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Cancer poses a major threat to human health worldwide. The development of anti-tumor materials provides new modalities for cancer diagnosis and treatment. In this review, we comprehensively summarize the research progress and clinical applications of anti-tumor materials. First, we introduce the etiology and pathogenesis of cancer, and the significance and challenges of anti-tumor materials research. Then, we classify anti-tumor materials and discuss their mechanisms of action. After that, we elaborate the research advances and clinical applications of anti-tumor materials, including those targeting tumor cells and therapeutic instruments. Finally, we discuss the future perspectives and challenges in the field of anti-tumor materials. This review aims to provide an overview of the current status of anti-tumor materials research and application, and to offer insights into future directions in this rapidly evolving field, which holds promise for more precise, efficient and customized treatment of cancer., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Chimeric antigen receptor (CAR)-engineered T cells have been defined as 'living drug'. Adding a co-stimulatory domain (CSD) has enhanced the anti-hematological effects of CAR-T cells, thereby elevating their viability for medicinal applications. Various CSDs have helped prepare CAR-T cells to study anti-tumor efficacy. Previous studies have described and summarized the anti-tumor efficacy of CAR-T cells obtained from different CSDs. However, the underlying molecular mechanisms by which different CSDs affect CAR-T function have been rarely reported. The role of CSDs in T cells has been significantly studied, but whether they can play a unique role as a part of the CAR structure remains undetermined. Here, we summarized the effects of CSDs on CAR-T signaling pathways based on the limited references and speculated the possible mechanism depending on the specific characteristics of CAR-T cells. This review will help understand the molecular mechanism of CSDs in CAR-T cells that exert different anti-tumor effects while providing potential guidance for further interventions to enhance anti-tumor efficacy in 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 Elsevier Inc. All rights reserved.)

Background: Sexual differences across molecular levels profoundly impact cancer biology and outcomes. Patient gender significantly influences drug responses, with divergent reactions between men and women to the same drugs. Despite databases on sex differences in human tissues, understanding regulations of sex disparities in cancer is limited. These resources lack detailed mechanistic studies on sex-biased molecules., Methods: In this study, we conducted a comprehensive examination of molecular distinctions and regulatory networks across 27 cancer types, delving into sex-biased effects. Our analyses encompassed sex-biased competitive endogenous RNA networks, regulatory networks involving sex-biased RNA binding protein-exon skipping events, sex-biased transcription factor-gene regulatory networks, as well as sex-biased expression quantitative trait loci, sex-biased expression quantitative trait methylation, sex-biased splicing quantitative trait loci, and the identification of sex-biased cancer therapeutic drug target genes. All findings from these analyses are accessible on SexAnnoDB ( https://ccsm.uth.edu/SexAnnoDB/ )., Results: From these analyses, we defined 126 cancer therapeutic target sex-associated genes. Among them, 9 genes showed sex-biased at both the mRNA and protein levels. Specifically, S100A9 was the target of five drugs, of which calcium has been approved by the FDA for the treatment of colon and rectal cancers. Transcription factor (TF)-gene regulatory network analysis suggested that four TFs in the SARC male group targeted S100A9 and upregulated the expression of S100A9 in these patients. Promoter region methylation status was only associated with S100A9 expression in KIRP female patients. Hypermethylation inhibited S100A9 expression and was responsible for the downregulation of S100A9 in these female patients., Conclusions: Comprehensive network and association analyses indicated that the sex differences at the transcriptome level were partially the result of corresponding sex-biased epigenetic and genetic molecules. Overall, SexAnnoDB offers a discipline-specific search platform that could potentially assist basic experimental researchers or physicians in developing personalized treatment plans., (© 2024. The Author(s).)

Immune-related adverse events (irAEs) impact outcomes, with most research focusing on early prediction (baseline data), rather than near-term prediction (one cycle before the occurrence of irAEs and the current cycle). We aimed to explore the near-term predictive value of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), absolute eosinophil count (AEC) for severe irAEs induced by PD-1 inhibitors. Data were collected from tumor patients treated with PD-1 inhibitors. NLR, PLR, and AEC data were obtained from both the previous and the current cycles of irAEs occurrence. A predictive model was developed using elastic net logistic regression Cutoff values were determined using Youden's Index. The predicted results were compared with actual data using Bayesian survival analysis. A total of 138 patients were included, of whom 47 experienced grade 1-2 irAEs and 18 experienced grade 3-5 irAEs. The predictive model identified optimal α and λ through 10-fold cross-validation. The Shapiro-Wilk test, Kruskal-Wallis test and logistic regression showed that only current cycle data were meaningful. The NLR was statistically significant in predicting irAEs in the previous cycle. Both NLR and AEC were significant predictors of irAEs in the current cycle. The model achieved an area under the ROC curve (AUC) of 0.783, with a sensitivity of 77.8% and a specificity of 80.8%. A probability ≥ 0.1345 predicted severe irAEs. The model comprising NLR, AEC, and sex may predict the irAEs classification in the current cycle, offering a near-term predictive advantage over baseline models and potentially extending the duration of immunotherapy for patients.

The development of therapeutic drugs and methods has been greatly facilitated by the emergence of tumor models. However, due to their inherent complexity, establishing a model that can fully replicate the tumor tissue situation remains extremely challenging. With the development of tissue engineering, the advancement of bioprinting technology has facilitated the upgrading of tumor models. This article focuses on the latest advancements in bioprinting, specifically highlighting the construction of 3D tumor models, and underscores the integration of these two technologies. Furthermore, it discusses the challenges and future directions of related techniques, while also emphasizing the effective recreation of the tumor microenvironment through the emergence of 3D tumor models that resemble in vitro organs, thereby accelerating the development of new anticancer therapies., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Yu et al.)

Immune checkpoint inhibitors have unveiled promising clinical prospects in cancer treatment. Nonetheless, their effectiveness remains restricted, marked by consistently low response rates and affecting only a subset of patients. The co-blockade of TIGIT with PD-1 has exhibited substantial anti-tumor effects. Notably, there is a dearth of reports on small-molecule inhibitors concurrently targeting both TIGIT and PD-1. In this study, we employed Microscale Thermophoresis (MST) to screen our laboratory's existing repository of small molecules. Our findings illuminated Gln(TrT) 's affinity for both TIGIT and PD-1, affirming its potential to effectively inhibit TIGIT/PVR and PD-1/PD-L1 pathways. In vitro co-culture experiments substantiated Gln(TrT)'s proficiency in restoring Jurkat T-cell functionality by blocking both TIGIT/PVR and PD-1/PD-L1 interactions. In the MC38 murine tumor model, Gln(TrT) emerges as a pivotal modulator, promoting the intratumoral infiltration and functional competence of CD8 + T cells. Furthermore, whether used as a monotherapy or in conjunction with radiotherapy, Gln(TrT) substantially impedes MC38 tumor progression, significantly extending the survival of murine subjects., 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 Inc. All rights reserved.)

Nanotechnology profoundly affects the advancement of medicine. Limitations in diagnosing and treating cancer and chronic diseases promote the growth of nanomedicine. However, there are very few analytical and descriptive studies regarding the trajectory of nanomedicine, key research powers, present research landscape, focal investigative points, and future outlooks. Herein, articles and reviews published in the Science Citation Index Expanded of Web of Science Core Collection from first January 2000 to 18th July 2023 are analyzed. Herein, a bibliometric visualization of publication trends, countries/regions, institutions, journals, research categories, themes, references, and keywords is produced and elaborated. Nanomedicine-related academic output is increasing since the COVID-19 pandemic, solidifying the uneven global distribution of research performance. While China leads in terms of publication quantity and has numerous highly productive institutions, the USA has advantages in academic impact, commercialization, and industrial value. Nanomedicine integrates with other disciplines, establishing interdisciplinary platforms, in which drug delivery and nanoparticles remain focal points. Current research focuses on integrating nanomedicine and cell ferroptosis induction in cancer immunotherapy. The keyword "burst testing" identifies promising research directions, including immunogenic cell death, chemodynamic therapy, tumor microenvironment, immunotherapy, and extracellular vesicles. The prospects, major challenges, and barriers to addressing these directions are discussed., (© 2024 Wiley‐VCH GmbH.)

Small molecular organic optical agents with synergistic effects of photothermal therapy (PTT) and photodynamic therapy (PDT), hold credible promise for anti-tumor therapy by overcoming individual drawbacks and enhancing photon utilization efficiency. However, developing effective dual-function PTT-PDT photosensitizers (PSs) for efficient synergistic phototherapy remains challenging. Here, a benz[c,d]indolium-substituted hemicyanine named Rh-BI, which possesses a high photothermal conversion efficiency of 41.67% by exhaustively suppressing fluorescence emission, is presented. Meanwhile, the rotating phenyl group at meso-site induces charge recombination to enhance the molar extinction coefficient up to 13.58 × 10 4 M -1 cm -1 , thereby potentiating the photodynamic effect. Under 808 nm irradiation, Rh-BI exhibits significant phototoxicity in several cancer cell types in vitro with IC 50 values as low as ≈0.5 µM. Moreover, treatment of 4T1 tumor-bearing mice with Rh-BI under laser irradiation successfully inhibits tumor growth. In a word, an effective strategy is developed to build PTT-PDT dual-functional optical materials based on hemicyanine backbone for tumor therapy by modulating conjugation system interaction to adjust the energy consumption pathway., (© 2023 Wiley‐VCH GmbH.)

Therapeutic cancer vaccines fail to produce satisfactory outcomes against solid tumors since vaccine-induced anti-tumor immunity is significantly hampered by immunosuppression. Generating an in situ cancer vaccine targeting immunological cold tumor microenvironment (TME) appears attractive. Here, a type of free-field based whole-body ultrasound (US)-driven nanovaccines are constructed, named G5-CHC-R, by conjugating the sonosensitizer, Chenghai chlorin (CHC) and the immunomodulator, resiquimod (R848) on top of a super small-sized dendrimeric nanoscaffold. Once entering tumors, R848 can be cleaved from a hypoxia-sensitive linker, thus modifying the TME via converting macrophage phenotypes. The animals bearing orthotopic pancreatic cancer with intestinal metastasis and breast cancer with lung metastasis are treated with G5-CHC-R under a free-field based whole-body US system. Benefit from the deep penetration capacity and highly spatiotemporal selectiveness, G5-CHC-R triggered by US represented a superior alternative for noninvasive irradiation of deep-seated tumors and magnification of local immune responses via driving mass release of tumor antigens and "cold-warm-hot" three-state transformation of TME. In addition to irradiating primary tumors, a robust adaptive anti-tumor immunity is potentiated, leading to successful induction of systemic tumor suppression. The sono-nanovaccines with good biocompatibility posed wide applicability to a broad spectrum of tumors, revealing immeasurable potential for translational research in oncology., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background: Cancer threat is relevant to age, and the threat of a foreshortened life coupled with a lengthy treatment process negatively affects middle-aged and older adults. Understanding the coping throughout the cancer experience in middle-aged and older cancer survivors will help develop supportive care to promote their physiological and psychological coping effects., Objectives: To explore the cancer coping experiences of middle-aged adults aged 40-59 and older adults over 60., Design: A descriptive phenomenological study was employed., Methods: Face-to-face, in-depth, semistructured interviews were conducted with 22 oncology patients in a tertiary university hospital aged 40 or above from August to October 2023. The interview data were analyzed using thematic analysis procedures., Results: Five themes and 13 subthemes were formed through analysis: acceptance of cancer (considering cancer as chronic, believing in fate and attributing cancer to karma); having different information needs (desired to be truthfully informed, information-seeking behaviour, information avoidance behaviour); getting families involved (developing dependent behaviours, feeling emotional support, family members suffering worse); striving to maintain positive psychological state (positive thinking, seeking peer support) and negative experience (undesirable, low self-esteem)., Conclusion: Our study reveals that cancer survivors' attitudes towards having cancer have changed from a death sentence to a more positive perception of a chronic disease. Supportive programmes for developing coping strategies should consider the cultural traditions and religious beliefs, different information needs, involvement of family and promoting a positive psychological state while avoiding negative factors., Patient or Public Contribution: Participants with experience of coping with cancer were involved in the semistructured interview., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: Targeting the tumor microenvironment (TME) has emerged as a promising strategy in cancer treatment, particularly through the utilization of immune checkpoint blockade (ICB) agents such as PD-1/PD-L1 inhibitors. Despite partial success, the presence of tumor-associated macrophages (TAMs) contributes to an immunosuppressive TME that fosters tumor progression, and diminishes the therapeutic efficacy of ICB. Blockade of the CD47/SIRPα pathway has proven to be an effective intervention, that restores macrophage phagocytosis and yields substantial antitumor effects, especially when combined with PD-1/PD-L1 blockade. Therefore, the identification of small molecules capable of simultaneously blocking CD47/SIRPα and PD-1/PD-L1 interactions has remained imperative., Methods: SMC18, a small molecule with the capacity of targeting both SIRPα and PD-L1 was obtained using MST. The efficiency of SMC18 in interrupting CD47/SIRPα and PD-1/PD-L1 interactions was tested by the blocking assay. The function of SMC18 in enhancing the activity of macrophages and T cells was tested using phagocytosis assay and co-culture assay. The antitumor effects and mechanisms of SMC18 were investigated in the MC38-bearing mouse model., Results: SMC18, a small molecule that dual-targets both SIRPα and PD-L1 protein, was identified. SMC18 effectively blocked CD47/SIRPα interaction, thereby restoring macrophage phagocytosis, and disrupted PD-1/PD-L1 interactions, thus activating Jurkat cells, as evidenced by increased secretion of IL-2. SMC18 demonstrated substantial inhibition of MC38 tumor growths through promoting the infiltration of CD8 + T and M1-type macrophages into tumor sites, while also priming the function of CD8 + T cells and macrophages. Moreover, SMC18 in combination with radiotherapy (RT) further improved the therapeutic efficacy., Conclusion: Our findings suggested that the small molecule compound SMC18, which dual-targets the CD47/SIRPα and PD-1/PD-L1 pathways, could be a candidate for promoting macrophage- and T-cell-mediated phagocytosis and immune responses in cancer immunotherapy., (© 2024. The Author(s).)

Runt-related transcription factors (RUNX) are a family of transcription factors that are essential for normal and malignant hematopoietic processes. Their most widely recognized role in malignancy is to promote the occurrence and development of acute myeloid leukemia. However, it is worth noting that during the last decade, studies of RUNX proteins in solid tumors have made considerable progress, suggesting that these proteins are directly involved in different stages of tumor development, including tumor initiation, progression, and invasion. RUNX proteins also play a role in tumor angiogenesis, the maintenance of tumor cell stemness, and resistance to antitumor drugs. These findings have led to the consideration of RUNX as a tumor biomarker. All RUNX proteins are involved in the occurrence and development of solid tumors, but the role of each RUNX protein in different tumors and the major signaling pathways involved are complicated by tumor heterogeneity and the interacting tumor microenvironment. Understanding how the dysregulation of RUNX in tumors affects normal biological processes is important to elucidate the molecular mechanisms by which RUNX affects malignant tumors., (© 2024. The Author(s).)

Immunogenic cell death (ICD) is associated with the release of damage-associated molecular patterns, including ATP, to promote an effective immune cycle against tumors. However, tumors have evolved an effective strategy for degrading extracellular immunostimulatory ATP via the ATP-adenosine axis, allowing the sequential action of the ectonucleotidases CD39 to degrade accumulated immunostimulatory ATP into pleiotropic immunosuppressive adenosine. Here, an ingenious dissolving microneedle patch (DMNs) is designed for the intralesional delivery of CD39 inhibitor (sodium polyoxotungstate, POM-1) and ICD inducer (IR780) co-encapsulated solid lipid nanoparticles (P/I SLNs) for antitumor therapy. Upon insertion into the tumor site, IR780 induces ICD modalities with the release of damage-associated molecular patterns from endogenous tissues, which activates the antitumor immune cycle. Simultaneously, POM-1 promotes the liberation of immunostimulatory ATP and lowers the level of immunosuppressive extracellular adenosine, which supported immune control of tumors via recruiting CD39-expressing immune cells. In vivo antitumor studies prove that this platform can effectively eliminate mice melanoma (tumor growth inhibitory rate of 96.5%) and colorectal adenocarcinoma (tumor growth inhibitory rate of 93.5%). Our results shed light on the immunological aspects of combinatorial phototherapy and ATP-adenosine regulation, which will broaden the scope of synergistic antitumor immunotherapy., Competing Interests: Declaration of competing interest The authors declared that there was no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Pyroptosis, mediated by gasdermin proteins, has shown excellent efficacy in facilitating cancer immunotherapy. The strategies commonly used to induce pyroptosis suffer from a lack of tissue specificity, resulting in the nonselective activation of pyroptosis and consequent systemic toxicity. Moreover, pyroptosis activation usually depends on caspase, which can induce inflammation and metabolic disorders. In this study, inspired by the tumor-specific expression of SRY-box transcription factor 4 (Sox4) and matrix metalloproteinase 2 (MMP2), we constructed a doubly regulated plasmid, pGMD, that expresses a biomimetic gasdermin D (GSDMD) protein to induce the caspase-independent pyroptosis of tumor cells. To deliver pGMD to tumor cells, we used a hyaluronic acid (HA)-shelled calcium carbonate nanoplatform, H-CNP@pGMD, which effectively degrades in the acidic endosomal environment, releasing pGMD into the cytoplasm of tumor cells. Upon the initiation of Sox4, biomimetic GSDMD was expressed and cleaved by MMP2 to induce tumor-cell-specific pyroptosis. H-CNP@pGMD effectively inhibited tumor growth and induced strong immune memory effects, preventing tumor recurrence. We demonstrate that H-CNP@pGMD-induced biomimetic GSDMD expression and tumor-specific pyroptosis provide a novel approach to boost cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair., Competing Interests: Conflict of interest The authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In recent years, tumor catalytic therapy based on nanozymes has attracted widespread attention. However, its application is limited by the tumor hypoxic microenvironment (TME). In this study, we developed oxygen-supplying magnetic bead nanozymes that integrate hemoglobin and encapsulate the photosensitizer curcumin, demonstrating reactive oxygen species (ROS)-induced synergistic breast cancer therapy. Fe 3 O 4 magnetic bead-mediated catalytic dynamic therapy (CDT) generates hydroxyl radicals (˙OH) through the Fenton reaction in the tumor microenvironment. The Hb-encapsulated Fe 3 O 4 magnetic beads can be co-loaded with the photosensitizer/chemotherapeutic agent curcumin (cur), resulting in Fe 3 O 4 -Hb@cur. Under hypoxic conditions, oxygen molecules are released from Fe 3 O 4 -Hb@cur to overcome the TME hypoxia, resulting in comprehensive effects favoring anti-tumor responses. Upon near-infrared (NIR) irradiation, Fe 3 O 4 -Hb@cur activates the surrounding molecular oxygen to generate a certain amount of singlet oxygen (1 O 2 ), which is utilized for photodynamic therapy (PDT) in cancer treatment. Meanwhile, we validated that the O 2 carried by Hb significantly enhances the intracellular ROS level, intensifying the catalytic therapy mediated by Fe 3 O 4 magnetic beads and inflicting lethal damage to cancer cells, effectively inhibiting tumor growth. Therefore, significant in vivo synergistic therapeutic effects can be achieved through catalytic-photodynamic combination therapy.

Background: Cancer posed a serious threat to human health, and early diagnosis of cancer biomarker was extremely important for the treatment and control of cancer. Electrochemistry-based assays were low-cost, responsive and easy to operate, but there were some challenges in terms of accuracy, detection limit, efficiency and portability. The combination of microfluidic devices and electrochemical methods was expected to construct a high-performance sensing platform, but long-time antigen-antibody incubation was still required. Therefore, a novel microfluidic chip needs to be developed, which has the advantages of good portability, short incubation time, high accuracy, low detection limit and great application to point-of-care testing., Results: A microfluidic sensor based on microcolumn array electrodes was developed, in which microcolumns could create local mixed flow to reduce the incubation time of target molecules and enhance their interaction with the sensing interface. Besides, three dimensional Mxene fibers-gold nanoparticles (3D MF-Au) was modified on the microcolumn array electrodes to increase active sites and provide more electrolyte shuttle holes. The electrolyte turbulence caused by the microcolumn array electrodes could heighten the contact between the target molecules and sensing interface and accelerate the transfer of redox pairs, thus reducing the incubation time of the target molecules and improving the electrochemical responses in synergy with the 3D MF-Au. Herein, the detection of AFP was chosen as a model, and the microfluidic sensor possessed superior performance for analysis of AFP in the range of 0.1 pg mL -1 - 200 ng mL -1 with a low detection limit (LOD) of 0.0648 pg mL -1 ., Significance: This microfluidic chip integrating with microcolumn array electrodes has been successfully implemented to detect AFP in human serum, and the results were consistent with that of electrochemical chemiluminescence method. The microfluidic chip provided a new strategy of portability, shortening incubation time and enhancing electrical signals for antigen detection of real samples, which showed great utilization potentiality in point-of-care testing., 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.)

Developing effective near-infrared (NIR) photosensitizers (PSs) has been an attractive goal of photodynamic therapy (PDT) for cancer treatment. In this study, we synthesized N, N-diethylaminomethylphenyl-containing Aza-BODIPY photosensitizers and comprehensively investigated their photophysical/photochemical properties, as well as cell-based and animal-based anti-tumor studies. Among them, BDP 1 has strong NIR absorption at 680 nm and higher singlet oxygen yield in PBS which showed favorable pH-activatable and lysosome-targeting ability. BDP 1 could be easily taken up by tumor cells and showed negligible dark activity (IC 50  > 50 μM), however strong phototoxicity upon exposure to light irradiation. The acceptable fluorescence emission from BDP 1 allowed convenient in vivo fluorescence imaging for organ distribution studies in mice. After PDT treatment with upon single time PDT treatment at the beginning using relatively low light dose (54 J/ cm 2 ), BDP 1 (2 mg/kg, 0.1 mL) was found to have strong efficacy to inhibit tumor growth and even to ablate off tumor without causing body weight loss. Therefore, pH-activatable and lysosome-targeted PS may become an effective way to develop potent PDT agent., 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 © 2023 Elsevier Ltd. All rights reserved.)

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRK WT , TRK G595R and TRK G667C with IC 50 values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC 50  = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T 1/2  = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization., 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 Ltd. All rights reserved.)

Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy., (© 2024. The Author(s).)

Radiotherapy serves as a pivotal treatment modality for malignant tumors. However, the accuracy of radiotherapy is significantly compromised due to respiratory-induced fluctuations in the size, shape, and position of the tumor. To address this challenge, we introduce a deep learning-anchored, volumetric tumor tracking methodology that employs single-angle X-ray projection images. This process involves aligning the intraoperative two-dimensional (2D) X-ray images with the pre-treatment three-dimensional (3D) planning Computed Tomography (CT) scans, enabling the extraction of the 3D tumor position and segmentation. Prior to therapy, a bespoke patient-specific tumor tracking model is formulated, leveraging a hybrid data augmentation, style correction, and registration network to create a mapping from single-angle 2D X-ray images to the corresponding 3D tumors. During the treatment phase, real-time X-ray images are fed into the trained model, producing the respective 3D tumor positioning. Rigorous validation conducted on actual patient lung data and lung phantoms attests to the high localization precision of our method at lowered radiation doses, thus heralding promising strides towards enhancing the precision of radiotherapy., 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 © 2023 Elsevier B.V. All rights reserved.)

Chimeric antigen receptor (CAR) T cell therapies have successfully treated hematological malignancies. Macrophages have also gained attention as an immunotherapy owing to their immunomodulatory capacity and ability to infiltrate solid tumors and phagocytize tumor cells. The first-generation CD3ζ-based CAR-macrophages could phagocytose tumor cells in an antigen-dependent manner. Here we engineered induced pluripotent stem cell-derived macrophages (iMACs) with toll-like receptor 4 intracellular toll/IL-1R (TIR) domain-containing CARs resulting in a markedly enhanced antitumor effect over first-generation CAR-macrophages. Moreover, the design of a tandem CD3ζ-TIR dual signaling CAR endows iMACs with both target engulfment capacity and antigen-dependent M1 polarization and M2 resistance in a nuclear factor kappa B (NF-κB)-dependent manner, as well as the capacity to modulate the tumor microenvironment. We also outline a mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we provide a second-generation CAR-iMAC with an ability for orthogonal phagocytosis and polarization and superior antitumor functions in treating solid tumors relative to first-generation CAR-macrophages., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Resveratrol (RSV) is a natural polyphenolic compound detected in grapes, berries, and red wine. The anticancer activities of RSV have been observed in vivo and in vitro studies. However, the pharmacology mechanism of RSV is confusing due to its low bioavailability. According to studies of the metabolic characteristics of RSV, the gut intestine is a crucial site of its health benefits. Dietary RSV exhibits a profound effect on the gut microbiota structure and metabolic function. In addition, emerging evidence demonstrates a protective effect of RSV metabolites against carcinogenesis. Therefore, to better understand the anticancer mechanisms of dietary RSV, it is vital to evaluate the role of RSV-microbiota-host interactions in cancer therapy. In this review, we summarized significant findings on the anticancer activities of RSV based on epidemiological, experimental and clinical studies involved in investigating the metabolic characteristics and the traditional anticancer mechanisms of RSV. Special attention is given to the putative mechanisms involving microbiota-host interactions, such as the modulation of gut microecology and the anticancer effects of RSV metabolites. The changes in microbiota-host interactions after RSV supplementation play vital roles in cancer prevention and thus offering a new perspective on nutritional interventions to treat cancer.

With the popularity of Coronavirus disease 2019 (COVID-19) vaccine and the development of vaccination strategies, the impact of COVID-19 vaccine on cancer patients receiving immune checkpoint inhibitors (ICIs) is still unclear. In the systematic review and meta-analysis of patients with ICIs, we assessed the serological response of cancer patients receiving COVID-19 vaccine, and explored the risk of immune related adverse events (irAEs). We searched PubMed, EMBASE and Cochrane Library as of 10 June 2023, and included cancer patients who received ICIs and COVID-19 vaccine. The systematic review and meta-analysis include cohort study, cross-sectional study and case report. The outcome included the serological response, Spike-specific T-cell response, irAEs and rare adverse events. When possible, the data were analysed by random effect analysis, and the statistical heterogeneity was assessed by Q-test and I 2 statistics. We explored the sources of heterogeneity through L'Abbe plots, Galbraith radial plots, and sensitivity analysis. The publication bias was evaluated by Egger's, Begg's linear regression test and funnel plot, and the impact of publication bias was further analysed by trim and fill method. 27 studies were eligible (19 cohort studies, 1 cross-sectional study and 7 case reports), involving 8331 patients (with 4724 receiving ICIs). Most studies used mRNA vaccine (BNT162b2 or mRNA-1273). Compared with cancer patients receiving chemotherapy, cancer patients receiving ICIs were significantly more likely to have seroconversion (RR = 1.05, 95%CI 1.01-1.10, P = 0.02). There were no statistically significant differences in seroconversion rates when comparing cancer patients receiving ICIs with controls without cancer (RR = 0.95, 95% CI 0.89-1.01, P = 0.09) or with cancer patients receiving targeted therapy (RR = 1.05, 95% CI 0.79-1.39, P = 0.75). The incidence of irAEs in patients receiving ICIs before and after COVID-19 vaccination was (21.96%, 95%CI 16.66%-28.94%) and (14.88%, 95%CI 8.65%-25.57%), respectively. The most common irAEs were endocrine abnormalities, skin disorders, etc. The certainty of evidence was low in cancer patients with ICIs, compared with those receiving chemotherapy, and very low versus controls without cancer. Cancer patients treated with ICIs seem to be able to receive COVID-19 vaccine safely without increasing the incidence of irAEs., (© 2023 John Wiley & Sons Ltd.)

The limitations of light source limit the clinical application of optical therapy technology. How to improve the application efficiency of radiant light has become the focus of researchers. Here, we synthesize a kind of UCNPs@PVP-GOx-PpIX-Fe 3+ (UPGPF) nanoreactors with rare earth upconversion nanoparticles (UCNPs) as the substrate for the enhancement of ferroptosis effect by the synergistic starvation/photodynamic therapies. Firstly, glucose oxidase (GOx) and Fe 3+ loaded in UPGPF nanoreactors are used to directly face the problems of insufficient H 2 O 2 level in tumor tissue and low Fenton reaction efficiency. Further, UCNPs can absorb NIR light at 980 nm and convert low-energy photons into high-energy photons, thereby cleverly generating ultraviolet (UV) radiation induction in vivo, which can produce a synergistic effect of enhancing iron death. The in vivo experimental results of breast cancer model mice show that the UPGPF nanoreactors have significant anticancer effect and good biosafety. With the help of the optical conversion characteristics of UCNPs, this kind of treatment idea of building a UV radiation-induced microplatform in the tumor microenvironment, which leads to the synergistic enhancement of iron death effect, provides a promising innovative design strategy for tumor research., 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 © 2023 Elsevier Inc. All rights reserved.)

Aim: To understand the degree of oncology patients' awareness of drug clinical trials and oncology patients' willingness to participate in drug clinical trials and the factors influencing them., Methods: The differences in the relevant variables of patients' willingness to accept clinical trials were analyzed, and a descriptive analysis was done for the measurement data (mean and standard deviation). Pearson's correlation coefficient analysis was used to examine the correlation between willingness and the demographic variables. Stepwise regression analysis was used to explore the influencing factors of patients' willingness to accept clinical trials., Results: There were no statistical differences in age, gender, education level, marital status, place of residence, monthly income, medical payment method, and treatment time ( P > 0.05). Patients' willingness to accept drug clinical trials differed in their cognitive degree of clinical drug trials ( P = 0.002). Patients' willingness to accept drug clinical trials differed in their experience in clinical trials ( P < 0.001). The correlation difference was statistically significant. The willingness to accept drug clinical trials was negatively correlated with treatment time ( R = -0.16, P < 0.05) and positively correlated with awareness of clinical trials and whether they had been subjects ( R = 0.16 and 0.43, P < 0.05). Multiple regression analysis showed that patients' willingness was directly influenced by age, treatment time, and whether they had been subjects ( F = 21.315, P < 0.001)., Conclusion: Age, treatment time, and whether they had been subjects were the direct influencing factors of patients' willingness. This study pointed out that hospitals should do a good job in the publicity of clinical trials of new drugs, expand publicity channels, increase publicity efforts, improve the awareness of clinical trials of the masses, and promote the enthusiasm of the masses to participate in clinical trials of drugs., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Jiangjie Sun et al.)

Due to the complexity of tumors, multimodal therapy for them has always been of concern to researchers. How to design a multifunctional drug nanoplatform with cascade effect and capable of responding to specific stimuli in the tumor microenvironment is the key to achieve efficient multimodal synergistic therapy of cancer. Here, we prepare a kind of GNRs@SiO 2 @PDA-CuO 2 -l-Arg (GSPRs-CL) nanomotors for systematic treatment of tumor. First, under near-infrared (NIR) irradiation, GSPRs-CL can generate heat and exhibit excellent photothermal therapy effect. Then under acidic conditions, CuO 2 can be decomposed to release Cu 2+ and generate H 2 O 2 , which not only complemented the limited endogenous H 2 O 2 in cells, but also further triggered Fenton-like reaction, converting H 2 O 2 into •OH to kill cancer cells, thereby achieving chemodynamic therapy. Furthermore, both endogenous and exogenous H 2 O 2 can release nitric oxide (NO) in response to the occurrence of l-Arg of nanomotors to enhance gas therapy. In addition, as a dual-mode drive, NIR laser and NO can promote the penetration ability of nanomotors at tumor sites. The experimental results in vivo show that the drug nanoplatform had good biosafety and significant tumor killing effect triggered by NIR light and acidic conditions of tumor. It provide a promising strategy for the development of advanced drug nanoplatform 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 © 2023 Elsevier Inc. All rights reserved.)

Collagen is abundant but exposed in tumor due to the abnormal tumor blood vessels, thus is considered as a tumor-specific target. The A3 domain of von Willebrand factor (vWF A3) is a kind of collagen-binding domain (CBD) which could bind collagen specifically. Previously we reported a chemosynthetic CBD-SIRPαFc conjugate, which could block CD47 and derived tumor-targeting ability by CBD. CBD-SIRPαFc conjugate represented improved anti-tumor efficacy with increased MHC II + M1 macrophages, but the uncertain coupling ratio remained a problem. Herein, we produced a vWF A3-SIRPαFc fusion protein through eukaryotic expression system. It was examined at both molecular and cellular levels with its collagen affinity, uninfluenced original affinity to targets and phagocytosis-promoting function compared to unmodified SIRPαFc. Living imaging showed that vWF A3-SIRPαFc fusion protein derived the improved accumulation and retention in tumor than SIRPαFc. In the MC38 allograft model, vWF A3-SIRPαFc demonstrated a superior tumor-suppressing effect, characterized by increased MHC II + M1 macrophages and T cells (particularly CD4 + T cells). These results revealed that vWF A3-SIRPαFc fusion protein derived tumor-targeting ability, leading to improved anti-tumor immunotherapeutic efficacy compared to SIRPαFc. Altogether, vWF A3 improved the anti-tumor efficacy and immune-activating function of SIRPαFc, supporting targeting tumor collagen as a possible targeted strategy., 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 © 2023 Elsevier B.V. All rights reserved.)

Recently, disulfiram (DSF), an anti-alcoholism drug, has attracted increasing biomedical interest due to its anticancer effects. However, the anticancer activity of DSF is Cu(II)-dependent and it is extremely unstable, which severely hinders its clinical translation. Herein, we report the fabrication of a multifunctional nanoplatform (MCDGF) that can improve the stability of diethyldithiocarbamate (DTC), a main metabolite of DSF, by modifying the aryl boronic ester group to form a prodrug (DQ), and also realize the in situ generation of Cu(DTC) 2 , which relies on a cascade reaction. The delivered Cu/DQ induces immunogenic cell death (ICD) and powerfully enhances immune responses of cytotoxic T lymphocytes (CTLs) and the infiltration of dendritic cells as well as T cells. Furthermore, the grafted glucose oxidase (GOx) decomposes glucose, thus "starving" the cancer cells and providing H 2 O 2 for the production of Cu(DTC) 2 . More importantly, H 2 O 2 significantly promotes the polarization of macrophages to the anti-tumor subtype. The nano-carrier "mesoporous polydopamine (MPDA)" also displays a good photothermal therapeutic effect. The nanoplatform-integrated chemotherapy, starvation therapy, photothermal therapy, and immunotherapy synergistically stimulated CTL activation and M1 macrophage polarization. Taken together, the as-prepared nanoplatform could regulate the tumor immune microenvironment and eliminate cancer with combined cancer therapy, which will offer a promising strategy for cancer treatment and promote the clinical application of DSF in breast cancer.

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression., Competing Interests: Declaration of interests D.N.I. is a co-founder and a shareholder of E3 Bioscience LLC, a commercial entity that manufactures FRET-active E2∼Ub conjugates used in this study., (Published by Elsevier Inc.)

Importance: Realizing the benefits of cancer screening requires testing of eligible individuals and processes to ensure follow-up of abnormal results., Objective: To test interventions to improve timely follow-up of overdue abnormal breast, cervical, colorectal, and lung cancer screening results., Design, Setting, and Participants: Pragmatic, cluster randomized clinical trial conducted at 44 primary care practices within 3 health networks in the US enrolling patients with at least 1 abnormal cancer screening test result not yet followed up between August 24, 2020, and December 13, 2021., Intervention: Automated algorithms developed using data from electronic health records (EHRs) recommended follow-up actions and times for abnormal screening results. Primary care practices were randomized in a 1:1:1:1 ratio to (1) usual care, (2) EHR reminders, (3) EHR reminders and outreach (a patient letter was sent at week 2 and a phone call at week 4), or (4) EHR reminders, outreach, and navigation (a patient letter was sent at week 2 and a navigator outreach phone call at week 4). Patients, physicians, and practices were unblinded to treatment assignment., Main Outcomes and Measures: The primary outcome was completion of recommended follow-up within 120 days of study enrollment. The secondary outcomes included completion of recommended follow-up within 240 days of enrollment and completion of recommended follow-up within 120 days and 240 days for specific cancer types and levels of risk., Results: Among 11 980 patients (median age, 60 years [IQR, 52-69 years]; 64.8% were women; 83.3% were White; and 15.4% were insured through Medicaid) with an abnormal cancer screening test result for colorectal cancer (8245 patients [69%]), cervical cancer (2596 patients [22%]), breast cancer (1005 patients [8%]), or lung cancer (134 patients [1%]) and abnormal test results categorized as low risk (6082 patients [51%]), medium risk (3712 patients [31%]), or high risk (2186 patients [18%]), the adjusted proportion who completed recommended follow-up within 120 days was 31.4% in the EHR reminders, outreach, and navigation group (n = 3455), 31.0% in the EHR reminders and outreach group (n = 2569), 22.7% in the EHR reminders group (n = 3254), and 22.9% in the usual care group (n = 2702) (adjusted absolute difference for comparison of EHR reminders, outreach, and navigation group vs usual care, 8.5% [95% CI, 4.8%-12.0%], P < .001). The secondary outcomes showed similar results for completion of recommended follow-up within 240 days and by subgroups for cancer type and level of risk for the abnormal screening result., Conclusions and Relevance: A multilevel primary care intervention that included EHR reminders and patient outreach with or without patient navigation improved timely follow-up of overdue abnormal cancer screening test results for breast, cervical, colorectal, and lung cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT03979495.

The situation of air pollution in Guanzhong Plain has been increasing in recent years; hence, it is very important to study the characteristics of volatile organic compounds (VOCs) and their health risks in urban functional zones. We analyzed 115 VOCs using gas chromatography-mass spectrometry/hydrogen ion flame detector (GC-MS/FID) and high performance liquid chromatography (HPLC) at four sampling sites in the traffic, comprehensive, industrial, and scenic zones of Baoji. We analyzed the main components and key species in the different functional zones. Ozone formation potential (OFP),·OH consumption rate ( L ·OH ), and secondary organic aerosol formation potential (SOAFP) were used to evaluate the environmental impact, and the hazard index (HI) and lifetime cancer risk (LCR) methods were employed. The results revealed that the mean values of φ (TVOCs) in the traffic, comprehensive, industrial, and scenic zones were (59.63±23.85)×10 -9 , (42.92±11.88)×10 -9 , (60.27±24.09)×10 -9 , and (55.54±7.44)×10 -9 , respectively. The dominant contributors at the traffic zone were alkanes, and those at the other functional zones were OVOCs. Acetaldehyde, acetone, n-butane, and isopentane were abundant at different functional zones. According to the characteristic ratios of VOCs, the average ratio of toluene to benzene (T/B) at the traffic, comprehensive, industrial, and scenic zones were 1.84, 2.39, 1.28, and 1.64, respectively, and the ratio of iso-pentane to n-pentane ( i/n ) was mainly between 1 and 4. The results indicated that VOCs in Baoji were significantly affected by vehicle emissions and gasoline evaporation, biomass and coal combustion, and industrial coatings and foundry. The ratio of m/p -xylene to ethylbenzene (X/E) was lower than 2 at the four functional zones, and the minimum was 1.79 at the scenic zones; the results revealed that X/E was small, and the aging degree of air masses was high, indicating the influence of regional transport. According to the ratio of formaldehyde to acetaldehyde (C1/C2) and the ratio of acetaldehyde to propanal (C2/C3), it was suggested that there may have been evident anthropogenic emission sources, and the photochemical reaction had an important effect on aldehydes and ketones. Environmental impact assessment results revealed that OVOCs and alkenes contributed significantly to OFP and OFP from large to small was as follows:industrial zone>scenic zone>traffic zone>comprehensive zone. The range of L ·OH in each functional zone was 8.77-15.82 s -1 , with isoprene contributing the most in the industrial zone and acetaldehyde contributing the most at other functional zones. The SOAFP of each functional zone was as follows:scenic zone>comprehensive zone>traffic zone>industrial zone. Toluene, m/p -xylene, and isoprene were the notable species. According to the health risk assessment of EPA, the HI of toxic VOCs in all functional zones was lower than 1, which was at an acceptable level. However, the number of days with HI>1 in industrial zones accounted for 42.86% of the total sampling days, indicating a high risk. The lifetime carcinogenic risk (LCR) of the traffic, comprehensive, industrial, and scenic zones were 1.83×10 -5 , 1.21×10 -5 , 1.85×10 -5 , and 1.63×10 -5 , respectively, which were all in grade Ⅲ of the rating system, indicating a high probability of cancer risk. Species with LCR greater than 10 -6 were formaldehyde; acetaldehyde; 1,2-dibromoethane; 1,2-dichloroethane; 1,2-dichloropropane; and chloroform.

Background: Waist circumference (WC), calf circumference (CC), and body mass index (BMI) have been independently linked to mortality. However, it's not yet clear how the waist-calf circumference ratio (WCR) relates to mortality. This study aims to investigate the relationship between WCR, WC, CC, and BMI with all-cause and cause-specific mortality in older adults., Methods: In the 2014 Chinese Longitudinal Healthy Longevity Survey, 4627 participants aged 65 years and older were included, and they were subsequently followed up in 2018. Cox proportional hazards models were utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality, based on WCR, WC, CC, and BMI., Results: During a median follow-up of 3.4 years, 1671 deaths (36.1%) occurred. Compared to the second quartile of WCR, the highest quartile had a higher risk of mortality from all causes (HR 1.42, 95%CI 1.24-1.64), cardiovascular disease (CVD) (HR 1.88, 95%CI 1.38-2.56), and other causes (HR 1.37, 95%CI 1.15-1.63). The first and fourth quartiles of WC had HRs of 2.19 (1.00-4.79) and 2.69 (1.23-5.89), respectively, for cancer mortality. The highest quartile of CC was associated with a lower risk of all-cause and other-cause mortality, whereas the lowest quartile was associated with a higher risk of all-cause, CVD, and other-cause mortality compared to the second CC quartile. Additionally, the lowest quartile of BMI was associated with a higher risk of all-cause and respiratory disease mortality. Interaction analyses showed that the effects of CC on all-cause and CVD mortality were more pronounced in adults aged ≥ 80 years (P-interaction < .05)., Conclusions: Higher WCR and lower CC increased the risk of all-cause, CVD, and other-cause mortality. Lower BMI was associated with higher all-cause and respiratory disease mortality risk, while WC only predicted cancer mortality., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Protein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Due to their complexity and variability, tumors need to be treated with multimodal combined therapy, which requires the development of therapeutic agents that can provide multimodal therapeutic effects. Herein, CuMoO 4 nanodots smaller than 10 nm that can be prepared by simple hydrothermal method are reported. These nanodots can be well dispersed in water and have good biosafety and biodegradability. Further studies show that these nanodots also present multienzyme activities, such as catalase, peroxidase and glutathione peroxidase. In addition, CuMoO 4 nanodots exhibit high photothermal conversion efficiency (41%) under 1064 nm near-infrared laser irradiation. In vitro and in vivo experimental results indicate that CuMoO 4 nanodots can effectively inhibit the instinctive regulation of tumor cells to oxidative stress, provide sustained treatment to achieve photothermal synergistic ferroptosis, and trigger immune responses to immunogenic cell death. It is worth mentioning that the CuMoO 4 nanodots also cause cuproptosis of tumor cells. This study provides a promising nanoplatform for multimodal combined therapy of cancer., (© 2023 Wiley-VCH GmbH.)

The success of pregnancy mainly depends on immune tolerance of the mother for the semi-allogeneic fetus. The placenta carrying paternal antigens develops in the maternal uterus without suffering immune attack, making the underlying mechanism of maternal tolerance an enduring mystery. As we all know, human leukocyte antigen (HLA) plays an important role in antigen processing and presentation, thus inducing specific immune responses. Therefore, it is reasonable to speculate that the absence of classical HLA class-I（HLA-I) and HLA class-II (HLA-II) molecules in trophoblasts may account for the maternal-fetal tolerance. Here, we review the HLA-involved interactions between trophoblast cells and decidual immune cells, which contribute to the immunotolerance in the development of normal pregnancy. We also compare the similarity between the maternal-fetal interface and tumor-immune microenvironment because the important role of HLA molecules in tumor immune invasion can provide some references to studies of maternal-fetal immune tolerance. Besides, the abnormal HLA expression is likely to be associated with unexplained miscarriage, making HLA molecules potential therapeutic targets. The advances reported by these studies may exert profound influences on other research areas, including tumor immunity, organ transplantation and autoimmune disease in the future., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in the authorship or publication., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cancer originates from somatic cells that have accumulated mutations. These mutations alter the phenotype of the cells, allowing them to escape homeostatic regulation that maintains normal cell numbers. The emergence of malignancies is an evolutionary process in which the random accumulation of somatic mutations and sequential selection of dominant clones cause cancer cells to proliferate. The development of technologies such as high-throughput sequencing has provided a powerful means to measure subclonal evolutionary dynamics across space and time. Here, we review the patterns that may be observed in cancer evolution and the methods available for quantifying the evolutionary dynamics of cancer. An improved understanding of the evolutionary trajectories of cancer will enable us to explore the molecular mechanism of tumorigenesis and to design tailored treatment strategies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery., Methods: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days., Results: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups., Conclusions: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium., Clinical Trial Registration: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257)., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

China is the world's largest consumer of cigarettes. However, the potential cancer risk posed by polycyclic aromatic hydrocarbons (PAHs) in mainstream cigarette smoke, especially species other than benzo[a]pyrene (BaP) remains unclear. In this study, we collected yield data on multiple PAH species from a variety of cigarettes in the China market and calculated their smoking-related incremental lifetime cancer risk (ILCR) values. The computed ILCRs of the total PAHs (ILCR ΣPAHs ) for ≥95% of the brands were one order of magnitude higher than the acceptable level. ILCR BaP accounted for only 5.0%-37.7% of ILCR ΣPAHs among brands, indicating that using single analyte BaP to represent ΣPAHs would significantly underestimate ILCR ΣPAHs . No clear trend of changes in ILCR ΣPAHs was found for Chinese cigarettes over multiple years, suggesting that smoking cessation is still the best option to minimize the cancer risk of PAHs. The comparison study showed that rarely reported PAHs from Chinese cigarettes can contribute over half of ILCR ΣPAHs for several American cigarettes, highlighting the imperativeness to improve the diversity of analytes for Chinese cigarettes. Adults would need to inhale the air-borne PAHs with a BaP equivalent concentration of at least 53.1 ng/m 3 to reach the ILCR value comparable to that obtained from smoking., 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 © 2023 Elsevier Inc. All rights reserved.)

Despite the initiation of tumor arises from tumorigenic transformation signaling in cancer cells, cancer cell survival, invasion, and metastasis also require a dynamic and reciprocal association with extracellular signaling from tumor microenvironment (TME). Primary cilia are the antenna-like structure that mediate signaling sensation and transduction in different tissues and cells. Recent studies have started to uncover that the heterogeneous ciliation in cancer cells and cells from the TME in tumor growth impels asymmetric paracellular signaling in the TME, indicating the essential functions of primary cilia in homeostasis maintenance of both cancer cells and the TME. In this review, we discussed recent advances in the structure and assembly of primary cilia, and the role of primary cilia in tumor and TME formation, as well as the therapeutic potentials that target ciliary dynamics and signaling from the cells in different tumors and the TME., (© 2023 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

N 6 -methyladenosine (m 6 A), the richest post-transcriptional modification of RNA in eukaryotic cells, is dynamically installed/uninstalled by the RNA methylase complex ("writer") and demethylase ("eraser") and recognized by the m 6 A-binding protein ("reader"). M 6 A modification on RNA metabolism involves maturation, nuclear export, translation and splicing, thereby playing a critical role in cellular pathophysiology and disease processes. Circular RNAs (circRNAs) are a class of non-coding RNAs with a covalently closed loop structure. Due to its conserved and stable properties, circRNAs could participate in physiological and pathological processes through unique pathways. Despite the recent discovery of m 6 A and circRNAs remains in the initial stage, research has shown that m 6 A modifications are widespread in circRNAs and regulates circRNA metabolism, including biogenesis, cell localization, translation, and degradation. In this review, we describe the functional crosstalk between m 6 A and circRNAs, and illustrate their roles in cancer development. Moreover, we discuss the potential mechanisms and future research directions of m 6 A modification and circRNAs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery., Methods: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival., Results: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298., Conclusions: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival., Clinical Trial Registrations: ChiCTR-IPR-15006209; NCT02660411., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Reactive oxygen species (ROS) are small reactive molecules produced by cellular metabolism and regulate various physiological and pathological functions. Many studies have shown that ROS plays an essential role in the proliferation and inhibition of tumor cells. Different concentrations of ROS can have a "double-edged sword" effect on the occurrence and development of tumors. A certain concentration of ROS can activate growth-promoting signals, enhance the proliferation and invasion of tumor cells, and cause damage to biomacromolecules such as proteins and nucleic acids. However, ROS can enhance the body's antitumor signal at higher levels by initiating oxidative stress-induced apoptosis and autophagy in tumor cells. This review analyzes ROS's unique bidirectional regulation mechanism on tumor cells, focusing on the key signaling pathways and regulatory factors that ROS affect the occurrence and development of tumors and providing ideas for an in-depth understanding of the mechanism of ROS action and its clinical application.

Cancer is one of the leading causes of human death. As metabolomics techniques become more and more widely used in cancer research, metabolites are increasingly recognized as crucial factors in both cancer diagnosis and treatment. In this study, we developed MACdb (https://ngdc.cncb.ac.cn/macdb), a curated knowledgebase to recruit the metabolic associations between metabolites and cancers. Unlike conventional data-driven resources, MACdb integrates cancer-metabolic knowledge from extensive publications, providing high quality metabolite associations and tools to support multiple research purposes. In the current implementation, MACdb has integrated 40,710 cancer-metabolite associations, covering 267 traits from 17 categories of cancers with high incidence or mortality, based entirely on manual curation from 1,127 studies reported in 462 publications (screened from 5,153 research papers). MACdb offers intuitive browsing functions to explore associations at multi-dimensions (metabolite, trait, study, and publication), and constructs knowledge graph to provide overall landscape among cancer, trait, and metabolite. Furthermore, NameToCid (map metabolite name to PubChem Cid) and Enrichment tools are developed to help users enrich the association of metabolites with various cancer types and traits., Implication: MACdb paves an informative and practical way to evaluate cancer-metabolite associations and has a great potential to help researchers identify key predictive metabolic markers in cancers., (©2023 The Authors; Published by the American Association for Cancer Research.)

PD-1/PD-L1 blockade has achieved substantial clinical results in cancer treatment. However, the expression of other immune checkpoints leads to resistance and hinders the efficacy of PD-1/PD-L1 blockade. T cell immunoglobulin and mucin domain 3 (TIM-3), a non-redundant immune checkpoint, synergizes with PD-1 to mediate T cell dysfunction in tumor microenvironment. Development of small molecules targeting TIM-3 is a promising strategy for cancer immunotherapy. Here, to identify small molecule inhibitors targeting TIM-3, the docking pocket in TIM-3 was analyzed by Molecular Operating Environment (MOE) and the Chemdiv compound database was screened. The small molecule SMI402 could bind to TIM-3 with high affinity and prevent the ligation of PtdSer, HMGB1, and CEACAM1. SMI402 reinvigorated T cell function in vitro. In the MC38-bearing mouse model, SMI402 inhibited tumor growth by increasing CD8 + T and natural killing (NK) cells infiltration at the tumor site, as well as restoring the function of CD8 + T and NK cells. In conclusions, the small molecule SMI402 shows promise as a leading compound which targets TIM-3 for cancer 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 © 2023 Elsevier Inc. All rights reserved.)

Aims: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment., Methods: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations., Results: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers., Conclusions: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses., (© 2023 British Pharmacological Society.)

Despite vaccination having the potency to revolutionize disease treatments, some critical issues including lack of safe and effective delivery system, insufficient internalization and ineffective antigen cross-presentation by dendritic cells (DCs) severely hamper its extensive clinical applications. Herein, we developed a whole cell-encapsulated antitumor vaccine microneedle patch (TCV-DMNs) potentiated with transdermal co-delivery of granulocyte-macrophage colony-stimulating factor (GM-CSF) and autophagy promoter (Tat-beclin 1). After transdermal vaccination with TCV-DMNs, GM-CSF released from DMNs serves as a potent adjuvant to recruit and promote the phagocytosis of antigens by DCs. Subsequently, Tat-beclin 1 promoted DCs maturation and MHC-I-mediated cross-presentation via up-regulated autophagy of DCs. We found that vaccination with TCV-DMNs could not only effectively suppress melanoma challenge, but also lead to regression of established malignancies, followed by a relapse-free survival of >40 days. Collectively, whole cell-encapsulated microneedle-assisted transdermal vaccination TCV-DMNs in combination with autophagy regulation could induce a robust antitumor immune response via enhancing transdermal delivery efficiency, promoting antigen internalization and cross-presentation, together with boosting T cell activities., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2023. Published by Elsevier B.V.)

Tumors are often polyclonal due to copy number alteration (CNA) events. Through the CNA profile, we can understand the tumor heterogeneity and consistency. CNA information is usually obtained through DNA sequencing. However, many existing studies have shown a positive correlation between the gene expression and gene copy number identified from DNA sequencing. With the development of spatial transcriptome technologies, it is urgent to develop new tools to identify genomic variation from the spatial transcriptome. Therefore, in this study, we developed CVAM, a tool to infer the CNA profile from spatial transcriptome data. Compared with existing tools, CVAM integrates the spatial information with the spot's gene expression information together and the spatial information is indirectly introduced into the CNA inference. By applying CVAM to simulated and real spatial transcriptome data, we found that CVAM performed better in identifying CNA events. In addition, we analyzed the potential co-occurrence and mutual exclusion between CNA events in tumor clusters, which is helpful to analyze the potential interaction between genes in mutation. Last but not least, Ripley's K-function is also applied to CNA multi-distance spatial pattern analysis so that we can figure out the differences of different gene CNA events in spatial distribution, which is helpful for tumor analysis and implementing more effective treatment measures based on spatial characteristics of genes.

Costimulatory domains (CSD) of 4-1BB and CD28 are most widely used in chimeric antigen receptor (CAR)-engineered T cells. These CAR T cells have shown encouraging efficacy in the treatment of hematologic malignancies but have limited efficacy in solid tumors. The herpes virus entry mediator (HVEM) is a costimulatory molecule with a novel downstream signaling pathway. In response to target cells, CAR T cells with a HVEM CSD (HVEM-CAR T) displayed more robust cytokine release and cytotoxicity than 4-1BB-CAR T or CD28-CAR T in vitro. Furthermore, HVEM-CAR T showed superior therapeutic efficacy in several mouse tumor models. Mechanistically, the HVEM CSD endowed CAR T cells with attenuated exhaustion, improved function and persistence, and enhanced metabolic activities in tumor tissue compared with 4-1BB-based or CD28-based CAR T cells. These studies establish that the HVEM CSD has the potential to improve the therapeutic efficacy of CAR T cells against solid tumors., (©2023 American Association for Cancer Research.)