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The human microbiome has recently emerged as a focal point in cancer research, specifically in anti-tumor immunity, immunotherapy, and chemotherapy. This review explores microbial-derived metabolites, emphasizing their crucial roles in shaping fundamental aspects of cancer treatment. Metabolites such as short-chain fatty acids (SCFAs), Trimethylamine N-Oxide (TMAO), and Tryptophan Metabolites take the spotlight, underscoring their diverse origins and functions and their profound impact on the host immune system. The focus is on SCFAs' remarkable ability to modulate immune responses, reduce inflammation, and enhance anti-tumor immunity within the intricate tumor microenvironment (TME). The review critically evaluates TMAO, intricately tied to dietary choices and gut microbiota composition, assessing its implications for cancer susceptibility, progression, and immunosuppression. Additionally, the involvement of tryptophan and other amino acid metabolites in shaping immune responses is discussed, highlighting their influence on immune checkpoints, immunosuppression, and immunotherapy effectiveness. The examination extends to their dynamic interaction with chemotherapy, emphasizing the potential of microbial-derived metabolites to alter treatment protocols and optimize outcomes for cancer patients. A comprehensive understanding of their role in cancer therapy is attained by exploring their impacts on drug metabolism, therapeutic responses, and resistance development. In conclusion, this review underscores the pivotal contributions of microbial-derived metabolites in regulating antitumor immunity, immunotherapy responses, and chemotherapy outcomes. By illuminating the intricate interactions between these metabolites and cancer therapy, the article enhances our understanding of cancer biology, paving the way for the development of more effective treatment options in the ongoing battle against cancer. [ABSTRACT FROM AUTHOR]

Radiated tumor cell‐derived extracellular vesicles (RT‐EVs) encapsulate abundant DNA fragments from irradiated tumor cells, in addition to acting as integrators of multiple tumor antigens. Accumulating evidence indicates these DNA fragments from damaged cells are involved in downstream immune responses, but most of them are degraded in cells before incorporation into derived RT‐EVs, thus the low abundance of DNA fragments limits immune responses of RT‐EVs. Here, this study found that different radiations affected fates of DNA fragments in RT‐EVs. Boron neutron capture therapy (BNCT) induced DNA accumulation in RT‐EVs (BEVs) by causing more DNA breaks and DNA oxidation resisting nuclease degradation. This is attributed to the high‐linear energy transfer (LET) properties of alpha particles from the neutron capture reaction of 10B. When being internalized by dendritic cells (DCs), BEVs activated the DNA sensing pathway, resulting in functional enhancements including antigen presentation, migration capacity, and cytokine secretion. After vaccination of the BEVs‐educated DCs (BEV@BMDCs), the effector T cells significantly expanded and infiltrated into tumors, suggesting robust anti‐tumor immune activation. BEV@BMDCs not only effectively inhibited the primary tumor growth and metastasis formation but also elicited long‐term immune memory. In conclusion, a successful DC vaccine is provided as a promising candidate for tumor vaccine. [ABSTRACT FROM AUTHOR]

AbstractTo quantitatively investigate the effects of chronic low-dose internal exposure to Cesium-137 on DNA damage, carcinogenicity, and offspring over multiple generations. The potential genetic risk in humans was predicted based on next-generation murine mutation rates to confirm the reasonableness of the current Cesium-137 dose limits for food. Cesium-137 (100 Bq/mL) was provided in drinking water to A/J mice, facilitating chronic, low-dose, low-dose-rate internal exposure through sibling mating over 25 generations (G25). The A/J mice were compared with a control strain with the same origin ancestry (no Cesium-137 water) for DNA double-strand breaks (DSBs), oxidative stress, chromosome aberrations, micronucleus test results, whole genome analysis, carcinogenicity, tumor growth rate, and immune competence. Compared to the control group, DNA DSBs and oxidative stress were significantly increased in the Cesium-137 group. However, no significant differences were observed between the groups regarding chromosome aberration, micronuclei, or the whole genome sequence mutation analysis. Although the carcinogenic rate did not differ between the groups, the rate of tumor growth was significantly suppressed in the Cesium-137 group. The anti-tumor cytokine trend in the Cesium-137 group likely contributed to this effect. No pathological or genetic effects were observed in the offspring of mice drinking water containing 100 Bq/mL Cesium-137 after G25. The contribution of low dose-rate radiation to carcinogenicity was not additive but growth-inhibitory. Although the negative data are not conclusive, these findings are deemed highly reliable. [ABSTRACT FROM AUTHOR]

Recent studies have linked elevated tumor aneuploidy to anti-tumor immune suppression and adverse survival following immunotherapy. Herein, we provide supportive evidence for tumor aneuploidy as a biomarker of response to immunotherapy in patients with non-small cell lung cancer (NSCLC). We identify a dose–response relationship between aneuploidy score and patient outcomes. In two independent NSCLC cohorts (n = 659 patients), we demonstrate a novel association between elevated aneuploidy and non-smoking-associated oncogenic driver mutations. Lastly, we report enrichment of TERT amplification and immune-suppressive phenotypes of highly aneuploid NSCLC. Taken together, our findings emphasize a potentially critical role for tumor aneuploidy in guiding immunotherapy treatment strategies. [ABSTRACT FROM AUTHOR]

Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 (Lrp10) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10 -deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy. Synopsis: Lrp10 is a putative cell surface receptor with unknown functions in immunity. This study shows that Lrp10 prevents accumulation of peripheral CD8 T cells, suppresses IL7R expression to limit homeostatic expansion, and impairs anti-tumor immune responses. Genetic deletion of Lrp10 causes an increased number of peripheral CD8 T cells in mice. Lrp10 is induced upon T cell activation and post-translationally suppresses IL7R expression. Lrp10 reduces CD8 central memory differentiation, T cell homeostatic expansion, and IL7 responsiveness. Lrp10 deletion promotes CD8 T cell infiltration, resulting in enhanced anti-tumor immunity and susceptibility to immune checkpoint inhibition. Lrp10 is a putative cell surface receptor with unknown functions in immunity. This study shows that Lrp10 prevents accumulation of peripheral CD8 T cells, suppresses IL7R expression to limit homeostatic expansion, and impairs anti-tumor immune responses. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy remains a significant challenge due to insufficient proliferation of immune cells and the sturdy immunosuppressive tumor microenvironment. Herein, we proposed the hypothesis of cuproptosis-lactate regulation to provoke cuproptosis and enhance anti-tumor immunity. For this purpose, copper-human serum albumin nanocomplex loaded gold nanocages with bacterial membrane coating (BAu-CuNCs) were developed. The targeted delivery and disassembly of BAu-CuNCs in tumor cells initiated a cascade of reactions. Under near infrared (NIR) laser irradiation, the release of copper-human serum albumin (Cu-HSA) was enhanced that reacted with intratumoral glutathione (GSH) via a disulfide exchange reaction to liberate Cu2+ ions and exert cuproptosis. Subsequently, the cuproptosis effect triggered immunogenic cell death (ICD) in tumor by the release of damage associated molecular patterns (DAMPs) to realize anti-tumor immunity via robust production of cytotoxic T cells (CD8+) and helper T cells (CD4+). Meanwhile, under NIR irradiation, gold nanocages (AuNCs) promoted excessive reactive oxygen species (ROS) generation that played a primary role in inhibiting glycolysis, reducing the lactate and ATP level. The combine action of lower lactate level, ATP reduction and GSH depletion further sensitized the tumor cells to cuproptosis. Also, the lower lactate production led to the significant blockage of immunosuppressive T regulatory cells (Tregs) and boosted the anti-tumor immunity. Additionally, the effective inhibition of breast cancer metastasis to the lungs enhanced the anti-tumor therapeutic impact of BAu-CuNCs + NIR treatment. Hence, BAu-CuNCs + NIR concurrently induced cuproptosis, ICD and hindered lactate production, leading to the inhibition of tumor growth, remodeling of the immunosuppressive tumor microenvironment and suppression of lung metastasis. Therefore, leveraging cuproptosis-lactate regulation, this approach presents a novel strategy for enhanced tumor immunotherapy. [Display omitted] • Developed BAu-CuNCs, a biomimetic nanosystem for targeted tumor immunotherapy via cuproptosis-lactate regulation. • Triggered cuproptosis and reduced lactate production under NIR irradiation for robust anti-tumor immune response. • Significant inhibition of tumor growth and metastasis. • Offers potent anti-tumor effects and reshaping of the immunosuppressive tumor microenvironment, suggesting a novel strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

The immunosuppressive microenvironment of malignant tumors severely hampers the effectiveness of anti-tumor therapy. Moreover, abnormal tumor vasculature interacts with immune cells, forming a vicious cycle that further interferes with anti-tumor immunity and promotes tumor progression. Our pre-basic found excellent anti-tumor effects of c -di-AMP and RRx-001, respectively, and we further explored whether they could be combined synergistically for anti-tumor immunotherapy. We chose to load these two drugs on PVA-TSPBA hydrogel scaffolds that expressly release drugs within the tumor microenvironment by in situ injection. Studies have shown that c -di-AMP activates the STING pathway, enhances immune cell infiltration, and reverses tumor immunosuppression. Meanwhile, RRx-001 releases nitric oxide, which increases oxidative stress injury in tumor cells and promotes apoptosis. Moreover, the combination of the two presented more powerful pro-vascular normalization and reversed tumor immunosuppression than the drug alone. This study demonstrates a new design option for anti-tumor combination therapy and the potential of tumor environmentally responsive hydrogel scaffolds in combination with anti-tumor immunotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Recent studies have linked elevated tumor aneuploidy to anti-tumor immune suppression and adverse survival following immunotherapy. Herein, we provide supportive evidence for tumor aneuploidy as a biomarker of response to immunotherapy in patients with non-small cell lung cancer (NSCLC). We identify a dose–response relationship between aneuploidy score and patient outcomes. In two independent NSCLC cohorts (n = 659 patients), we demonstrate a novel association between elevated aneuploidy and non-smoking-associated oncogenic driver mutations. Lastly, we report enrichment of TERT amplification and immune-suppressive phenotypes of highly aneuploid NSCLC. Taken together, our findings emphasize a potentially critical role for tumor aneuploidy in guiding immunotherapy treatment strategies.

Abstract Background In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. Methods We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. Results HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. Conclusions Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

Abstract Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.

Abstract Background Telomerase, by safeguarding damaged telomeres and bolstering DNA damage repair, has the capacity to heighten the radioresistance of tumour cells. Thus, in turn, can compromise the efficacy of radiotherapy (RT) and radioimmunotherapy. Our previous studies have revealed that the highly selective telomerase inhibitor, BIBR1532, possesses the potential to enhance the radiosensitivity of Non-small cell lung cancer (NSCLC). In this study, we delve further into the impact of BIBR1532 on the immune activation induced by RT and elucidate the underlying mechanisms. Methods Biological information analyses, immunofluorescence assays, western blot assays, flow cytometry analysis were conducted to elucidate the functions of the combination of BIBR1532 with radiotherapy in NSCLC. Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Both in vitro and in vivo studies were conducted to examine the antitumor effects. Results Our findings indicate that the confluence of BIBR1532 with RT significantly augments the activation of the cGAS-STING pathway in both in vivo and in vitro settings, thereby fostering an effective anti-tumoral immune response. The effects can be ascribed to two key processes. Firstly, ionizing radiation, in precipitating DNA double-strand breaks (DSBs), prompts the release of tumour-derived double-stranded DNA (dsDNA) into the cytoplasm. Subsequently, BIBR1532 amplifies the activation of antigen-presenting cells by dsDNA post-RT and instigates the cGAS-STING pathway. Secondly, BIBR1532 enhances the ferroptosis response in NSCLC following RT, thereby promoting unrestrained lipid peroxidation and elevated levels of reactive oxygen species (ROS) within tumour cells. This ultimately leads to mitochondrial stress and the release of endogenous mitochondrial DNA (mtDNA) into the cytoplasm, thus facilitating the activation of the STING pathway and the induction of a type I interferon (IFN)-linked adaptive immune response. Conclusion This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC.

Abstract Interleukin-12 (IL-12) can be used as an immunomodulator in cancer immunotherapy. And it has demonstrated enormous potential in inhibiting tumor growth and improving the tumor microenvironment (TME) by several preclinical models. However, some disappointing results have showed in the early clinical trials when IL-12 used as a single agent for systemic cancer therapy. Combination therapy is an effective way to significantly fulfill the great potential of IL-12 as an immunomodulator. Here, we discuss the effects of IL-12 combined with traditional methods (chemotherapy, radiotherapy and surgery), targeted therapy or immunotherapy in the preclinical and clinical studies. Moreover, we summarized the potential mechanism underlying the anti-tumor effect of IL-12 in the combination strategies. And we also discussed the delivery methods and tumor-targeted modification of IL-12 and outlines future prospects for IL-12 as an immunomodulator.

This study delves into the unexplored realm of castration‐resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms using high‐throughput single‐cell transcriptome sequencing and advanced bioinformatics analysis. Our comprehensive examination unveiled dynamic TRIM28 expression changes, particularly in immune cells such as macrophages and CD8+ T cells within CRPC. Correlation analyses with TCGA data highlighted the connection between TRIM28 and immune checkpoint expression and emphasized its pivotal influence on the quantity and functionality of immune cells. Using TRIM28 knockout mouse models, we identified differentially expressed genes and enriched pathways, unraveling the potential regulatory involvement of TRIM28 in the cGAS‐STING pathway. In vitro, experiments further illuminated that TRIM28 knockout in prostate cancer cells induced a notable anti‐tumor immune effect by inhibiting M2 macrophage polarization and enhancing CD8+ T cell activity. This impactful discovery was validated in an in situ transplant tumor model, where TRIM28 knockout exhibited a deceleration in tumor growth, reduced proportions of M2 macrophages, and enhanced infiltration of CD8+ T cells. In summary, this study elucidates the hitherto unknown anti‐tumor immune role of TRIM28 in CRPC and unravels its potential regulatory mechanism via the cGAS‐STING signaling pathway. These findings provide novel insights into the immune landscape of CRPC, offering promising directions for developing innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. Methods: We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. Results: HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. Conclusions: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC. [ABSTRACT FROM AUTHOR]

With its unique properties and potential applications, nanoparticle-based delivery platforms for messenger RNA (mRNA) vaccines have gained significant attention in recent years. Nanoparticles have the advantages of enhancing immunogenicity, targeting delivery, and improving stability, providing a new solution for drug and vaccine delivery. In some clinical studies, a variety of nanoparticle delivery platforms have been gradually applied to a wide range of vaccine applications. Current research priorities are exploring various types of nanoparticles as vaccine delivery systems to enhance vaccine stability and immunogenicity. Lipid nanoparticles (LNPs) have shown promising potential in preclinical and clinical studies on the efficient delivery of antigens to immune cells. Moreover, lipid nanoparticles and other nanoparticles for nucleic acids, especially for mRNA delivery systems, have shown vast potential for vaccine development. In this review, we present various vaccine platforms with an emphasis on nanoparticles as mRNA vaccine delivery vehicles. We describe several novel nanoparticle delivery platforms for mRNA vaccines, such as lipid-, polymer-, and protein-based nanoparticles. In addition, we provide an overview of the anti-tumor immunity of nanovaccines against different tumors in cancer immunotherapy. Finally, we outline future perspectives and remaining challenges for this promising technology of nanoparticle-based delivery platforms for vaccines. [ABSTRACT FROM AUTHOR]

Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC. [ABSTRACT FROM AUTHOR]

Background: Telomerase, by safeguarding damaged telomeres and bolstering DNA damage repair, has the capacity to heighten the radioresistance of tumour cells. Thus, in turn, can compromise the efficacy of radiotherapy (RT) and radioimmunotherapy. Our previous studies have revealed that the highly selective telomerase inhibitor, BIBR1532, possesses the potential to enhance the radiosensitivity of Non-small cell lung cancer (NSCLC). In this study, we delve further into the impact of BIBR1532 on the immune activation induced by RT and elucidate the underlying mechanisms. Methods: Biological information analyses, immunofluorescence assays, western blot assays, flow cytometry analysis were conducted to elucidate the functions of the combination of BIBR1532 with radiotherapy in NSCLC. Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Both in vitro and in vivo studies were conducted to examine the antitumor effects. Results: Our findings indicate that the confluence of BIBR1532 with RT significantly augments the activation of the cGAS-STING pathway in both in vivo and in vitro settings, thereby fostering an effective anti-tumoral immune response. The effects can be ascribed to two key processes. Firstly, ionizing radiation, in precipitating DNA double-strand breaks (DSBs), prompts the release of tumour-derived double-stranded DNA (dsDNA) into the cytoplasm. Subsequently, BIBR1532 amplifies the activation of antigen-presenting cells by dsDNA post-RT and instigates the cGAS-STING pathway. Secondly, BIBR1532 enhances the ferroptosis response in NSCLC following RT, thereby promoting unrestrained lipid peroxidation and elevated levels of reactive oxygen species (ROS) within tumour cells. This ultimately leads to mitochondrial stress and the release of endogenous mitochondrial DNA (mtDNA) into the cytoplasm, thus facilitating the activation of the STING pathway and the induction of a type I interferon (IFN)-linked adaptive immune response. Conclusion: This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Lactococcus lactis subsp. cremoris C60, a probiotic lactic acid bacteria (LAB) strain, induces immunomodulation in myeloid cells, including macrophages. C60 was reported to suppress murine melanoma in our previous study, while the effect of this strain on macrophage anti-tumor activity is still uncharacterized. Here, we report that C60 enhances macrophage function by altering metabolic preference to glycolysis, allowing the cell to produce more adenosine triphosphate (ATP) and maintain an inflammatory status. Intratumor (IT) macrophages in C60-administered mice increase glycolysis rather than fatty acid oxidation (FAO) in their metabolism, which enables the cells to generate sufficient energy resources to increase their immune activity, including antigen-dependent CD8+ T cell activation in a murine melanoma model. This is the first report demonstrating that probiotic LAB assists macrophage function in anti-tumor immunity, providing a novel possibility for LAB adaptation in maintaining our health. Lactococcus lactis subsp. cremoris C60 is a probiotic strain of lactic acid bacteria (LAB) which induces various immune modifications in myeloid lineage cells. These modifications subsequently regulate T cell function, resulting in enhanced immunity both locally and systemically. Here, we report that C60 suppresses tumor growth by enhancing macrophage function via metabolic alterations, thereby increasing adenosine triphosphate (ATP) production in a murine melanoma model. Intragastric (i.g.) administration of C60 significantly reduced tumor volume compared to saline administration in mice. The anti-tumor function of intratumor (IT) macrophage was upregulated in mice administered with C60, as evidenced by an increased inflammatory phenotype (M1) rather than an anti-inflammatory/reparative (M2) phenotype, along with enhanced antigen-presenting ability, resulting in increased tumor antigen-specific CD8+ T cells. Through this functional modification, we identified that C60 establishes a glycolysis-dominant metabolism, rather than fatty acid oxidation (FAO), in IT macrophages, leading to increased intracellular ATP levels. To address the question of why orally supplemented C60 exhibits functions in distal places, we found a possibility that bacterial cell wall components, which could be distributed throughout the body from the gut, may induce stimulatory signals in peripheral macrophages via Toll-like receptors (TLRs) signaling activation. Thus, C60 strengthens macrophage anti-tumor immunity by promoting a predominant metabolic shift towards glycolysis upon TLR-mediated stimulation, thereby increasing substantial energy production. [ABSTRACT FROM AUTHOR]

Interleukin-12 (IL-12) can be used as an immunomodulator in cancer immunotherapy. And it has demonstrated enormous potential in inhibiting tumor growth and improving the tumor microenvironment (TME) by several preclinical models. However, some disappointing results have showed in the early clinical trials when IL-12 used as a single agent for systemic cancer therapy. Combination therapy is an effective way to significantly fulfill the great potential of IL-12 as an immunomodulator. Here, we discuss the effects of IL-12 combined with traditional methods (chemotherapy, radiotherapy and surgery), targeted therapy or immunotherapy in the preclinical and clinical studies. Moreover, we summarized the potential mechanism underlying the anti-tumor effect of IL-12 in the combination strategies. And we also discussed the delivery methods and tumor-targeted modification of IL-12 and outlines future prospects for IL-12 as an immunomodulator. [ABSTRACT FROM AUTHOR]

Background: Metastatic breast cancer is a leading cause of cancer death in woman. Current treatment options are often associated with adverse side effects and poor outcomes, demonstrating the need for effective new treatments. Immunotherapies can provide durable outcomes in many cancers; however, limited success has been achieved in metastatic triple negative breast cancer. We tested whether combining different immunotherapies can target metastatic triple negative breast cancer in pre-clinical models. Methods: Using primary and metastatic 4T1 triple negative mammary carcinoma models, we examined the therapeutic effects of oncolytic vesicular stomatitis virus (VSVΔM51) engineered to express reovirus-derived fusion associated small transmembrane proteins p14 (VSV-p14) or p15 (VSV-p15). These viruses were delivered alone or in combination with natural killer T (NKT) cell activation therapy mediated by adoptive transfer of α-galactosylceramide-loaded dendritic cells. Results: Treatment of primary 4T1 tumors with VSV-p14 or VSV-p15 alone increased immunogenic tumor cell death, attenuated tumor growth, and enhanced immune cell infiltration and activation compared to control oncolytic virus (VSV-GFP) treatments and untreated mice. When combined with NKT cell activation therapy, oncolytic VSV-p14 and VSV-p15 reduced metastatic lung burden to undetectable levels in all mice and generated immune memory as evidenced by enhanced in vitro recall responses (tumor killing and cytokine production) and impaired tumor growth upon rechallenge. Conclusion: Combining NKT cell immunotherapy with enhanced oncolytic virotherapy increased anti-tumor immune targeting of lung metastasis and presents a promising treatment strategy for metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect of midchain fatty acid decanoic acid on CD8+ T cell activation and its effect and mechanism in CD8+ T cell-mediated anti-tumor immune response. Methods: Subcutaneous melanoma B16F10 cells tumor-bearing C57BL/6 mouse models were established and randomly divided into the decanoic acid group (10 mg/kg decanoic acid by gavage) and the control group (equal amount of solvent by gavage). The effect of decanoic acid on the growth of mouse tumors and their survival rate were measured. The activation of tumor-infiltrated CD8+ T cells in the tumor microenvironment was detected by flow cytometry. The α-CD8 mAb was used to deplete CD8+ T cells in B16F10 tumor-bearing mice, and the effect on the tumor volume was observed. Mouse primary CD8+ T cells were treated with decanoic acid, and T cell receptor (TCR) activation, effector cytokine production as well as proliferation and metabolism levels were detected by WB, ELISA, qPCR, and flow cytometry. In B16F10 tumor-bearing mouse model, the effects of administration of α-PD-1 mAb combined with decanoic acid on the growth of mouse tumors and mouse survival rate were observed. Results: In the mouse melanoma model, compared with those in the control group the volume of mouse transplanted tumors significantly reduced and mouse survival rate significantly increased in the decanoic acid group. (both P<0.05). The expression levels of IFN-γ and TNF-α in tumor-infiltrating CD8+ T cells were significantly higher in the decanoic acid group than that in the control group (P<0.01). The killing ability of OT-I T cells against B16F10-OVA cells was significantly elevated after treatment with decanoic acid (P<0.01). The suppressive effect of decanoic acid on transplanted tumors was significantly reduced after CD8+ T cells were depleted with α-CD8 mAb in the melanoma mouse model (P<0.000 1). Mouse-derived primary CD8+ T cells treated with decanoic acid showed significantly higher levels of TCR activation, increased production of cytokines IL-2 and IFN-γ, and significantly up-regulated the mitochondrial metabolic level (all P<0.05). In the melanoma mouse model, decanoic acid in combination with α-PD-1 mAb significantly inhibited tumor growth and increased the survival rate (both P<0.05). Conclusion: Decanoic acid can enhance the anti-tumor immune responses by promoting CD8+ T cell activation. [ABSTRACT FROM AUTHOR]

B7 ligands (CD80 and CD86), expressed by professional antigen-presenting cells (APCs), activate the main co-stimulatory receptor CD28 on T cells in trans. However, in peripheral tissues, APCs expressing B7 ligands are relatively scarce. This raises the questions of whether and how CD28 co-stimulation occurs in peripheral tissues. Here, we report that CD8+ T cells displayed B7 ligands that interacted with CD28 in cis at membrane invaginations of the immunological synapse as a result of membrane remodeling driven by phosphoinositide-3-kinase (PI3K) and sorting-nexin-9 (SNX9). cis-B7:CD28 interactions triggered CD28 signaling through protein kinase C theta (PKCθ) and promoted CD8+ T cell survival, migration, and cytokine production. In mouse tumor models, loss of T cell-intrinsic cis-B7:CD28 interactions decreased intratumoral T cells and accelerated tumor growth. Thus, B7 ligands on CD8+ T cells can evoke cell-autonomous CD28 co-stimulation in cis in peripheral tissues, suggesting cis-signaling as a general mechanism for boosting T cell functionality.

Tertiary Lymphoid Structures (TLS) are organized aggregates of immune cells such as T cells, B cells, and Dendritic Cells (DCs), as well as fibroblasts, formed postnatally in response to signals from cytokines and chemokines. Central to the function of TLS are DCs, professional antigen-presenting cells (APCs) that coordinate the adaptive immune response, and which can be classified into different subsets, with specific functions, and markers. In this article, we review current data on the contribution of different DC subsets to TLS function in cancer and autoimmunity, two opposite sides of the immune response. Different DC subsets can be found in different tumor types, correlating with cancer prognosis. Moreover, DCs are also present in TLS found in autoimmune and inflammatory conditions, contributing to disease development. Broadly, the presence of DCs in TLS appears to be associated with favorable clinical outcomes in cancer while in autoimmune pathologies these cells are associated with unfavorable prognosis. Therefore, it is important to analyze the complex functions of DCs within TLS in order to enhance our fundamental understanding of immune regulation but also as a possible route to create innovative clinical interventions designed for the specific needs of patients with diverse pathological diseases.

Ovarian cancer (OC) is one of the leading causes of death from malignancy in women and lacks safe and efficient treatment. The novel biomaterial, recombinant humanized collagen type III (rhCOLIII), has been reported to have various biological functions, but its role in OC is unclear. This study aimed to reveal the function and mechanism of action of rhCOLIII in OC. We developed an injectable recombinant human collagen (rhCOL)-derived material with a molecular weight of 45 kDa, with a stable triple helix structure, high biocompatibility, water solubility and biosafety. The anti-tumor activity of rhCOLIII was comprehensively evaluated through in vitro and in vivo experiments. In vitro, our results showed that rhCOLIII inhibited the proliferation, migration, and invasion of ovarian cancer cells (OCCs), and induced apoptosis. In addition, rhCOLIII not only inhibited autophagy of OCCs but also increased the expression of MHC-1 molecule within OCCs. To further elucidate the mechanism of rhCOLIII in OC, we conducted joint analysis of RNA-Seq and proteomics, and found that rhCOLIII exerted anti-tumor function and autophagy inhibition by downregulating Glutathione S-transferase P1 (GSTP1). Furthermore, various rescue experiments were designed to demonstrate that rhCOLIII suppressed autophagy and proliferation of OCCs by mediating GSTP1. In vivo, we found that rhCOLIII could inhibit tumor growth and promote CD8+ T cell infiltration. Our results indicate that rhCOLIII has great anti-tumor potential activity in OC, and induces protective anti-tumor immunity by regulating autophagy through GSTP1. These findings illustrate the potential therapeutic prospects of rhCOLIII for OC treatment.

Abstract Radiated tumor cell‐derived extracellular vesicles (RT‐EVs) encapsulate abundant DNA fragments from irradiated tumor cells, in addition to acting as integrators of multiple tumor antigens. Accumulating evidence indicates these DNA fragments from damaged cells are involved in downstream immune responses, but most of them are degraded in cells before incorporation into derived RT‐EVs, thus the low abundance of DNA fragments limits immune responses of RT‐EVs. Here, this study found that different radiations affected fates of DNA fragments in RT‐EVs. Boron neutron capture therapy (BNCT) induced DNA accumulation in RT‐EVs (BEVs) by causing more DNA breaks and DNA oxidation resisting nuclease degradation. This is attributed to the high‐linear energy transfer (LET) properties of alpha particles from the neutron capture reaction of 10B. When being internalized by dendritic cells (DCs), BEVs activated the DNA sensing pathway, resulting in functional enhancements including antigen presentation, migration capacity, and cytokine secretion. After vaccination of the BEVs‐educated DCs (BEV@BMDCs), the effector T cells significantly expanded and infiltrated into tumors, suggesting robust anti‐tumor immune activation. BEV@BMDCs not only effectively inhibited the primary tumor growth and metastasis formation but also elicited long‐term immune memory. In conclusion, a successful DC vaccine is provided as a promising candidate for tumor vaccine.

The human microbiome has recently emerged as a focal point in cancer research, specifically in anti-tumor immunity, immunotherapy, and chemotherapy. This review explores microbial-derived metabolites, emphasizing their crucial roles in shaping fundamental aspects of cancer treatment. Metabolites such as short-chain fatty acids (SCFAs), Trimethylamine N-Oxide (TMAO), and Tryptophan Metabolites take the spotlight, underscoring their diverse origins and functions and their profound impact on the host immune system. The focus is on SCFAs’ remarkable ability to modulate immune responses, reduce inflammation, and enhance anti-tumor immunity within the intricate tumor microenvironment (TME). The review critically evaluates TMAO, intricately tied to dietary choices and gut microbiota composition, assessing its implications for cancer susceptibility, progression, and immunosuppression. Additionally, the involvement of tryptophan and other amino acid metabolites in shaping immune responses is discussed, highlighting their influence on immune checkpoints, immunosuppression, and immunotherapy effectiveness. The examination extends to their dynamic interaction with chemotherapy, emphasizing the potential of microbial-derived metabolites to alter treatment protocols and optimize outcomes for cancer patients. A comprehensive understanding of their role in cancer therapy is attained by exploring their impacts on drug metabolism, therapeutic responses, and resistance development. In conclusion, this review underscores the pivotal contributions of microbial-derived metabolites in regulating anti-tumor immunity, immunotherapy responses, and chemotherapy outcomes. By illuminating the intricate interactions between these metabolites and cancer therapy, the article enhances our understanding of cancer biology, paving the way for the development of more effective treatment options in the ongoing battle against cancer.

Summary: Increasing evidence indicates that immunotherapy is hindered by a hostile tumor microenvironment (TME) featured with deprivation of critical nutrients and pooling of immunosuppressive metabolites. Tumor cells and immunosuppressive cells outcompete immune effector cells for essential nutrients. Meanwhile, a wide range of tumor cell-derived toxic metabolites exerts negative impacts on anti-tumor immune response, diminishing the efficacy of immunotherapy. Nanomedicine with excellent targetability offers a novel approach to improving cancer immunotherapy via metabolically reprogramming the immunosuppressive TME. Herein, we review recent strategies of enhancing immunotherapeutic effects through rewiring tumor metabolism via nanomedicine. Attention is drawn on immunometabolic tactics for immune cells and stromal cells in the TME via nanomedicine. Additionally, we discuss future directions of developing metabolism-regulating nanomedicine for precise and efficacious cancer immunotherapy.

Targeting nucleotide enzymes emerges as a promising avenue for impeding tumor proliferation and fortifying anti-tumor immunogenicity. The non-canonical role of nucleotide enzymes remains poorly understood. In this study, we have identified that Phosphoglucomutase 2 (PGM2) rapidly accumulates at the DNA damage site to govern the DNA damage response mediated by the phosphorylation at Serine 165 and by forming a complex with Rho-associated coiled-coil-containing protein kinase 2 (ROCK2). Silencing PGM2 in Glioblastoma Multiforme (GBM) cells heightens DNA damage in vitro and enhances the sensitivity of temozolomide (TMZ) treatment by activating anti-tumor immunity in vivo. Furthermore, we demonstrate that pharmacological inhibition of ROCK2 synergistically complements TMZ treatment and pembrolizumab (PD-L1) checkpoint immunotherapy, augmenting anti-tumor immunity. This study reveals the non-canonical role of the nucleotide enzyme PGM2 in the regulation of DNA damage response and anti-tumor immunity, with implications for the development of therapeutic approaches in cancer treatment.

In a recent article, Maxwell et al. report that loss of tumor cell-specific AT-rich interaction domain 1A (ARID1A), a component of the chromatin remodeling SWI/SNF complex, triggers antitumor immunity via R-loop-mediated upregulation of the type-I interferon (IFN) pathway. These recent findings uncover a molecular mechanism underlying improved responses to immune checkpoint therapy (ICT) seen in patients harboring an ARID1A loss-of-function mutation. [ABSTRACT FROM AUTHOR]

Abstract High-throughput sequencing has ushered in a paradigm shift in gastric microbiota, breaking the stereotype that the stomach is hostile to microorganisms beyond H. pylori. Recent attention directed toward the composition and functionality of this 'community' has shed light on its potential relevance in cancer. The microbial composition in the stomach of health displays host specificity which changes throughout a person's lifespan and is subject to both external and internal factors. Distinctive alterations in gastric microbiome signature are discernible at different stages of gastric precancerous lesions and malignancy. The robust microbes that dominate in gastric malignant tissue are intricately implicated in gastric cancer susceptibility, carcinogenesis, and the modulation of immunosurveillance and immune escape. These revelations offer fresh avenues for utilizing gastric microbiota as predictive biomarkers in clinical settings. Furthermore, inter-individual microbiota variations partially account for differential responses to cancer immunotherapy. In this review, we summarize current literature on the influence of the gastric microbiota on gastric carcinogenesis, anti-tumor immunity and immunotherapy, providing insights into potential clinical applications.

Treating non-small-cell lung cancer (NSCLC) has gained increased importance in recent years due to the high mortality rate and dismal five-year survival rate. Immune checkpoint inhibitors (ICI) are a promising approach with exceptional outcomes in NSCLC thanks to the antigenic nature of cells. Conversely, immune system over-stimulation with ICI is a double-edged sword that can lead to various negative effects ranging from mild to life-threatening. This review explores current breakthroughs in nanoparticle-based ICI and their limitations. The PubMed, Scopus and Web of Science were examined for relevant publications. Thirty-eight trials (N = 16,781) were included in the analyses. The mixed effects analyses on quantifying the treatment effect contributed significantly to the subgroups within studies for ICI treatment effect. Models confirmed ICI’s higher impact on treatment effectivity and the decrease in respondents’ mortality compared to conventional treatment regiments. ICI might be used as first-line therapy due to their proven effectiveness and safety profile.

High-throughput sequencing has ushered in a paradigm shift in gastric microbiota, breaking the stereotype that the stomach is hostile to microorganisms beyond H. pylori. Recent attention directed toward the composition and functionality of this 'community' has shed light on its potential relevance in cancer. The microbial composition in the stomach of health displays host specificity which changes throughout a person's lifespan and is subject to both external and internal factors. Distinctive alterations in gastric microbiome signature are discernible at different stages of gastric precancerous lesions and malignancy. The robust microbes that dominate in gastric malignant tissue are intricately implicated in gastric cancer susceptibility, carcinogenesis, and the modulation of immunosurveillance and immune escape. These revelations offer fresh avenues for utilizing gastric microbiota as predictive biomarkers in clinical settings. Furthermore, inter-individual microbiota variations partially account for differential responses to cancer immunotherapy. In this review, we summarize current literature on the influence of the gastric microbiota on gastric carcinogenesis, anti-tumor immunity and immunotherapy, providing insights into potential clinical applications. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME)‐induced nanocatalytic therapy is a promising strategy for cancer treatment, but the low catalytic efficiency limits its therapeutic efficacy. Single‐atom catalysts (SACs) are a new type of nanozyme with incredible catalytic efficiency. Here, a single‐atom manganese (Mn)‐N/C nanozyme is constructed. Mn‐N/C catalyzes the conversion of cellular H2O2 to ∙OH through a Fenton‐like reaction and enables the sufficient generation of reactive oxygen species (ROS), which induces immunogenic cell death (ICD) of tumor cells and significantly promotes CD8+T anti‐tumor immunity. Moreover, RNA sequencing analysis reveals that Mn‐N/C treatment activates type I interferon (IFN) signaling, which is critical for Mn‐N/C‐mediated anti‐tumor immune response. Mechanistically, the release of cytosolic DNA and Mn2+ triggered by Mn‐N/C collectively activates the cGAS‐STING pathway, subsequently stimulating type I IFN induction. A highly efficient single‐atom nanozyme, Mn‐N/C, which enhances anti‐tumor immune response and exhibits synergistic therapeutic effects when combined with the anti‐PD‐L1 blockade, is proposed. [ABSTRACT FROM AUTHOR]

Lactic acid bacteria (LAB) possess the ability to argument T cell activity through functional modification of antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages. Nevertheless, the precise mechanism underlying LABinduced enhancement of antigen presentation in APCs remains incompletely understood. To address this question, we investigated the detailed mechanism underlying the enhancement of major histocompatibility complex (MHC) class Irestricted antigen presentation in DCs using a probiotic strain known as Lactococcus lactis subsp. Cremoris C60. We found that Heat-killed-C60 (HK-C60) facilitated the processing and presentation of ovalbumin (OVA) peptide antigen OVA257-264 (SIINFEKL) via H-2Kb in bone marrow-derived dendritic cells (BMDCs), leading to increased generation of effector CD8+ T cells both in vitro and in vivo. We also revealed that HK-C60 stimulation augmented the activity of 20S immunoproteasome (20SI) in BMDCs, thereby enhancing the MHC class I-restricted antigen presentation machinery. Furthermore, we assessed the impact of HK-C60 on CD8+ T cell activation in an OVA-expressing B16-F10 murine melanoma model. Oral administration of HK-C60 significantly attenuated tumor growth compared to control treatment. Enhanced Ag processing and presentation machineries in DCs from both Peyer's Patches (PPs) and lymph nodes (LNs) resulted in an increased tumor antigen specific CD8+ T cells. These findings shed new light on the role of LAB in MHC class-I restricted antigen presentation and activation of CD8+ T cells through functional modification of DCs. [ABSTRACT FROM AUTHOR]

Simple Summary: The proximity to tumor cells is pivotal to the anti-tumor functions of CD8+ T cells, but the mechanism underlying the regulation of CD8+ T cell spatial distribution remains elusive. Here, we utilize the cellular neighborhood algorithm to identify the spatial architectures that regulate the localization and inter-cellular communication of CD8+ T cells in human pancreatic ductal adenocarcinoma. The presence of CD8+ T cells, CD4+ T cells, and other lymphocytes in the same cellular neighborhoods were identified as one type of spatial architecture that restricted the proximity of CD8+ T cells to tumor cells and heralded a poor prognosis. In such architecture, CD8+ T cells tended to aggregate around themselves and CD4+ T cells instead of approaching tumor cells. In this study, we identified a spatial architecture for the regulation of CD8+ T cells and deciphered a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner. The anti-tumor function of CD8+ T cells is dependent on their proximity to tumor cells. Current studies have focused on the infiltration level of CD8+ T cells in the tumor microenvironment, while further spatial information, such as spatial localization and inter-cellular communication, have not been defined. In this study, co-detection by indexing (CODEX) was designed to characterize PDAC tissue regions with seven protein markers in order to identify the spatial architecture that regulates CD8+ T cells in human pancreatic ductal adenocarcinoma (PDAC). The cellular neighborhood algorithm was used to identify a total of six conserved and distinct cellular neighborhoods. Among these, one unique spatial architecture of CD8+ T and CD4+ T cell-enriched neighborhoods enriched the majority of CD8+ T cells, but heralded a poor prognosis. The proximity analysis revealed that the CD8+ T cells in this spatial architecture were significantly closer to themselves and the CD4+ T cells than to the tumor cells. Collectively, we identified a unique spatial architecture that restricted the proximity of CD8+ T cells to tumor cells in the tumor microenvironment, indicating a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner and providing new insights into the biology of PDAC. [ABSTRACT FROM AUTHOR]

Background and aims: T cells are master effectors of anti-tumor immunity in cancer. Recent studies suggest that altered lipid metabolism imposed by the tumor microenvironment constrains anti-tumor immunity. However, the tumor-associated lipid species changes that dampen T cell ability to control tumor progression are not fully understood. Here, we plan to clarify the influences of distinctly altered lipid components in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) on T-cell function, aiming to seek lipid metabolic targets for improving T cell anti-tumor effects. Methods: Tumor tissues and non-tumor liver from HCC patients were collected for RNA-sequencing, lipid profiling and T cell characterizing, followed by correlation analysis. Additionally, the effects of significantly changed lipid components on anti-tumor potential of T cells were tested by in vitro cell experiments and/or in vivo tumor inoculated model. Results: Altered lipid metabolism coincides with impaired T cell response in HBV-related HCC. Characteristic lipid composition, significantly marked by accumulation of long-chain acylcarnitines (LCACs) and reduction of lysophosphatidylcholines (LPCs), are found in the tumor tissue. Notably, LCACs accumulated are associated with T cells exhaustion and deficient functionality, while LPCs correlate to anti-tumor effects of T cells. In particular, supplement of LPCs, including LPC (20:0) and LPC (22:0), directly promote the activation and IFN-γ secretion of T cells in vitro, and suppress tumor growth in vivo. Conclusions: Our study highlights the distinctly changed lipid components closely related to T cell dysregulation in HCC, and suggests a promising strategy by decreasing LCACs and increasing LPCs for anti-tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-tumor effects of Pien Tze Huang (PZH) in mouse models of B16–F10 melanoma, MC38 colorectal cancer, Hep1-6 hepatocellular carcinoma and chemically induced hepatocellular carcinoma model. Methods: Various tumor models, including B16–F10, MC38 and Hep1-6 tumor hypodermic inoculation models, B16–F10 and Hep1-6 pulmonary metastasis models, Hep1-6 orthotopic implantation model, and chemically induced hepatocellular carcinoma model, were utilized to evaluate the anti-tumor function of PZH. Tumor growth was assessed by measuring tumor size and weight of solid tumors isolated from C57BL/6 mice. For cell proliferation and death of tumor cells in vitro, as well as T cell activation markers, cytokine production and immune checkpoints analysis, single-cell suspensions were prepared from mouse spleen, lymph nodes, and tumors after PZH treatment. Results: PZH demonstrated significant therapeutic efficacy in inhibiting tumor growth (P<0.01). Treatment with PZH resulted in a reduction in tumor size in subcutaneous MC38 colon adenocarcinoma and B16–F10 melanoma models, and decreased pulmonary metastasis of B16–F10 melanoma and Hep1-6 hepatoma (P<0.01). However, in vitro experiments showed that PZH only had slight impact on the cell proliferation and survival of tumor cells (P>0.05). Nevertheless, PZH exhibited a remarkable ability to enhance T cell activation and the production of interferon gamma, tumor necrosis factor alpha, and interleukin 2 in CD4+ T cells in vitro (P<0.01 or P<0.05). Importantly, PZH substantially inhibited T cell exhaustion and boosted cytokine production by tumor-infiltrating CD8+ T cells (P<0.01 or P<0.05). Conclusion: This study has confirmed a novel immunomodulatory function of PZH in T cell-mediated anti-tumor immunity, indicating that PZH holds promise as a potential therapeutic agent for cancer treatment. [ABSTRACT FROM AUTHOR]

PRKCSH, also known as Glucosidase II beta subunit (GluIIb), is a crucial component of the endoplasmic reticulum (ER) quality control system for N-linked glycosylation, essential for identifying and eliminating misfolded proteins. Glucosidase II consists of the catalytic alpha subunit (GluIIa) and the regulatory beta subunit (GluIIb), ensuring proper protein folding and release from the ER. The induction of PRKCSH in cancer and its interaction with various cellular components suggest broader roles beyond its previously known functions. Mutations in the PRKCSH gene are linked to autosomal dominant polycystic liver disease (ADPLD). Alternative splicing generates distinct PRKCSH isoforms, which can influence processes like epithelial-mesenchymal transition (EMT) and the proliferation of lung cancer cells. PRKCSH's involvement in cancer is multifaceted, impacting cell growth, metastasis, and response to growth factors. Additionally, PRKCSH orchestrates cell death programs, affecting both autophagy and apoptosis. Its role in facilitating N-linked glycoprotein release from the ER is hypothesized to assist cancer cells in managing increased demand and ER stress. Moreover, PRKCSH modulates anti-tumor immunity, with its suppression augmenting NK cell and T cell activity, promising enhanced cancer therapy. PRKCSH's diverse functions, including regulation of IGF1R and IRE1a, implicate it as a therapeutic target and biomarker in cancer immunotherapy. However, targeting its glucosidase II activity alone may not fully counteract its effects, suggesting broader mechanisms in cancer development. Further investigations are needed to elucidate PRKCSH's precise role and validate its therapeutic potential in cancer treatment. [ABSTRACT FROM AUTHOR]

PDL1 blockade therapy holds great promise in cancer immunotherapy. Ultrasound imaging of PDL1 expression in the tumor is of great importance in predicting the therapeutic efficacy. As a proof‐of‐concept study, a novel ultrasound contrast agent has been innovated here to image and block PDL1 in the tumor tissue. Briefly, extracellular vesicles (EVs) are engineered to display truncated PD1 (tPD1) on the surface to bind PDL1 with high affinity by fusion to EV‐abundant transmembrane protein PTGFRN. The engineered EVs are then encapsulated with Ca(HCO3)2 via electroporation and designated as Gp‐EVtPD1, which would recognize PDL1 highly expressed cells and produce gas in the endosomes and lysosomes. On the one hand, the echogenic signal intensity correlates well with the PDL1 expression and immune response inhibition in the tumor. On the other hand, during the trajectory of Gp‐EVtPD1 in the recipient cells, tPD1 on the EV binds PDL1 and triggers the PDL1 endocytosis and degradation in endosomes/lysosomes in a sequential manner, and thus boosts the anti‐tumor immunity of cytotoxic T cells. In summary, Gp‐EVtPD1 serves as a novel ultrasound contrast agent and blocker of PDL1, which might be of great advantage in imaging PDL1 expression and conquering immune checkpoint blocker resistance. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed to cure hematological malignancies, such as acute myeloid leukemia (AML), through the graft-versus-leukemia (GVL) effect. In this immunological process, donor immune cells eliminate residual cancer cells in the patient and exert tumor control through immunosurveillance. However, GVL failure and subsequent leukemia relapse are frequent and associated with a dismal prognosis. A better understanding of the mechanisms underlying AML immune evasion is essential for developing novel therapeutic strategies to boost the GVL effect. Cellular metabolism has emerged as an essential regulator of survival and cell fate for both cancer and immune cells. Leukemia and T cells utilize specific metabolic programs, including the orchestrated use of glucose, amino acids, and fatty acids, to support their growth and function. Besides regulating cell-intrinsic processes, metabolism shapes the extracellular environment and plays an important role in cell-cell communication. This review focuses on recent advances in the understanding of how metabolism might affect the antileukemia immune response. First, we provide a general overview of the mechanisms of immune escape after allo-HCT and an introduction to leukemia and T cell metabolism. Further, we discuss how leukemia and myeloid cell metabolism contribute to an altered microenvironment that impairs T cell function. Next, we review the literature linking metabolic processes in AML cells with their inhibitory checkpoint ligand expression. Finally, we focus on recent findings concerning the role of systemic metabolism in sustained GVL efficacy. While the majority of evidence in the field still stems from basic and preclinical studies, we discuss translational findings and propose further avenues for bridging the gap between bench and bedside. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy is booming around the world. However, strategies to activate the immune system and alleviate the immunosuppression still need to be refined. Here, we demonstrate for the first time that low-intensity pulsed ultrasound (LIPUS, spatial average time average intensity (Isata) is 200 mW/cm2, frequency is 0.3 MHz, repetition frequency is 1 kHz, and duty cycle is 20%) triggers the immune system and further reverses the immunosuppressive state in the mouse models of breast cancer by irradiating the spleen of mice. LIPUS inhibited tumor growth and extended survival in mice with 4 T-1 tumors. Further studies had previously shown that LIPUS enhanced the activation of CD4+ and CD8+ T cells in the spleen and led to significant changes in cytokines, as well as induced upregulation of mRNA levels involved in multiple immune regulatory pathways in the spleen. In addition, LIPUS promoted tumor-infiltrating lymphocyte accumulation and CD8+ T cell activation and improved the dynamics of cytokines/chemokines in the tumor microenvironment, resulting in a reversal of the immunosuppressive state of the tumor microenvironment. These results suggest a novel approach to activate the immune response by irradiating the spleen with LIPUS. [ABSTRACT FROM AUTHOR]

X-ray excited photodynamic therapy (X-PDT) is the bravo answer of photodynamic therapy (PDT) for deep-seated tumors, as it employs X-ray as the irradiation source to overcome the limitation of light penetration depth. However, high X-ray irradiation dose caused organ lesions and side effects became the major barrier to X-PDT application. To address this issue, this work employed a classical co-precipitation reaction to synthesize NaLuF4:15%Tb3+ (NLF) with an average particle size of (23.48 ± 0.91) nm, which was then coupled with the photosensitizer merocyanine 540 (MC540) to form the X-PDT system NLF–MC540 with high production of singlet oxygen. The system could induce antitumor efficacy to about 24% in relative low dose X-ray irradiation range (0.1–0.3 Gy). In vivo, when NLF–MC540 irradiated by 0.1 Gy X-ray, the tumor inhibition percentage reached 89.5% ± 5.7%. The therapeutic mechanism of low dose X-PDT was found. A significant increase of neutrophils in serum was found on the third day after X-PDT. By immunohistochemical staining of tumor sections, the Ly6G+, CD8+, and CD11c+ cells infiltrated in the tumor microenvironment were studied. Utilizing the bilateral tumor model, the NLF–MC540 with 0.1 Gy X-ray irradiation could inhibit both the primary tumor and the distant tumor growth. Detected by enzyme linked immunosorbent assay (ELISA), two cytokines IFN-γ and TNF-α in serum were upregulated 7 and 6 times than negative control, respectively. Detected by enzyme linked immune spot assay (ELISPOT), the number of immune cells attributable to the IFN-γ and TNF-α levels in the group of low dose X-PDT were 14 and 6 times greater than that in the negative control group, respectively. Thus, it conclude that low dose X-PDT system could successfully upregulate the levels of immune cells, stimulate the secretion of cytokines (especially IFN-γ and TNF-α), activate antitumor immunity, and finally inhibit colon tumor growth. [ABSTRACT FROM AUTHOR]

The tumor microenvironment is composed of tumor cells, stromal cells and leukocytes, including innate and adaptive immune cells, and represents an ecological niche that regulates tumor development and progression. In general, inflammatory cells are considered to contribute to tumor progression through various mechanisms, including the formation of an immunosuppressive microenvironment. Macrophages and neutrophils are important components of the tumor microenvironment and can act as a double-edged sword, promoting or inhibiting the development of the tumor. Targeting of the immune system is emerging as an important therapeutic strategy for cancer patients. However, the efficacy of the various immunotherapies available is still limited. Given the crucial importance of the crosstalk between macrophages and neutrophils and other immune cells in the formation of the anti-tumor immune response, targeting these interactions may represent a promising therapeutic approach against cancer. Here we will review the current knowledge of the role played by macrophages and neutrophils in cancer, focusing on their interaction with other immune cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Androgen receptor signaling is an important target to investigate in urothelial carcinoma of the bladder because basic and clinical evidence strongly suggests that the androgen receptor is involved in bladder carcinogenesis. Moreover, androgen receptor signaling may suppress anti-tumor immunity. These factors may also be important contributors to the strong male sex bias in urothelial carcinoma of the bladder. Preclinical and clinical data suggest that androgen receptor signaling strongly contributes to bladder cancer development. The roles of the androgen receptor in bladder carcinogenesis have obvious implications for understanding the strong male sex bias in this disease and for potential therapeutic strategies as well. In this review, we summarize what is known about androgen receptor signaling in urothelial carcinoma as well as in tumor-infiltrating immune cells, reviewing preclinical and clinical data. We also highlight clinical trial efforts in this area. [ABSTRACT FROM AUTHOR]

The role of Pleckstrin homology-like domain family B member 2 (PHLDB2) in the regulation of cell migration has been extensively studied. However, the exploration of PHLDB2 in head and neck squamous cell carcinoma (HNSCC) is still limited in terms of expression, function, and therapeutic potential. In this study, we discovered an upregulation of PHLDB2 expression in HNSCC tissues which was correlated with a negative prognosis in patients with HNSCC. Additionally, we determined that a high level of expression of PHLDB2 is crucial for maintaining cell migration through the regulation of the epithelial–mesenchymal transition (EMT). Furthermore, we demonstrated that the ablation of PHLDB2 in tumor cells inhibited tumorigenicity in a C3H syngeneic tumor-bearing mouse model. Mechanistically, PHLDB2 was found to be involved in the regulation of T cell anti-tumor immunity, primarily by enhancing the activation and infiltration of CD8+ T cells. In light of these findings, PHLDB2 emerges as a promising biomarker and therapeutic target for interventions in HNSCC. [ABSTRACT FROM AUTHOR]

Disulfidptosis, an innovative type of controlled cellular death linked to metabolic dysfunction, has garnered attention. However, there is limited knowledge regarding the involvement of disulfidptosisrelated lnRNAs (DRlncRNAs) in laryngeal squamous cell carcinoma (LSCC). The objective of our team in this study seeks to establish a DRlncRNAs signature, investigate their prognostic value in LSCC, and explore their associations with immune cell subpopulations, biological signaling pathways, and exploring implications for drug sensitivity. We accessed LSCC patients’ RNA-seq data and pertinent clinical data for subsequent further analysis from The Cancer Genome Atlas (TCGA) portal. A literature search was conducted focusing on disulfidptosis-related genes. Pearson correlation coefficients were calculated to identify DRlncRNAs. Differential expression analysis of lncRNAs was performed. Utilizing univariate Cox regression analysis, we identified disulfidptosis-associated prognostic lncRNAs. The LASSO-Cox regression analysis was employed to refine this set of lncRNAs and construct a disulfidptosis-related lncRNAs signature. Various statistical techniques were employed to appraise model predictive performance. Subsequently, risk groups were stratified based on the risk score derived from the DRlncRNAs signature. The superiority of the risk score in prognostication over traditional clinicopathological features in LSCC patients was demonstrated. Evident distinctions emerged between risk groups, particularly in immune cell subpopulations like activated mast cells, eosinophils, and activated NK cells. Finally, the low-risk group demonstrated reduced IC50 values for specific chemotherapeutics like cisplatin and gemcitabine. The in vitro experiments indicated differential behavior of our DRlncRNAs. The DRlncRNAs signature can serve as a robust biomarker with the ability to predict both prognosis and therapeutic responses among patients with LSCC.

Abstract Cancer stem cells (CSCs), being the primary contributors in tumor initiation, metastasis, and relapse, ought to have seminal roles in evasion of immune surveillance. Tumor-promoting CD4+CD25+FOXP3+ T-regulatory cells (Tregs) have been described to abolish host defense mechanisms by impeding the activities of other immune cells including effector T cells. However, whether CSCs can convert effector T cells to immune-suppressive Treg subset, and if yes, the mechanism underlying CSC-induced Treg generation, are limitedly studied. In this regard, we observed a positive correlation between breast CSC and Treg signature markers in both in-silico and immunohistochemical analyses. Mirroring the conditions during tumor initiation, low number of CSCs could successfully generate CD4+CD25+FOXP3+ Treg cells from infiltrating CD4+ T lymphocytes in a contact-independent manner. Suppressing the proliferation potential as well as IFNγ production capacity of effector T cells, these Treg cells might be inhibiting antitumor immunity, thereby hindering immune-elimination of CSCs during tumor initiation. Furthermore, unlike non-stem cancer cells (NSCCs), CSCs escaped doxorubicin-induced apoptosis, thus constituting major surviving population after three rounds of chemotherapy. These drug-survived CSCs were also able to generate CD4+CD25+FOXP3+ Treg cells. Our search for the underlying mechanism further unveiled the role of CSC-shed immune-suppressive cytokine TGFβ, which was further increased by chemotherapy, in generating tumor Treg cells. In conclusion, during initiation as well as after chemotherapy, when NSCCs are not present in the tumor microenvironment, CSCs, albeit present in low numbers, generate immunosuppressive CD4+CD25+FOXP3+ Treg cells in a contact-independent manner by shedding high levels of immune-suppressive Treg-polarizing cytokine TGFβ, thus escaping immune-elimination and initiating the tumor or causing tumor relapse.

Abstract CD8+ T cells are the executor in adaptive immune response, especially in anti-tumor immunity. They are the subset immune cells that are of high plasticity and multifunction. Their development, differentiation, activation and metabolism are delicately regulated by multiple factors. Stimuli from the internal and external environment could remodel CD8+ T cells, and correspondingly they will also make adjustments to the microenvironmental changes. Here we describe the most updated progresses in CD8+ T biology from transcriptional regulation to metabolism mechanisms, and also their interactions with the microenvironment, especially in cancer and immunotherapy. The expanding landscape of CD8+ T cell biology and discovery of potential targets to regulate CD8+ T cells will provide new viewpoints for clinical immunotherapy.