expression of PD-L1. In the future, drugs that can induce cuproptosis may be a promising approach to improve MSS CC immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The mechanisms underlying the development and progression of colon cancer are not fully understood. Herein, Src kinase associated phosphoprotein 1 (SKAP1), an immune cell adaptor, is identified as a novel colon cancer-related gene. SKAP1 expression is significantly increased in colon cancer cells. High SKAP1 levels are independently predictive of poor survival in patients with colon cancer. Notably, SKAP1 expression in colon cancer cells exerted a significant tumor-promoting effect in vivo rather than in vitro. Screening of tumor-infiltrating immune cells revealed the involvement of neutrophils in SKAP1-induced colon tumor promotion. Enhanced formation of neutrophil extracellular traps (NETs) is found to be a key downstream event that contributed to the pro-tumor role of SKAP1. In colon cancer cells, SKAP1 increased the expression of C-X-C motif chemokine ligand 8 (CXCL8) via nuclear factor of activated T cells c1 (NFATc1). The blockade of CXCL8 or NFATc1 largely attenuated neutrophil infiltration, NET formation, and tumor promotion induced by SKAP1. Furthermore, inhibiting SKAP1-induced NET significantly enhanced the antitumor efficiency of adoptive natural killer cell therapy in colon tumor models. In conclusion, SKAP1 significantly promotes colon cancer growth via the cancer cell/neutrophil NFATc1/CXCL8/NET axis, suggesting that SKAP1 is a potential target for colon cancer therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Pyroptosis is a form of regulated necrosis that occurs in many cell and tissue types and plays a critical role in tumor progression. The diagnostic value of pyroptosis-related genes (PRGs) in colon cancer has been widely investigated. In the present study, we explored the relationship between PRG expression and colon cancer., Methods: We retrieved genomic and clinical data pertaining to The Cancer Genome Atlas-Colon Adenocarcinoma from the UCSC Xena database, along with the corresponding genome annotation information from the GENCODE data portal. Utilising these data and a list of 33 pyrogenic genes, we performed principal component analysis and unsupervised clustering analysis to assess the pyroptosis subtypes. We analysed the differential expression between these subtypes to obtain PRGs, ultimately selecting 10 PRGs. We conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set variation analysis, protein-protein interaction, and immune infiltration analyses of these PRGs. We validated the expression of TNNC1 via immunohistochemistry (IHC) and real-time quantitative PCR., Results: After rigorous screening, excluding patients with incomplete survival data and unmatched transcriptomes, we refined our study cohort to 431 patients. We performed differential mRNA analysis and identified 445 PRGs, 10 of which were selected as hub genes. These genes were associated with various immune cell types. Specifically, TNNC1 expression was positively associated with immature dendritic cells and NK CD56 + cells. IHC staining indicated higher TNNC1 expression levels in tumor samples. Notably, TNNC1 expression levels were high in all the colon cancer cell lines, particularly in SW480 cells., Conclusion: In this study, we explored the characteristics of PRGs in colon cancer and identified novel biological targets for early individualised treatment and accurate diagnosis of colon cancer, thus contributing to the advancement of clinical oncology., Competing Interests: The authors declare there are no competing interests., (©2024 Shang et al.)

Objective: Colorectal cancer (CRC), specifically colon adenocarcinoma, is the third most prevalent and the second most lethal form of cancer. Anoikis is found to be specialized form of programmed cell death (PCD), which plays a pivotal role in tumor progression. This study aimed to investigate the role of the anoikis related genes (ARGs) in colon cancer., Methods: Consensus unsupervised clustering, differential expression analysis, tumor mutational burden analysis, and analysis of immune cell infiltration were utilized in the study. For the analysis of RNA sequences and clinical data of COAD patients, data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were obtained. A prognostic scoring system for overall survival (OS) prediction was developed using Cox regression and LASSO regression analysis. Furthermore, loss-of-function assay was utilized to explore the role of RAD9A played in the progression of colon cancer., Results: The prognostic value of a risk score composed of NTRK2, EPHA2, RAD9A, CDC25C, and SNAI1 genes was significant. Furthermore, these findings suggested potential mechanisms that may influence prognosis, supporting the development of individualized treatment plans and management of patient outcomes. Further experiments confirmed that RAD9A could promote proliferation and metastasis of colon cancer cells. These effects may be achieved by affecting the phosphorylation of AKT., Conclusion: Differences in survival time and the tumor immune microenvironment (TIME) were observed between two gene clusters associated with ARGs. In addition, a prognostic risk model was established and confirmed as an independent risk factor. Furthermore, our data indicated that RAD9A promoted tumorigenicityby activating AKT in colon cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The route of oncolytic virotherapy is pivotal for immunotherapeutic efficacy in advanced cancers. In this preclinical study, an oncolytic reovirus (RC402) is orally administered to induce antitumor immunity. Oral reovirus treatment shows no gross toxicities and effectively suppresses multifocal tumor lesions. Orally administered reovirus interacts with the host immune system in the Peyer's patch of the terminal ileum, increases IgA + antibody-secreting cells in the lamina propria through MAdCAM-1 + blood vessels, and reshapes the gut microbiome. Oral reovirus promotes antigen presentation, type I/II interferons, and T cell activation within distant tumors, but does not reach or directly infect tumor cells beyond the gastrointestinal tract. In contrast to intratumoral reovirus injection, the presence of the gut microbiome, Batf3 + dendritic cells, type I interferons, and CD8 + T cells are indispensable for orally administered reovirus-induced antitumor immunity. Oral reovirus treatment is most effective when combined with αPD-1(L1) and/or αCTLA-4, leading to complete colon tumor regression and protective immune memory. Collectively, oral reovirus virotherapy is a feasible and effective immunotherapeutic strategy in preclinical studies., (© 2024. The Author(s).)

Background: Colorectal cancer (CRC) remains a significant healthcare burden worldwide, characterized by a complex interplay between obesity and chronic inflammation. While the relationship between CRC, obesity and altered lipid metabolism is not fully understood, there are evidences suggesting a link between them. In this study, we hypothesized that dysregulated lipid metabolism contributes to local accumulation of foam cells (FC) in CRC, which in turn disrupts antitumor immunosurveillance., Methods: Tumor infiltrating FC and CD8 + were quantified by digital pathology in patients affected by T2-T4 CRC with any N stage undergoing radical upfront surgery (n=65) and correlated with patients' clinical outcomes. Multiparametric high-resolution flow cytometry analysis and bulk RNAseq of CRC tissue were conducted to evaluate the phenotype and transcriptomic program of immune cell infiltrate in relation to FC accumulation. The immunosuppressive effects of FC and mechanistic studies on FC-associated transforming growth factor-beta (TGF-β) and anti-PD-L1 inhibition were explored using an in-vitro human model of lipid-engulfed macrophages., Results: FC (large CD68 + Bodipy + macrophages) accumulated at the tumor margin in CRC samples. FC high tumors exhibited reduced CD8 + T cells and increased regulatory T cells (Tregs). Functional transcriptional profiling depicted an immunosuppressed milieu characterized by reduced interferon gamma, memory CD8 + T cells, and activated macrophages mirrored by increased T-cell exhaustion and Treg enrichment. Furthermore, FC high tumor phenotype was independent of standard clinical factors but correlated with high body mass index (BMI) and plasma saturated fatty acid levels. In CD8 low tumors, the FC high phenotype was associated with a 3-year disease-free survival rate of 8.6% compared with 28.7% of FC low (p=0.001). In-vitro studies demonstrated that FC significantly impact on CD8 proliferation in TFG-β dependent manner, while inhibition of TGF-β FC-related factors restored antitumor immunity., Conclusions: FC exert immunosuppressive activity through a TGF-β-related pathway, resulting in a CD8-excluded microenvironment and identifying immunosuppressed tumors with worse prognosis in patients with primary CRC. FC association with patient BMI and dyslipidemia might explain the link of CRC with obesity, and offers novel therapeutic and preventive perspectives in this specific clinical setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine., Methods: Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses., Results: MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-κB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy., Discussion: These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness., Competing Interests: Author RS reports support from Freenome, Exact Sciences, and Immunovia during the conduct of the study. Author OF reports personal fees from PDS Biotech, Invectys, Immodulon, and Ardigen outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cameron, Raghu, Richardson, Zagore, Tamilselvan, Golden, Cartwright, Schoen, Finn, Benos and Cameron.)

The abundance and biological contribution of natural killer (NK) cells in cancer are controversial. Here, we aim to uncover clinical relevance and cellular roles of NK cells in colon cancer liver metastasis (CCLM). Here, we integrated single-cell RNA-sequencing, spatial transcriptomics (ST), and bulk RNA-sequencing datasets to investigate NK cells' biological properties and functions in the microenvironment of primary and liver metastatic tumors. Results were validated through an in vitro co-culture experiment based on bioinformatics analysis. Useing single-cell RNA-sequencing and ST, we mapped the immune cellular landscape of colon cancer and well-matched liver metastatic cancer. We discovered that GZMK+ resting NK cells increased significantly in tumor tissues and were enriched in the tumor regions of both diseases. After combining bulk RNA and clinical data, we observed that these NK cell subsets contributed to a worse prognosis. Meanwhile, KIR2DL4+ activated NK cells exhibited the opposite position and relevance. Pseudotime cell trajectory analysis revealed the evolution of activated to resting NK cells. In vitro experiments further confirmed that tumor-cell-co-cultured NK cells exhibited a decidual-like status, as evidenced by remarkable increasing CD9 expression. Functional experiments finally revealed that NK cells exhibited tumor-activating characteristics by promoting the dissociation of SCF (stem cell factor) on the tumor cells membrane depending on cell-to-cell interaction, as the supernatant of the co-culture system enhanced tumor progression. In summary, our findings revealed resting NK cells exhibited a clinical relevance with CCLM, which may be exploited for novel strategies to improve therapeutic outcomes for patients with CCLM., Competing Interests: CM, YC, DX, TZ, YL, CL, JY, YL, TM, WX, ZH, DM, DX, ML, XS, XX No competing interests declared, (© 2024, Mao, Chen, Xing et al.)

Oncolytic virotherapy is emerging as a promising therapeutic avenue for cancer treatment, harnessing both innate and tumor-specific immune responses for targeted tumor elimination. In this study, we present a novel oncolytic virus (oHSV1-IL15B) derived from herpes simplex virus-1 (HSV-1), armed with IL-15/IL-15Rα complex, with a focus on treating colon cancer combined with oncolytic HSV-1 expressing anti-PD-1 antibody (oHSV1-aPD1). Results from our study reveal that recombinant oHSV-1 virus equipped with IL-15/IL-15Rα complex exhibited significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Notably, oHSV1-IL15B combined with oHSV-1-aPD1 demonstrates superior tumor inhibition and prolonged overall survival compared to oHSV1-mock and monotherapy groups. Further exploration highlights the impact of oHSV1-IL15B, oHSV-1-aPD1 and combined group on antitumor capacity, revealing a substantial increase in CD8 + T and CD4 + T cell proportions of CT26-bearing BALB/c mice and promoting apoptosis in tumor tissue. The study emphasizes the pivotal role of cytotoxic CD8 + T cells in oncolytic virotherapy, demonstrating that recombinant oHSV1-IL15B combined with oncolytic HSV-1-aPD1 induces a robust tumor-specific T cell response. RNA sequence analysis highlighted oHSV1-IL15B combined with oHSV1-aPD1 improved tumors immune microenvironment on immune response, antiviral response-related genes and apoptosis-related genes, which contributed to anti-tumor immunotherapy. The findings underscore the promising antitumor activity achieved through the combination of IL-15/IL-15Rα complex and anti-PD-1 antibody with oHSV-1. This research opens avenues for diverse therapeutic strategies, suggesting the potential of synergistically utilizing cytokines and anti-PD-1 antibody with oncolytic viruses to enhance immunotherapy for cancer management., (© 2024. The Author(s).)

MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses., (©2024 American Association for Cancer Research.)

Summary: Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P <0.001), more often male (57.3% vs. 50.7%, P <0.001), had more private insurance (44.1% vs. 33.7%; P <0.001), had more left-sided tumors (49.5% vs. 39.1%; P <0.001) and liver metastasis (80.2% vs. 61.7%; P <0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P <0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P =0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P =0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P =0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P =0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Until 2021, colon cancer was a leading cancer globally. Early detection improves outcomes; however, advanced cases still having poor prognosis. Therefore, an understanding of associated molecular mechanisms is crucial for developing new preventive and therapeutic strategies for colon cancer., Methods: The TCGA database was analyzed to assess melanocortin 1receptor (MC1R) expression in colon cancer and its link with patient prognosis. Further, models and diverse experimental techniques were employed to investigate the impact of MC1R on colon cancer progression and its underlying mechanism was elucidated., Results: In a follow-up study of clinical patients, the important role of MC1R was identified in the development of colon cancer. First, MC1R was expressed more highly in colon tumor tissues than in adjacent tissues. In addition, MC1R was associated with colon cancer prognosis, and higher expression of MC1R tended to predict a worse prognosis. This conclusion was verified in MC1R -/- mice, which showed a greater resistance to tumor growth than wild-type mice, as expected. Further investigation revealed a significant change in the portion of Tregs in MC1R -/- mice, while the portion of CD4 + and CD8 + T cells remained unchanged. The in vitro experiments revealed a weaker ability of the MC1R -/- T cells to differentiate into Tregs. Previous studies report that the functional integrity of Tregs is interwoven with cellular metabolism. Therefore, MC1R was deduced to regulate the differentiation of Tregs by reprogramming the metabolism. As expected, MC1R -/- T cells exhibited weaker mitochondrial function and a lower aerobic oxidation capacity. Concurrently, the MC1R -/- T cells had stronger limiting effects on colon cancer cells. According to these results, the MC1R inhibitor was hypothesized as a potential therapeutic agent to suppress colon cancer. The results showed that upon MC1R suppression, the tumors in the mice developed more slowly, and the mice survived longer, potentially providing a novel strategy to treat clinical colon cancer., Conclusion: By regulating Tregs differentiation, MC1R overexpression in colon cancer correlates with poor prognosis, while MC1R inhibition shows potential as a therapeutic approach to slow tumor growth and enhance survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: A growing body of research indicates significant differences between left-sided colon cancers (LCC) and right-sided colon cancers (RCC). Pan-immune-inflammation value (PIV) is a systemic immune response marker that can predict the prognosis of patients with colon cancer. However, the specific distinction between PIV of LCC and RCC remains unclear., Aim: To investigate the prognostic and clinical significance of PIV in LCC and RCC patients., Methods: This multicenter retrospective cohort study included 1510 patients with colon cancer, comprising 801 with LCC and 709 with RCC. We used generalized lifting regression analysis to evaluate the relative impact of PIV on disease-free survival (DFS) in these patients. Kaplan-Meier analysis, as well as univariate and multivariate analyses, were used to examine the risk factors for DFS. The correlation between PIV and the clinical characteristics was statistically analyzed in these patients., Results: A total of 1510 patients {872 female patients (58%); median age 63 years [interquartile ranges (IQR): 54-71]; patients with LCC 801 (53%); median follow-up 44.17 months (IQR 29.67-62.32)} were identified. PIV was significantly higher in patients with RCC [median (IQR): 214.34 (121.78-386.72) vs 175.87 (111.92-286.84), P < 0.001]. After propensity score matching, no difference in PIV was observed between patients with LCC and RCC [median (IQR): 182.42 (111.88-297.65) vs 189.45 (109.44-316.02); P = 0.987]. PIV thresholds for DFS were 227.84 in LCC and 145.99 in RCC. High PIV (> 227.84) was associated with worse DFS in LCC [PIV-high: Adjusted hazard ratio (aHR) = 2.39; 95% confidence interval: 1.70-3.38; P < 0.001] but not in RCC (PIV-high: aHR = 0.72; 95% confidence interval: 0.48-1.08; P = 0.114)., Conclusion: These findings suggest that PIV may predict recurrence in patients with LCC but not RCC, underscoring the importance of tumor location when using PIV as a colon cancer biomarker., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Pyroptosis-related genes have great potential for prognosis, an accurate prognostic model based on pyroptosis genes has not been seen in Colorectal adenocarcinoma (COAD). Furthermore, understanding the mechanisms of gene expression characteristics and the Tumor Immune Microenvironment associated with the prognosis of COAD is still largely unknown. Constructing a prognostic model based on pyroptosis-related genes, and revealing prognosis-related mechanisms associated with the gene expression characteristics and tumor microenvironment. 59 pyroptosis-related genes were collected. The gene expression data and clinical data of COAD were downloaded from The Cancer Genome Atlas. External validation datasets were downloaded from the Gene Expression Omnibus database. 10 characteristic genes with prognostic values were obtained using univariate and LASSO Cox. 10-gene Riskscore prognostic model was constructed. Both gene set enrichment analysis and network propagation methods were used to find pathways and key genes leading to different prognostic risks. The area under the ROC curves were used to evaluate the performance of the model to distinguish between high-risk and low-risk patients, the results were 0.718, 0.672, and 0.669 for 1-, 3-, and 5-year survival times. A nomogram based on Riskscore and clinical characteristics showed the probability of survival at 1, 3, and 5 years, and the calibration curves showed good agreement between the predicted and actual observations, its C-index is 0.793. The decision curves showed that the net benefit of the nomogram was significantly superior to that of the other single variables. Four key pathways leading to different prognostic risks were obtained. Six key genes with prognostic value, significant expression differences (P < .05) and significant survival differences (P < .05) between high/low risk groups were obtained from the gene set of all 4 key pathways. This study constructed a prognostic model for COAD using 10 pyroptosis-related genes with prognostic value. This study also revealed significant differences in specific pathways and the tumor immune microenvironment (TME) between the high-risk group and the low-risk group, highlighted the roles of ALDH5A1 and Wnt signaling in promoting COAD and the suppressive effects of the IL-4/IL-13 pathway and RORC on COAD. The study will be helpful for precision therapy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO 2 , IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What's more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment., (© 2024. The Author(s).)

This study tried to develop the α-Hederin/Oxaliplatin (OXA) dual-loaded rHDL (α-Hederin-OXA-rHDL) modified liposomes to improve the therapeutic index on colon adenocarcinoma (COAD). The α-Hederin-OXA-rHDL were prepared and evaluated for characterizations, accumulate to tumor tissues, and antitumor activity. A thorough investigation into oxaliplatin resistant and KRAS-mutant related hub keg genes were identified and performed to assess the prognosis role of the genetic signature in COAD. The potential immune signatures and molecular docking for verifing the predicted targets of α-Hederin-OXA-rHDL in tumor-bearing mice. Results suggested that α-Hederin-OXA-rHDL could enhance the sensitivity of oxaliplatin in HCT116/L-OHP cells via the regulation of KEAP1/NRF2 -mediated signaling and HO1 or GPX4 proteins. Furthermore, α-Hederin-OXA-rHDL regulated the predicted targets of PRDM1 interaction with miR-140-5p, efficient activing CD8 T cell to improve therapeutic response in vivo. Collectively, this work provides drug delivery with rHDL dual-loaded α-Hederin and oxaliplatin synergistically targets cancer cells and effectory T cells combating COAD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Background: Cellular senescence (CS) is believed to be a major factor in the evolution of cancer. However, CS-related lncRNAs (CSRLs) involved in colon cancer regulation are not fully understood. Our goal was to create a novel CSRLs prognostic model for predicting prognosis and immunotherapy and exploring its potential molecular function in colon cancer., Methods: The mRNA sequencing data and relevant clinical information of GDC TCGA Colon Cancer (TCGA-COAD) were obtained from UCSC Xena platform, and CS-associated genes was acquired from the CellAge website. Pearson correlation analysis was used to identify CSRLs. Then we used Kaplan-Meier survival curve analysis and univariate Cox analysis to acquire prognostic CSRL. Next, we created a CSRLs prognostic model using LASSO and multivariate Cox analysis, and evaluated its prognostic power by Kaplan-Meier and ROC curve analysis. Besides, we explored the difference in tumor microenvironment, somatic mutation, immunotherapy, and drug sensitivity between high-risk and low-risk groups. Finally, we verified the functions of MYOSLID in cell experiments., Results: Three CSRLs (AC025165.1, LINC02257 and MYOSLID) were identified as prognostic CSRLs. The prognostic model exhibited a powerful predictive ability for overall survival and clinicopathological features in colon cancer. Moreover, there was a significant difference in the proportion of immune cells and the expression of immunosuppressive point biomarkers between the different groups. The high-risk group benefited from the chemotherapy drugs, such as Teniposide and Mitoxantrone. Finally, cell proliferation and CS were suppressed after MYOSLID knockdown., Conclusion: CSRLs are promising biomarkers to forecast survival and therapeutic responses in colon cancer patients. Furthermore, MYOSLID, one of 3-CSRLs in the prognostic model, could dramatically regulate the proliferation and CS of colon cancer., Competing Interests: LC, FC, SZ, HZ and YB were employed by Shenzhen Nucleus Gene Technology Co., Ltd., and Shanghai Nucleus Biotechnology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cao, Chen, Xu, Zeng, Wang, Zhang, Ba and Zhang.)

Radiotherapy widely applied for local tumor therapy in clinic has been recently reinvigorated by the discovery that radiotherapy could activate systematic antitumor immune response. Nonetheless, the endogenous radio-immune effect is still incapable of radical tumor elimination due to the prevention of immune cell infiltration by the physical barrier in tumor microenvironment (TME). Herein, an engineered Salmonella secreting nattokinase (VNP NKase ) is developed to synergistically modulate the physical and immune characteristics of TME to enhance radio-immunotherapy of colon tumors. The facultative anaerobic VNP NKase enriches at the tumor site after systemic administration, continuously secreting abundant NKase to degrade fibronectin, dredge the extracellular matrix (ECM), and inactivate cancer-associated fibroblasts (CAFs). The VNP NKase - dredged TME facilitates the infiltration of CD103 + dendritic cells (DCs) and thus the presentation of tumor-associated antigens (TAAs) after radiotherapy, recruiting sufficient CD8 + T lymphocytes to specifically eradicate localized tumors. Moreover, the pre-treatment of VNP NKase before radiotherapy amplifies the abscopal effect and achieves a long-term immune memory effect, preventing the metastasis and recurrence of tumors. Our research suggests that this strategy using engineered bacteria to breach tumor physical barrier for promoting immune cell infiltration possesses great promise as a translational strategy to enhance the effectiveness of radio-immunotherapy in treating solid tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This panel was designed to characterize the immune cell landscape in the mouse tumor microenvironment as well as mouse lymphoid tissues (e.g., spleen). As an example, using the MC-38 mouse syngeneic tumor model, we demonstrated that we could measure the frequency and characterize the functional status of CD4 T cells, CD8 T cells, regulatory T cells, NK cells, B cells, macrophages, granulocytes, monocytes, and dendritic cells. This panel is especially useful for understanding the immune landscape in "cold" preclinical tumor models with very low immune cell infiltration and for investigating how therapeutic treatments may modulate the immune landscape., (© 2024 The Author(s). Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.)

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of in vivo-expanded MAIT cells into RAG1 -/- mice with MC38-derived tumours inhibits tumour growth compared to control. Multiplex cytokine analyses showed that tumours from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co-culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy., (© 2024 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Unravelling the mechanisms for the immunosuppressive tumor microenvironment and developing corresponding therapeutic strategies are of great importance to improve the cancer immunotherapy. This study has revealed that there are abundant senescent cells accumulated in the colon cancer tissue, which contributes greatly to the immunosuppressive microenvironment. Oral delivery of Dasatinib and Quercetin (D+Q) eliminates the senescent cells with compromised efficiency due to the poor tumor penetration and short half-life. To improve the efficacy of senescent cell clearance, this work has developed an extracellular vesicle (EV) based senolytic strategy. The engineered senolytic EVs have anti-GPNMB (a senescent cell surface marker) displayed on the surface and D+Q loaded on the membrane. In a syngeneic mouse model, senolytic EVs efficiently and selectively eradicate the senescent cells and in turn unleashes the antitumor immunity. With the antitumor immunity boosted, cancer growth is inhibited and the survival is prolonged. In summary, this work has illuminated that senescent cells contribute to the immunosuppressive microenvironment in colon cancer and proposes a novel strategy to conquer the problem by EV-based senolytics., (© 2024 Wiley‐VCH GmbH.)

Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8 + T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel., Competing Interests: The authors declare a patent application related to the hydrogel biomaterial used in this work., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Compensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP β, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP β effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy., (© 2024. The Author(s).)

Background: The unfolded protein response (UPR) is associated with immune cells that regulate the biological behavior of tumors. This article aims to combine UPR-associated genes with immune cells to find a prognostic marker and to verify its connection to the UPR., Methods: Univariate cox analysis was used to screen prognostically relevant UPRs and further screened for key UPRs among them by machine learning. ssGSEA was used to calculate immune cell abundance. Univariate cox analysis was used to screen for prognostically relevant immune cells. Multivariate cox analysis was used to calculate UPR&#95;score and Tumor Immune Microenvironment score (TIME&#95;score). WGCNA was used to screen UPR-Immune-related (UI-related) genes. Consensus clustering analysis was used to classify patients into molecular subtype. Based on the UI-related genes, we classified colon adenocarcinoma (COAD) samples by cluster analysis. Single-cell analysis was used to analyze the role of UI-related genes. We detected the function of TIMP1 by cell counting and transwell. Immunoblotting was used to detect whether TIMP1 was regulated by key UPR genes., Results: Combined UPR-related genes and immune cells can determine the prognosis of COAD patients. Cluster analysis showed that UI-related genes were associated with clinical features of COAD. Single-cell analysis revealed that UI-related genes may act through stromal cells. We defined three key UI-related genes by machine learning algorithms. Finally, we found that TIMP1, regulated by key genes of UPR, promoted colon cancer proliferation and metastasis., Conclusions: We found that TIMP1 was a prognostic marker and experimentally confirmed that TIMP1 was regulated by key genes of UPR., (© 2024. The Author(s).)

CD73 is a cell-surface ectoenzyme that hydrolyzes the conversion of extracellular adenosine monophosphate to adenosine, which in turn can promote resistance to immune checkpoint blockade therapy. Immune response may therefore be improved by targeting tumor CD73, and this possibility underlines the need to non-invasively assess tumor CD73 level. In this study, we developed a cysteine site-specific 89 Zr-labeled anti-CD73 ( 89 Zr-CD73) IgG immuno-PET technique that can image tumor CD73 expression in living bodies. Anti-CD73 IgG was reduced with tris(2-carboxyethyl)phosphine, underwent sulfohydryl moiety-specific conjugation with deferoxamine-maleimide, and was radiolabeled with 89 Zr. CT26 mouse colon cancer cells, CT26/CD73 cells engineered to constitutively overexpress CD73, and 4T1.2 mouse breast cancer cells underwent cell binding assays and western blotting. Balb/c nude mice bearing tumors underwent 89 Zr-CD73 IgG PET imaging and biodistribution studies. 89 Zr-CD73 IgG showed 20-fold higher binding to overexpressing CT26/CD73 cells compared to low-expressing CT26 cells, and moderate expressing 4T1.2 cells showed uptake that was 38.9 ± 1.51% of CT26/CD73 cells. Uptake was dramatically suppressed by excess unlabeled antibody. CD73 content proportionately increased in CT26 and CT26/CD73 cell mixtures was associated with linear increases in 89 Zr-CD73 IgG uptake. 89 Zr-CD73 IgG PET/CT displayed clear accumulation in CT26/CD73 tumors with greater uptake compared to CT26 tumors (3.13 ± 1.70%ID/g vs. 1.27 ± 0.31%ID/g at 8 days; P = 0.04). Specificity was further supported by low CT26/CD73 tumor-to-blood ratio of 89 Zr-isotype-IgG compared to 89 Zr-CD73 IgG (0.48 ± 0.08 vs. 2.68 ± 0.52 at 4 days and 0.53 ± 0.07 vs. 4.81 ± 1.02 at 8 days; both P < 0.001). Immunoblotting and immunohistochemistry confirmed strong CD73 expression in CT26/CD73 tumors and low expression in CT26 tumors. 4T1.2 tumor mice also showed clear 89 Zr-CD73 IgG accumulation at 8 days (3.75 ± 0.70%ID/g) with high tumor-to-blood ratio compared to 89 Zr-isotype-IgG (4.91 ± 1.74 vs. 1.20 ± 0.28; P < 0.005). 89 Zr-CD73 IgG specifically targeted CD73 on high expressing cancer cells in vitro and tumors in vivo. Thus, 89 Zr-CD73 IgG immuno-PET may be useful for the non-invasive monitoring of CD73 expression in tumors of living subjects., (© 2024. The Author(s).)

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of immune cells including granulocytic (CD14neg/CD15+/HLA-DRneg) and monocytic subtypes (CD14+/CD15neg/HLA-DRneg). In the present study, we found a population of monocytes expressing the granulocyte marker CD15 that significantly increased in both peripheral blood (PB) and tumoral tissues of patients with colorectal cancer (CRC). Further phenotypical analysis confirmed the granulocytic-like features of this monocyte subpopulation that is associated with an increase in granulocyte-monocyte precursors (GMPs) in the PB of these patients (pts). Mechanistically, this granulocyte-like monocyte population suppressed NK cell activity by inducing TIGIT and engaging NKp30. Accordingly, an increased frequency of TIGIT+ NK cells with impaired functions was found in both the PB and tumoral tissue of CRC pts. Collectively, we provided new mechanistic explanations for tumor immune escape occurring in CRC by showing the increase in this new kind of MDSC, in both PB and CRC tissue, which is able to significantly impair the effector functions of NK cells, thereby representing a potential therapeutic target for cancer immunotherapy.

Colon cancer (CC) is a primary human malignancy. Recently, the mechanism of the tumor microenvironment (TME) in CC has been a hot topic of research. However, there is uncertainty regarding the contribution of M2 macrophages and related genes to the prognosis for CC. M2 macrophage-related genes (M2RGs) were obtained from The Cancer Genome Atlas (TCGA) database. Immune cell infiltration in CC tissue was assessed by Cibersort. Based on the TCGA-COAD training set, a Least Absolute Shrinkage and Selection Operator (LASSO) Cox risk model was constructed and its efficiency was evaluated by analyzing risk profiles and survival profiles. Using gene set enrichment analysis (GSEA), the functional distinctions between high-risk and low-risk categories were further investigated. Finally, potential immune checkpoints, immunotherapy efficiency, and clinical treatment of high-risk patients were evaluated. A total of 1063 M2RGs were identified in TCGA-COAD, 32 of these were confirmed to be strongly related to overall survival (OS), and 14 of these were picked to construct an OS-oriented prognostic model in CC patients. The M2RG signature had a positive correlation with unfavorable prognosis according to the survival analysis. Correlation analysis revealed that the risk model was positively associated with clinicopathological characteristics, immune cell infiltration, immune checkpoint inhibitor targets, the risk of immune escape, and the efficiency of anti-cancer medications. The risk model created using M2RGs may be useful in predicting the prognosis of CC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Currently, sonodynamic therapy (SDT) has limited therapeutic outcomes and immune responses, highlighting the urgent need for enhanced strategies that can stimulate robust and long-lasting antitumor effects. Microcystis, a notorious microalga, reveals the possibility of mediating SDT owing to the presence of gas vesicles (GVs) and phycocyanin (PC). Herein, a nontoxic strain of Microcystis elabens (labeled Me) is developed as a novel agent for SDT because it generates O 2 under red light (RL) illumination, while GVs and PC act as cavitation nuclei and sonosensitizers, respectively. Moreover, algal debris is released after ultrasound (US) irradiation, which primes the Toll-like receptor pathway to initiate a cascade of immune responses. This sono-immune strategy inhibits CT26 colon tumor growth largely by promoting dendritic cell (DC) maturation and cytotoxic T-cell activation. After combination with the immune checkpoint blockade (ICB), the therapeutic outcome is further amplified, accompanied by satisfactory abscopal and immune memory effects; the similar potency is proven in the "cold" 4T1 triple-negative breast tumor. In addition, Me exhibits good biosafety without significant acute or chronic toxicity. Briefly, this study turns waste into wealth by introducing sono-immunotherapy based on Microcystis that achieved encouraging therapeutic effects on cancer, which is expected to be translated into the clinic., (© 2024 Wiley‐VCH GmbH.)

Background: Recent research indicates a positive correlation between DEP structural domain-containing 1B (DEPDC1B) and the cell cycle in various tumors. However, the role of DEPDC1B in the infiltration of the tumor immune microenvironment (TIME) remains unexplored., Methods: We analyzed the differential expression and prognostic significance of DEPDC1B in colon adenocarcinoma (COAD) using the R package "limma" and the Gene Expression Profiling Interactive Analysis (GEPIA) website. Gene set enrichment analysis (GSEA) was employed to investigate the functions and interactions of DEPDC1B expression in COAD. Cell Counting Kit-8 (CCK-8) assays and colony formation assays were utilized to assess the proliferative function of DEPDC1B. Correlations between DEPDC1B expression and tumor-infiltrating immune cells, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI) status were examined using Spearman correlation analysis and CIBERSORT., Results: DEPDC1B was highly expressed in COAD. Elevated DEPDC1B expression was associated with lower epithelial-to-mesenchymal transition (EMT) and TNM stages, leading to a favorable prognosis. DEPDC1B mRNA was prominently expressed in COAD cell lines. CCK-8 and colony formation assays demonstrated that DEPDC1B inhibited the proliferation of COAD cells. Analysis using the CIBERSORT database and Spearman correlation revealed that DEPDC1B correlated with four types of tumor-infiltrating immune cells. Furthermore, high DEPDC1B expression was linked to the expression of PD-L1, CTLA4, SIGLEC15, PD-L2, TMB, and MSI-H. High DEPDC1B expression also indicated responsiveness to anti-PD-L1 immunotherapy., Conclusions: DEPDC1B inhibits the proliferation of COAD cells and positively regulates the cell cycle, showing a positive correlation with CCNB1 and PBK expression. DEPDC1B expression in COAD is associated with tumor-infiltrating immune cells, immune checkpoints, TMB, and MSI-H in the tumor immune microenvironment. This suggests that DEPDC1B may serve as a novel prognostic marker and a potential target for immunotherapy in COAD., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Peritoneal carcinomatosis (PC) is characterized by a high recurrence rate and mortality following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), primarily due to incomplete cancer elimination. To enhance the standard of care for PC, we developed two cationic liposomal formulations aimed at localizing a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity to activate the immune system locally to specifically eradicate residual tumor cells. These formulations effectively extended R848 retention in the peritoneum by >10-fold, resulting in up to a 2-fold increase in interferon α (IFN-α) induction in the peritoneal fluid, without increasing the plasma levels. In a CT26 colon cancer model with peritoneal metastases, these liposomal R848 formulations, when combined with oxaliplatin (OXA)-an agent used in HIPEC that induces immunogenic cell death-increased tumor infiltration of effector immune cells, including DCs, CD4, and CD8 T cells. This led to the complete elimination of PC in 60-70% of the mice, while the control mice reached humane endpoints by 30 days. The cured mice developed specific antitumor immunity, as re-challenging them with the same tumor cells did not result in tumor establishment. However, inoculation with a different tumor line led to tumor development. Additionally, exposing CT26 tumor antigens to the splenocytes isolated from the cured mice induced the expansion of CD4 and CD8 T cells and the release of IFN-γ, demonstrating long-term immune memory to the specific tumor. The anti-tumor efficacy of these liposomal R848 formulations was mediated via CD8 T cells with different levels of involvement of CD4 and B cells, and the combination with an anti-PD-1 antibody achieved a cure rate of 90%., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The research aims to explore the characteristics of intestinal flora, nutritional status and immune function in patients with different types of obese colon cancer., Methods: A retrospective analysis is conducted on 64 cases of obese colon cancer diagnosed from June 2018 to January 2020. According to the histological staging of the cancer, they are classified into adenocarcinoma, adenosquamous carcinoma and undifferentiated carcinoma, with corresponding cases of 24, 22 and 18, respectively. The intestinal flora (Bifidobacterium, Lactobacillus, Enterococcus faecalis, Escherichia coli, and yeast), nutritional status (Hb, Alb, PA, TFN, and PNI), immune function (IgG, IgM, IgA, CD 4 + , CD 8 + , and CD 4 + /CD 8 + ) are analyzed in the different groups of patients. Survival curves are evaluated by Kaplan-Meier method and log-rank test for tumour death, local recurrence, and distant metastasis., Results: There were no statistically significant differences in intestinal flora (Bifidobacterium, Lactobacillus, Enterococcus faecalis, Escherichia coli, and yeast), nutritional status (Hb, Alb, PA, TFN, and PNI) and immune function (IgG, IgM, IgA, CD 4 + , CD 8 + , and CD 4 + /CD 8 + ) between different groups. There was a significant correlation between intestinal flora, nutritional status and immune function for all three. The survival curves of tumour death, local recurrence and distant metastasis in different groups of obese colon cancer patients were statistically significant. The tumor mortality rate, local recurrence, and distant metastasis rate in adenocarcinoma were 78.65%, 54.25% and 48.26% respectively., Conclusion: There are differences in intestinal flora, nutritional status and immune function among different types of obese colon cancer patients, but adenocarcinoma has the least benefit in intestinal flora, poor nutritional status, and weakest immune function., (© 2024. The Author(s).)

CD8 + T cells secreting granzyme A (GZMA) can induce pyroptosis in tumor cells by effectively cleaving gasdermin B (GSDMB), which is stimulated by interferon-γ (IFN-γ). However, the interaction between GZMA-expressing CD8 + T cells and GSDMB-expressing tumor cells in colon cancer remains poorly understood. Our research employed multi-color immunohistochemistry (mIHC) staining and integrated clinical data to explore the spatial distribution and clinical relevance of GZMA- and IFN-γ-expressing CD8 + tumor-infiltrating lymphocytes (TILs), as well as GSDMB-expressing CK + cells, within the tumor microenvironment (TME) of human colon cancer samples. Additionally, we utilizing single-cell RNA sequencing (scRNA-seq) data to examine the functional dynamics and interactions among these cell populations. scRNA-seq analysis of colorectal cancer (CRC) tissues revealed that CD8 + TILs co-expressed GZMA and IFN-γ, but not other cell types. Our mIHC staining results indicated that a significant reduction in the infiltration of GZMA + IFN-γ + CD8 + TILs in colon cancer patients (P < 0.01). Functional analysis results indicated that GZMA + IFN-γ + CD8 + TILs demonstrated enhanced activation and effector functions compared to other CD8 + TIL subsets. Furthermore, GSDMB-expressing CK + cells exhibited augmented immunogenicity. Correlation analysis highlighted a positive association between GSDMB + CK + cells and GZMA + IFN-γ + CD8 + TILs (r = 0.221, P = 0.033). Analysis of cell-cell interactions further showed that these interactions were mediated by IFN-γ and transforming growth factor-β (TGF-β), the co-stimulatory molecule ICOS, and immune checkpoint molecules TIGIT and TIM-3. These findings suggested that GZMA + IFN-γ + CD8 + TILs modulating GSDMB-expressing tumor cells, significantly impacted the immune microenvironment and patients' prognosis in colon cancer. By elucidating these mechanisms, our present study aims to provide novel insights for the advancement of immunotherapeutic strategies in colon cancer., (© 2024. The Author(s).)

At present, tumor immunotherapy has been widely applied to treat various cancers. However, the accuracy of predicting treatment efficacy has not yet achieved a significant breakthrough. This study aimed to construct a prediction model based on the modified WGCNA algorithm to precisely judge the anti-tumor immune response. First, we used a murine colon cancer model to screen corresponding DEGs according to different groups. GSEA was used to analyze the potential mechanisms of the immune-related DEGs (irDEGs) in each group. Subsequently, the intersection of the irDEGs in every group was acquired, and 7 gene-modules were mapped. Finally, 4 gene-modules including cogenes, antiPD-1 immu-genes, chemo immu-genes and comb immu-genes, were selected for subsequent study. Furthermore, a clinical dataset of gastric cancer patients receiving immunotherapy was enrolled, and the irDEGs were identified. A total of 34 vital irDEGs were obtained from the intersections of the vital irDEGs and the four gene-modules. Next, the vital irDEGs were analyzed by the modified WGCNA algorithm, and the correlation coefficients between the 4 gene-modules and the response status to immunotherapy were calculated. Thus, a prediction model based on correlation coefficients was built, and the corresponding model scores were acquired. The AUC calculated according to the model score was 0.727, which was non-inferior to that of the ESTIMATE score and the TIDE score. Meanwhile, the AUC calculated according to the classification of the model scores was 0.705, which was non-inferior to that of the ESTIMATE classification and the TIDE classification. The prediction accuracy of the model was validated in clinical datasets of other cancers., (© 2024. The Author(s).)

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen., Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects., Results: Tumors with volumes of 2,000 mm 3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory., Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors., Competing Interests: Author WO was formerly employed by the company Nektar Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rakhmilevich, Tsarovsky, Felder, Zaborek, Moram, Erbe, Pieper, Spiegelman, Cheng, Witt, Overwijk, Morris and Sondel.)

Ethnopharmacological Relevance: Sijunzi Decoction (SJZD), a traditional Chinese herbal remedy, is frequently employed in the treatment of various cancers, including colon cancer. Previous research suggests that SJZD plays a pivotal role in modulating the immune system and enhancing immunity against tumors. However, the precise role of SJZD in combating colon cancer and its potential molecular functions in regulating natural killer cells remain elusive., Aims of the Study: To elucidate the potential mechanism underlying the anticolon cancer effects of SJZD in synergy with natural killer (NK) cells through both in vivo and in vitro experiments., Materials and Methods: In vivo experiments: A subcutaneous tumor mouse model of colon cancer and in vivo NK cell depletion experiments were conducted to observe the anticolon cancer effects of SJZD. Flow cytometry assessed immune cell depletion in mouse spleens, while immunohistochemical (IHC) staining detected the expression of apoptotic genes in tumor tissues. In vitro experiments: The mechanism by which SJZD regulates the sensitization of colon cancer cells to NK cells was investigated using real-time polymerase chain reaction (RT-PCR), western blotting (WB), and co-culture experiments with NK cells., Results: Sijunzi Decoction (SJZD) significantly impeded tumor growth in mice; however, NK cell depletion markedly attenuated the tumor-suppressive effect of SJZD. Immunohistochemical (IHC) results indicated that SJZD increased the expression of P53, death receptor 4 (DR4), and death receptor 5 (DR5) in tumor tissues. In vitro experiments, 24 h SJZD-pretreated colon cancer cells showed a substantial elevation in P53, DR4, and DR5 levels, and the activity of colon cancer cells significantly diminished after co-culture with NK cells. These effects of SJZD were reversed with the addition of the P53 inhibitor pifithrin-α (PFT-α), resulting in reduced inhibition of colon cancer cells by NK cells., Conclusion: SJZD enhances the levels of DR4 and DR5 through the modulation of P53 expression, consequently increasing the sensitivity of colon cancer cells to NK cell-mediated killing. These findings provide a theoretical foundation for the clinical application of SJZD in patients with colon cancer. In this study, we first investigated the effect of SJZD on subcutaneous tumor growth in mice with colon cancer using in vivo assays and assessed the impact of NK cells on the anticolon cancer effect of SJZD in vivo through NK cell depletion. In vitro experiments were conducted to explore the potential mechanism of action of SJZD in NK cell-mediated anticolon cancer effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Γδ T cell infiltration into tumours usually correlates with improved patient outcome, but both tumour-promoting and tumoricidal effects of γδ T cells have been documented. Human γδ T cells can be divided into functionally distinct subsets based on T cell receptor (TCR) Vδ usage. Still, the contribution of these different subsets to tumour immunity remains elusive. Here, we provide a detailed γδ T cell profiling in colon tumours, using mass and flow cytometry, mRNA quantification, and TCR sequencing. δ chain usage in both the macroscopically unaffected colon mucosa and tumours varied considerably between patients, with substantial fractions of Vδ1, Vδ2, and non-Vδ1 Vδ2 cells. Sequencing of the Vδ complementarity-determining region 3 showed that almost all non-Vδ1 Vδ2 cells used Vδ3 and that tumour-infiltrating γδ clonotypes were unique for every patient. Non-Vδ1Vδ2 cells from colon tumours expressed several activation markers but few NK cell receptors and exhaustion markers. In addition, mRNA analyses showed that non-Vδ1 Vδ2 cells expressed several genes for proteins with tumour-promoting functions, such as neutrophil-recruiting chemokines, Galectin 3, and transforming growth factor-beta induced. In summary, our results show a large variation in γδ T cell subsets between individual tumours, and that Vδ3 cells make up a substantial proportion of γδ T cells in colon tumours. We suggest that individual γδ T cell composition in colon tumours may contribute to the balance between favourable and adverse immune responses, and thereby also patient outcome., (© 2024. The Author(s).)

Purpose: Personalized liposome-formulated mRNA vaccines (RNA-LPX) are a powerful new tool in cancer immunotherapy. In preclinical tumor models, RNA-LPX vaccines are known to achieve potent results when combined with conventional X-ray radiation therapy (XRT). Densely ionizing radiation used in carbon ion radiation therapy (CIRT) may induce distinct effects in combination with immunotherapy compared with sparsely ionizing X-rays., Methods and Materials: Within this study, we investigate the potential of CIRT and isoeffective doses of XRT to mediate tumor growth inhibition and survival in murine colon adenocarcinoma models in conjunction with neoantigen (neoAg)-specific RNA-LPX vaccines encoding both major histocompatibility complex (MHC) class I- and class II-restricted tumor-specific neoantigens. We characterize tumor immune infiltrates and antigen-specific T cell responses by flow cytometry and interferon-γ enzyme-linked immunosorbent spot (ELISpot) analyses, respectively., Results: NeoAg RNA-LPX vaccines significantly potentiate radiation therapy-mediated tumor growth inhibition. CIRT and XRT alone marginally prime neoAg-specific T cell responses detected in the tumors but not in the blood or spleens of mice. Infiltration and cytotoxicity of neoAg-specific T cells is strongly driven by RNA-LPX vaccines and is accompanied by reduced expression of the inhibitory markers PD-1 and Tim-3 on these cells. The neoAg RNA-LPX vaccine shows similar overall therapeutic efficacy in combination with both CIRT and XRT, even if the physical radiation dose is lower for carbon ions than for X-rays., Conclusions: We hence conclude that the combination of CIRT and neoAg RNA-LPX vaccines is a promising strategy for the treatment of radioresistant tumors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: T-cell immune infiltrates are robust prognostic variables in localised colon cancer. Evaluation of prognosis using artificial intelligence is an emerging field. We evaluated whether machine learning analysis improved prediction of patient outcome in comparison with analysis of T cell infiltrate only or in association with clinical variables., Methods: We used data from two phase III clinical trials (Prodige-13 and PETACC08) and one retrospective Italian cohort (HARMONY). Cohorts were split into training (N = 692), internal validation (N = 297) and external validation (N = 672) sets. Tumour slides were stained with CD3mAb. CD3 Machine Learning (CD3ML) score was computed using graphical parameters within the tumour tiles obtained from CD3 slides. CD3 infiltrates in tumour core and invasive margin were automatically detected. Associations of CD3 infiltrates and CD3ML with 5-year Disease-Free Survival (DFS) were examined using univariate and multivariable survival models by Cox regression., Findings: CD3 density both in the invasive margin and the tumour core were significantly associated with DFS in the different sets. Similarly, CD3ML score was significantly associated with DFS in all sets. CD3 assessment did not provide added value on top of CD3ML assessment (Likelihood Ratio Test (LRT), p = 0.13). In contrast, CD3ML improved prediction of DFS when combined with a clinical risk stage (LRT, p = 0.001). Stratified by clinical risk score (High or Low), patients with low CD3ML score had better DFS., Interpretation: In all tested sets, machine learning analysis of tumour cells improved prediction of prognosis compared to clinical parameters. Adding tumour-infiltrating lymphocytes assessment did not improve prognostic determination., Funding: This research received no external funding., Competing Interests: Declaration of interests JT has received honoraria as a speaker and/or in an advisory role from AMGEN, Astellas, Astra Zeneca, BMS, Merck KGaA, MSD, Novartis, ONO pharmaceuticals, Pierre Fabre, Roche Genentech, Sanofi and Servier. CL has received honoraria as a speaker and/or in an advisory role from AMGEN, AAA-Novartis, Takeda, Deciphera, Pierre Fabre, Servier. FG's institution has received grants or contracts from Astra, consulting fees from Roche, AMGEN and MSD, honoraria as a speaker from Merck and support for attending meetings and/or travel from AMGEN. FB has received honoraria for lectures, speakers, presentations, manuscript writing or educational events from MSD, Pierre Fabre, Sanofi, BMS, Incyte, Servier and Astellas and support for attending meetings and/or travel from AMGEN, Pierre Fabre and MSD., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG 2000 -SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG 2000 -SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG 2000 -SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG 2000 -SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG 2000 -SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background: Colon cancer (CC) is a malignancy associated with significant morbidity and mortality within the gastrointestinal tract. Recurrence and metastasis are the main factors affecting the prognosis of CC patients undergoing radical surgery; consequently, we attempted to determine the impact of immunity-related genes., Result: We constructed a CC risk model based on ZG16, MPC1, RBM47, SMOX, CPM and DNASE1L3. Consistently, we found that a significant association was found between the expression of most characteristic genes and tumor mutation burden (TMB), microsatellite instability (MSI) and neoantigen (NEO). Additionally, a notable decrease in RBM47 expression was observed in CC tissues compared with that in normal tissues. Moreover, RBM47 expression was correlated with clinicopathological characteristics and improved disease-free survival (DFS) and overall survival (OS) among patients with CC. Lastly, immunohistochemistry and co-immunofluorescence staining revealed a clear positive correlation between RBM47 and CXCL13 in mature tertiary lymphoid structures (TLS) region., Conclusion: We conclude that RBM47 was identified as a prognostic-related gene, which was of great significance to the prognosis evaluation of patients with CC and was correlated with CXCL13 in the TLS region., (© 2024. The Author(s).)

In the realm of colon carcinoma, significant genetic and epigenetic diversity is observed, underscoring the necessity for tailored prognostic features that can guide personalized therapeutic strategies. In this study, we explored the association between the type 2 bitter taste receptor (TAS2Rs) family-related genes and colon cancer using RNA-sequencing and clinical datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Our preliminary analysis identified seven TAS2Rs genes associated with survival using univariate Cox regression analysis, all of which were observed to be overexpressed in colon cancer. Subsequently, based on these seven TAS2Rs prognostic genes, two colon cancer molecular subtypes (Cluster A and Cluster B) were defined. These subtypes exhibited distinct prognostic and immune characteristics, with Cluster A characterized by low immune cell infiltration and less favorable outcomes, while Cluster B was associated with high immune cell infiltration and better prognosis. Finally, we developed a robust scoring system using a gradient boosting machine (GBM) approach, integrated with the gene-pairing method, to predict the prognosis of colon cancer patients. This machine learning model could improve our predictive accuracy for colon cancer outcomes, underscoring its value in the precision oncology framework.

Primary colon cancers arising from the left and right sides exhibit distinct clinical and molecular characteristics. Sidedness-associated heterogeneity relies intricately on the oncogenic properties of cancer cells and multicellular interactions in tumor microenvironments. Here, combining transcriptomic profiling of 426,863 single cells from 105 colon cancer patients and validation with spatial transcriptomics and large-scale histological analysis, we capture common transcriptional heterogeneity patterns between left- and right-sided malignant epithelia through delineating two side-specific expression meta-programs. The proliferation stemness meta-program is notably enriched in left-sided malignant epithelia that colocalize with Mph-PLTP cells, activated regulatory T cells (Tregs), and exhausted CD8-LAYN cells, constituting the glucose metabolism reprogramming niche. The immune secretory (IS) meta-program exhibits specific enrichment in right-sided malignant epithelia, especially in smoking patients with right-sided colon cancer. The IS high malignant epithelia spatially localize in hypoxic regions and facilitate immune evasion through attenuating Mph-SPP1 cell antigen presentation and recruiting innate-like cytotoxicity-reduced CD8-CD161 cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Immunotoxicity remains a major hindrance to chemotherapy in cancer therapy. Nanocarriers may alleviate the immunotoxicity, but the optimal design remains unclear. Here, we created two variants of maytansine (DM1)-loaded synthetic high-density lipoproteins (D-sHDL) with either physically entrapped ( E D-sHDL) or chemically conjugated ( C D-sHDL) DM1. We found that C D-sHDL showed less accumulation in the tumor draining lymph nodes (DLNs) and femur, resulting in a lower toxicity against myeloid cells than E D-sHDL via avoiding scavenger receptor class B type 1 (SR-B1)-mediated DM1 transportation into the granulocyte-monocyte progenitors and dendritic cells. Therefore, higher densities of lymphocytes in the tumors, DLNs, and blood were recorded in mice receiving C D-sHDL, leading to a better efficacy and immune memory of C D-sHDL against colon cancer. Furthermore, liposomes with conjugated DM1 ( C D-Lipo) showed lower immunotoxicity than those with entrapped drug ( E D-Lipo) through the same mechanism after apolipoprotein opsonization. Our findings highlight the critical role of drug loading patterns in dictating the biological fate and activity of nanomedicine.

Blockade of PD-1/PD-L1 immune checkpoint is wildly used for multiple types of cancer treatment, while the low response rate for patients is still completely unknown. As nuclear hormone receptor, PPARδ (peroxisome-proliferator-activated receptor) regulates cell proliferation, inflammation, and tumor progression, while the effect of PPARδ on tumor immune escape is still unclear. Here we found that PPARδ antagonist GSK0660 significantly reduced colon cancer cell PD-L1 protein and gene expression. Luciferase analysis showed that GSK0660 decreased PD-L1 gene transcription activity. Moreover, reduced PD-L1 expression in colon cancer cells led to increased T cell activity. Further analysis showed that GSK0660 decreased PD-L1 expression in a PPARδ dependent manner. Implanted tumor model analysis showed that GSK0660 inhibited tumor immune escape and the combined PD-1 antibody with GSK0660 effectively enhanced colorectal cancer immunotherapy. These findings suggest that GSK0660 treatment could be an effective strategy for cancer immunotherapy., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The lack of an efficient way to screen patients who are responsive to immunotherapy challenges PD1/CTLA4-targeting cancer treatment. Immunotherapeutic efficacy cannot be clearly determined by peripheral blood analyses, tissue gene markers or CT/MR value. Here, we used a radionuclide and imaging techniques to investigate the novel dual targeted antibody cadonilimab (AK104) in PD1/CTLA4-positive cells in vivo., Methods: First, humanized PD1/CTLA4 mice were purchased from Biocytogen Pharmaceuticals (Beijing) Co., Ltd. to express hPD1/CTLA4 in T-cells. Then, mouse colon cancer MC38-hPD-L1 cell xenografts were established in humanized mice. A bispecific antibody targeting PD1/CTLA4 (AK104) was labeled with radio-nuclide iodine isotopes. Immuno-PET/CT imaging was performed using a bispecific monoclonal antibody (mAb) probe 124 I-AK104, developed in-house, to locate PD1 + /CTLA4 + tumor-infiltrating T cells and monitor their distribution in mice to evaluate the therapeutic effect., Results: The 124 I-AK104 dual-antibody was successfully constructed with ideal radiochemical characteristics, in vitro stability and specificity. The results of immuno-PET showed that 124 I-AK104 revealed strong hPD1/CTLA4-positive responses with high specificity in humanized mice. High uptake of 124 I-AK104 was observed not only at the tumor site but also in the spleen. Compared with PD1- or CTLA4-targeting mAb imaging, 124 I-AK104 imaging had excellent standard uptake values at the tumor site and higher tumor to nontumor (T/NT) ratios., Conclusions: The results demonstrated the potential of translating 124 I-AK104 into a method for screening patients who benefit from immunotherapy and the efficacy, as well as the feasibility, of this method was verified by immuno-PET imaging of humanized mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Various cytokines have been implicated in cancer cachexia. One such cytokine is IL-6, deemed as a key cachectic factor in mice inoculated with colon carcinoma 26 (C26) cells, a widely used cancer cachexia model. Here we tested the causal role of IL-6 in cancer cachexia by knocking out the IL-6 gene in C26 cells. We found that the growth of IL-6 KO tumors was dramatically delayed. More strikingly, while IL-6 KO tumors eventually reached the similar size as wild-type tumors, cachexia still took place, despite no elevation in circulating IL-6. In addition, the knockout of leukemia inhibitory factor (LIF), another IL-6 family cytokine proposed as a cachectic factor in the model, also affected tumor growth but not cachexia. We further showed an increase in the infiltration of immune cell population in the IL-6 KO tumors compared with wild-type controls and the defective IL-6 KO tumor growth was rescued in immunodeficient mice while cachexia was not. Thus, IL-6 promotes tumor growth by facilitating immune evasion but is dispensable for cachexia., (© 2024. The Author(s).)