Cancer letters最新文献

{"title":"Cell adhesion molecule ITGB2 promotes CAR-T cell therapy in B-cell malignancies","authors":"Yang Su ,&nbsp;Xiaodi Xu ,&nbsp;Guang Yang ,&nbsp;Bi Chen ,&nbsp;Xi Chen ,&nbsp;Qiuni Chen ,&nbsp;Kebing Lv ,&nbsp;Zhe Zhang ,&nbsp;Hong Liu ,&nbsp;Xiaoqin Qi ,&nbsp;Yuan Liu ,&nbsp;Baiyan Yang ,&nbsp;Yun Li ,&nbsp;Dongnan Li ,&nbsp;Shenglong Li ,&nbsp;Chunling Wang ,&nbsp;Liang Yu","doi":"10.1016/j.canlet.2025.218014","DOIUrl":"10.1016/j.canlet.2025.218014","url":null,"abstract":"<div><div>CAR-T cell therapy, as a representative technology in cancer immunotherapy, has demonstrated notable success in the treatment of hematologic malignancies; however, a significant proportion of patients fail to achieve sustained remission. Through the analysis of bone marrow sequencing data prior to CD19 CAR-T cell therapy, we identified cellular adhesion as a pivotal factor influencing clinical outcomes. We developed a model to predict B-ALL treatment efficacy based on the core genes associated with cellular adhesion, which was validated in our clinical cohort. Both in vitro and in vivo experiments revealed that the inhibition or knockout of integrin subunit beta 2 (ITGB2, also known as CD18) in malignant B cells markedly diminished the cytotoxic efficacy of both CD19 and CD20 CAR-T cells against B-lineage tumor cells, with alterations in ITGB2-mediated cytotoxicity linked to the formation of immunological synapses within the tumor microenvironment. Notably, the upregulation of ITGB2 in Nalm6 cells via LPS or Venetoclax significantly augmented the cytotoxic activity of CAR-T cells against Nalm6 cells. Our findings provide a novel predictive model for clinical CD19 CAR-T cell therapy and elucidate a role of the ITGB2 pathway in CAR-T cell-mediated eradication of B-cell malignancies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218014"},"PeriodicalIF":10.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel role of MKRN2 in regulating tumor growth through host microenvironment and macrophage M1 to M2 switch","authors":"Jian-Ge Qiu ,&nbsp;Peng Sang ,&nbsp;Feng-Mei Zhou ,&nbsp;Xiao-Qi Zhang ,&nbsp;Wei Wang ,&nbsp;Ying-Chen Qian ,&nbsp;Ye Zhang ,&nbsp;Lin Wang ,&nbsp;Ling-Zhi Liu ,&nbsp;You-Qiu Xue ,&nbsp;Xin Zhao ,&nbsp;Qiang Shan ,&nbsp;Peng Huang ,&nbsp;Song Guo Zheng ,&nbsp;Bing-Hua Jiang","doi":"10.1016/j.canlet.2025.218035","DOIUrl":"10.1016/j.canlet.2025.218035","url":null,"abstract":"<div><div>The tumor microenvironment (TME) plays a pivotal role in cancer progression, though the molecular regulators governing its immunosuppressive properties remain incompletely characterized. In this study, we identify Makorin-2 (MKRN2) as a novel modulator of TME remodeling through integrated analyses of genetically engineered mouse models and human clinical data. Utilizing MKRN2 knockout mice, we observed significantly accelerated tumor growth compared to wild-type control, which was associated with profound alterations in immune cell composition, especially M2 macrophages. Specifically, MKRN2 deficiency promoted a phenotypic switch in tumor-associated macrophages (TAMs) from anti-tumor M1 to pro-tumorigenic M2 polarization, with quantitative analysis revealing a 3-fold increase in the M2:M1 ratio. Clinical correlation studies demonstrated that MKRN2 expression was frequently downregulated across multiple human malignancies, with low MKRN2 levels strongly correlating with advanced disease stage and reduced patient survival. Mechanistic investigations revealed a dual regulatory mechanism of MKRN2 downregulation: epigenetic silencing through promoter CpG methylation and post-transcriptional suppression by oncogenic miR-582-5p. At the molecular level, MKRN2 functioned as an E3 ubiquitin ligase that directly targeted NF-κB p65 for proteasomal degradation, thereby constraining NF-κB/COX2-mediated inflammatory signaling. Reconstitution experiments demonstrated that MKRN2 overexpression significantly inhibited tumor cell proliferation, migration/invasion and tumor growth. Our findings establish MKRN2 as a critical regulator of immunosuppressive TME formation through coordinated control of macrophage polarization and NF-κB/COX2 signaling, suggesting its potential as both a prognostic biomarker and therapeutic target for cancer immunotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218035"},"PeriodicalIF":10.1,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dendritic cells-derived extracellular vesicles in tumourigenesis: From biological roles to clinical implications","authors":"Qingning Chen ,&nbsp;Weiyuan Wang ,&nbsp;Xiaoyun He ,&nbsp;Chunrong Wang ,&nbsp;Hongbin Guo ,&nbsp;Chunlin Ou","doi":"10.1016/j.canlet.2025.218034","DOIUrl":"10.1016/j.canlet.2025.218034","url":null,"abstract":"<div><div>Dendritic cells (DCs) are the most powerful antigen-presenting cells (APCs) within the tumour microenvironment (TME), where they orchestrate T cell-mediated anti-tumour immunity and can also be reprogrammed to promote the progression of tumours in the TME. Extracellular vesicles (EVs) are very small and they are secreted by cells and wrapped in lipid bilayers that shuttle bioactive cargoes, including proteins, nucleic acids, and metabolites, to recipient cells, thereby influencing the progression of diseases, including cancer. DC-derived EVs (DC-EVs) play pivotal roles in the TME by mediating crosstalk with other immune and stromal cells to modulate inflammatory responses, angiogenesis, cell death, and immune evasion, thereby regulating the development and progression of tumours. In recent years, engineered DC-EVs have been widely used for cancer therapies, including cancer immunotherapy, chemotherapy, photodynamic therapy, and gene therapy. This review summarises the comprehensive roles of DC-EVs in tumourigenesis and the application of engineered DC-EVs in cancer therapy, potentially providing readers with a new theoretical basis for tumour-targeted therapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218034"},"PeriodicalIF":10.1,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategic radiotherapy: evidence before practice","authors":"Irfan Ahmad ,&nbsp;Alexis Andrew Miller ,&nbsp;Preetha Umesh ,&nbsp;Kratika Bhatia ,&nbsp;Kundan Singh Chufal","doi":"10.1016/j.canlet.2025.218031","DOIUrl":"10.1016/j.canlet.2025.218031","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218031"},"PeriodicalIF":10.1,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S100A4 facilitates radiation-induced tumor repopulation by driving polyploid giant cancer cells budding.","authors":"Ruyi Zhao, Yanwei Song, Jianzhu Xie, Haoran Sun, Yanping Gong, Binjie Hu, Jin Cheng, Zheng Deng, Yucui Zhao, Qian Huang","doi":"10.1016/j.canlet.2025.218017","DOIUrl":"10.1016/j.canlet.2025.218017","url":null,"abstract":"<p><p>Radiotherapy, a pivotal treatment for colorectal cancer, is compromised by tumor repopulation, which is characterized by accelerated growth and increased treatment resistance. Although radiation-induced DNA breaks eliminate most cells, a subset of polyploid giant cancer cells (PGCCs) evade death through massive genomic amplification, subsequently undergoing depolyploidization via a viral budding-like process to generate proliferative progeny. Critically, these PGCCs drive tumor repopulation and underpin therapeutic failure. However, the molecular mechanisms that regulate PGCCs budding and the mechanisms by which they bypass the intrinsic safeguards against abnormal proliferation remain unclear. In this study, we dissected the life cycle of PGCCs in colorectal cancer post-radiation. Specifically, we used a combination of single-cell transcriptomics, functional genomics, and longitudinal models to map the dynamic transition from polyploid persistence to PGCCs budding. We reveal that S100A4-a key mediator of PGCCs repopulation-is significantly upregulated in post-radiotherapy PGCCs. S100A4 depletion significantly suppresses budding capacity by blunting viral budding-like proliferation, mechanistically achieved through suppression of IRF3-mediated interferon-I signaling, thereby alleviating ISG15/BST2-mediated suppression of budding. Further mechanistic studies revealed that S100A4 binds the RAGE receptor to facilitate this process. Pharmacological inhibition of RAGE phenocopied S100A4 depletion, impairing PGCCs budding and restoring radiation sensitivity. These results nominate the S100A4-ISG15 axis as a central regulator of radiotherapy resistance and suggest that stratifying patients by S100A4-ISG15 expression or the \"viral budding score\" could predict radiotherapy resistance. Additionally, targeting this axis may offer an opportunity to overcome adaptive persistence in colorectal cancer and possibly other cancer types.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218017"},"PeriodicalIF":10.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear cGAS mediated replication stress and mitotic catastrophe can overcome gemcitabine resistance","authors":"Soon Young Park ,&nbsp;Kang Jin Jeong ,&nbsp;Alfonso Poire ,&nbsp;Bo Young Jeong ,&nbsp;Yuhan Sheng ,&nbsp;Tugba Y. Ozmen ,&nbsp;Matthew J. Rames ,&nbsp;Isabel A. English ,&nbsp;Jonathan R. Brody ,&nbsp;Rosalie C. Sears ,&nbsp;Gordon B. Mills","doi":"10.1016/j.canlet.2025.218009","DOIUrl":"10.1016/j.canlet.2025.218009","url":null,"abstract":"<div><div>Gemcitabine, a ribonucleotide reductase (RNR) inhibitor, is active in pancreatic ductal carcinoma (PDAC) patients, but unfortunately has a limited impact on long term outcomes. Gemcitabine induces nucleotide deficiency, DNA damage including single stranded DNA (ssDNA) and replication stress (RS). DNA damage can activate cyclic GMP-AMP synthase (cGAS), leading to genome instability, micronucleus generation, and immune activation. In model systems, gemcitabine resistance can be overcome by combination treatment with the ataxia telangiectasia and Rad3-related inhibitor (ATRi; AZD6738) that blocks S and G2 checkpoints, although underlying mechanisms remain to be fully elucidated. We show that cells with low basal RS are resistant to gemcitabine, which could be overcome by combination treatment with AZD6738 through elevation of RS, phospho-RPA32 exhaustion, and mitotic catastrophe in PDAC cell models. Gemcitabine induces nuclear cGAS accumulation independent of STING-mediated immune activation. The binding of nuclear cGAS to γH2AX at double strand DNA breaks (DSBs) plays a pivotal role in RS activation and mitotic catastrophe in gemcitabine and AZD6738 treated cells.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218009"},"PeriodicalIF":10.1,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotyping and clinical utility of phagocytic polyploid giant cancer macrophages in blood","authors":"Daniel L. Adams ,&nbsp;Massimo Cristofanilli ,&nbsp;Steven H. Lin ,&nbsp;Raymond C. Bergan ,&nbsp;Thai H. Ho ,&nbsp;Jeffrey R. Marks ,&nbsp;Stuart S. Martin ,&nbsp;Martin J. Edelman ,&nbsp;Saranya Chumsri ,&nbsp;Elizabeth J. Hager ,&nbsp;Cha-Mei Tang ,&nbsp;Susan Tsai ,&nbsp;R. Katherine Alpaugh","doi":"10.1016/j.canlet.2025.218007","DOIUrl":"10.1016/j.canlet.2025.218007","url":null,"abstract":"<div><div>Historically, polyploid giant cancer cells (PGCCs) within tumors have been ignored as superfluous inflammatory refuse with no intrinsic clinical or biological relevance. However recently, multiple studies have described the existence PGCCs in solid tumor masses that appear to correlate with tumor progression, and can also appear in blood circulation as cancer associated macrophage like cells (CAMLs). In an effort to understand the clinical and biological role of CAMLs (i.e. PGCCs in circulation), we initiated a multi-institutional 2 year prospective study of patients in an array of solid tumors (n = 293; breast, prostate, esophageal, lung, pancreas, or renal cell carcinoma), finding that CAMLs significantly correlate with progression and disease spread. We further evaluated the biological traits of CAMLs isolated from patients, identifying abnormal cellular characteristics including self-renewing proliferation, proangiogenic stem cell biomarkers, with overlapping myeloid, epithelial and endothelial characteristics. Here we report that CAMLs are highly indicative of disease progression in all cancer stages and appear to mimic phenotypes associated with metastatic niche initiation (i.e. traversing blood as self-renewing multipotent myeloid cells).</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 218007"},"PeriodicalIF":10.1,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer stem cell mechanisms and targeted therapeutic strategies in head and neck squamous cell carcinoma","authors":"Nagarajan Maharajan ,&nbsp;Daniel S. Benyamien-Roufaeil ,&nbsp;Robert A. Brown ,&nbsp;Benjamin A. Portney ,&nbsp;Aditi Banerjee ,&nbsp;Michal Zalzman","doi":"10.1016/j.canlet.2025.218015","DOIUrl":"10.1016/j.canlet.2025.218015","url":null,"abstract":"<div><div>Head and neck squamous cell carcinoma (HNSCC) originates in the epithelial lining of the oral cavity, pharynx, and larynx, with over 830,000 new cases diagnosed globally in 2020, making it the seventh most prevalent cancer. Despite treatment advances, high-grade HNSCCs remain associated with poor outcomes and a high risk of recurrence.</div><div>Although Cancer Stem Cells (CSCs) are rare in HNSCC tumors, they are key drivers of tumor relapses, as they evade apoptosis and survive current therapies through enhanced DNA repair and quiescence. This review integrates recent discoveries into a unified framework for understanding CSC mechanisms. It examines the role of pluripotency factors, biomarkers, replicative immortalization, metabolic reprogramming, redox regulation, and immune evasion in shaping CSC behavior and survival under treatment stress. Non-coding RNAs are also discussed as modulators of gene expression via epigenetic regulation in CSCs. Importantly, it highlights how these adaptive mechanisms intersect as potential vulnerabilities that could be exploited to eliminate CSCs through targeting multiple pathways.</div><div>Finally, it provides recent and emerging precision therapeutics, including CAR-T cells, immune checkpoint inhibitors, metabolic and redox-targeting agents, and epigenetic modulators currently in preclinical and clinical trials applications designed to eliminate CSCs and improve patient outcomes in HNSCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"634 ","pages":"Article 218015"},"PeriodicalIF":10.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subtype-specific HER3 enrichment in basal-like breast cancer is regulated via the GATA2/GATA3–FOXA1 axis","authors":"Congcong Tan ,&nbsp;Hui Lyu ,&nbsp;Sanbao Ruan ,&nbsp;Yakun Wu ,&nbsp;Margaret E. Larsen ,&nbsp;Shou-Ching Tang ,&nbsp;Bolin Liu","doi":"10.1016/j.canlet.2025.218001","DOIUrl":"10.1016/j.canlet.2025.218001","url":null,"abstract":"<div><div>Basal-like breast cancer (BLBC) is a major subtype of triple-negative breast cancer (TNBC), characterized by aggressive behavior, limited treatment options, and poor prognosis. While HER3 overexpression is frequently observed in TNBC and associated with poor outcomes, its subtype-specific expression and therapeutic potential remain unclear. Here, we demonstrated that HER3 signaling is selectively hyperactivated in BLBC compared to claudin-low breast cancer (CLBC) using transcriptomic profiling. Histone deacetylase inhibitors (HDACi), Romidepsin and Panobinostat, exerted potent antitumor effects on BLBC by selectively downregulating HER3 expression. HER3 levels were positively correlated with FOXA1, a key transcriptional activator. Mechanistically, we identified GATA2 and GATA3 as upstream regulators of both FOXA1 and HER3. HDACi disrupted the GATA2/GATA3-FOXA1-HER3 axis by suppressing GATA2 and GATA3 expressions. Specific knockdown of FOXA1, GATA2, or GATA3 enhanced HDACi-induced apoptosis and growth inhibition, while ectopic expression of any of these transcription factors restored HER3 levels and mitigated the effects of HDACi. Chromatin immunoprecipitation assays confirmed direct binding of GATA2 and GATA3 to the FOXA1 promoter. In BLBC xenograft models, GATA2 overexpression markedly attenuated the antitumor activity of Panobinostat and substantially reversed its effects on FOXA1 and HER3 expression, tumor growth, and apoptosis. Clinically, high expression of GATA2, GATA3, FOXA1, or HER3 is significantly associated with poor outcomes in BLBC patients. Collectively, our studies established a previously unrecognized GATA2/GATA3-FOXA1-HER3 axis as a key regulatory network in BLBC progression. We provide strong experimental data supporting that the two HDACi, Romidepsin and Panobinostat may be repurposed as effective therapeutic agents for BLBC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218001"},"PeriodicalIF":10.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyploid giant cancer cells: Unveiling a latent axis of resistance and tumor evolution in HER2-targeted therapy","authors":"Madhan Krishnan,&nbsp;Shyamaladevi Babu","doi":"10.1016/j.canlet.2025.217998","DOIUrl":"10.1016/j.canlet.2025.217998","url":null,"abstract":"<div><div>Recent findings by Yazdi et al. in <em>Cancer Letters</em> present a mechanistic breakthrough in understanding resistance to HER2-targeting antibody-drug conjugates (ADCs). Their identification of drug-persistent polyploid giant cancer cells (PGCCs) as active participants in resistance redefines our understanding of intratumoral plasticity and therapeutic evasion. Far from being senescent relics, PGCCs function as epigenetically plastic reservoirs of tumor regeneration, capable of entering dormancy and re-seeding therapy-resistant clones. This commentary explores the mechanistic, evolutionary, and clinical implications of this phenomenon, urging a shift toward integrated therapeutic designs that disrupt the adaptive survival circuitry of PGCCs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217998"},"PeriodicalIF":10.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}