Cancer letters最新文献

{"title":"PAF signaling axis functions as biomarker or target for esophageal squamous cell carcinoma diagnosis or treatment","authors":"Yanmeng Zhu ,&nbsp;Fenglong Wang ,&nbsp;Yuheng Zhu ,&nbsp;Jingyuan Pang ,&nbsp;Qingnan Wu ,&nbsp;Yan Wang ,&nbsp;Qimin Zhan ,&nbsp;Jie Chen","doi":"10.1016/j.canlet.2025.217937","DOIUrl":"10.1016/j.canlet.2025.217937","url":null,"abstract":"<div><div>Dysregulated lipid metabolism is one of the most extinguishing metabolic hallmarks, and contributes to tumorigenesis and tumor malignancy. Platelet-activating factor (PAF), the lipid metabolite, serves as an inflammatory stimulator to induce the aggressive progression of esophageal squamous cell carcinoma (ESCC). However, whether PAF and its downstream signaling axis can function as biomarker or therapeutic target for ESCC diagnosis or treatment are still unclear. In this study, we found that plasma PAF level can reflect the lymph node (LN) metastasis status of ESCC patients. Importantly, results from Olink assay showed that several cytokines in plasma, such as interleukin-8 (IL-8), C-X-C motif chemokine ligand 1 (CXCL1), CXCL5, or CXCL11 were positively related with the LN metastasis status of ESCC patients, the expression of these cytokines was also tightly correlated with that of PAF in the plasma from LN metastatic ESCC patients. Results from RNA-seq in ESCC cell lines and immunohistochemistry (IHC) in clinical ESCC samples showed that PAF signaling effectively induced the expression of these cytokines and some tumor-promoting molecules in ESCC. Therapeutically, ginkgetin, a natural biflavonoid isolated from <em>Ginkgo biloba</em> L, inhibited the PAF-mediated Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) activation, the expression of downstream inflammatory cytokines, glycolysis- and tumor-progression related molecules, and the malignancy of tumor cells both <em>in vitro</em> and <em>in vivo</em>, but generated barely significant toxicity towards the normal tissues of xenografted animals. Present study has illustrated that PAF can serve as biomarker for evaluation of ESCC LN metastasis, and ginkgetin could exert excellent antitumor effect on ESCC cells via suppressing PAF axis-controlled signaling pathways.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217937"},"PeriodicalIF":9.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665512","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":"SMARCA1-NPFF axis inhibits colorectal cancer metastasis by blocking epithelial-mesenchymal transition and macrophage-dependent immune reprogramming","authors":"Haojia Wang ,&nbsp;Shuya Du ,&nbsp;Songtao Ji ,&nbsp;Ge Miao ,&nbsp;Jianing Yu ,&nbsp;Mingzhen Zhou ,&nbsp;Yuanci Zhang ,&nbsp;Xuemei Li ,&nbsp;Wanqi Ma ,&nbsp;Ang Li ,&nbsp;Xiaohua Yang ,&nbsp;Yun Zhou ,&nbsp;Junshu Wang ,&nbsp;Xiaoyu Huang ,&nbsp;Xin Wang ,&nbsp;Zhenxiong Liu ,&nbsp;Xue Bai ,&nbsp;Yuanyuan Lu ,&nbsp;Xiaodi Zhao","doi":"10.1016/j.canlet.2025.217933","DOIUrl":"10.1016/j.canlet.2025.217933","url":null,"abstract":"<div><div>Dysregulation of chromatin remodeling represents an essential driving factor for cancer development and progression. Our previous work demonstrated that increased inclusion of exon 13 during alternative splicing functionally inactivates SMARCA1, the catalytic subunit of the ISWI chromatin remodeling complex, to promote colorectal cancer (CRC) metastasis, but the precise mechanism underlying SMARCA1-mediated metastasis suppression remains elusive. In this study, through ATAC-seq and RNA-seq analyses, we established an inverse correlation between SMARCA1 activity and neuropeptide FF (NPFF) transcriptional output in CRC cell lines and clinical specimens. Ectopic NPFF expression significantly enhanced CRC cell migration, invasion and metastatic potential, effectively counteracting the antimetastatic function mediated by SMARCA1. Mechanistically, SMARCA1 attenuates NPFF transcription by impairing the DNA-binding capacity of the ETS-family transcription factor SPIB at the NPFF promoter. SMARCA1-deficient CRC cells exhibit increased NPFF secretion, which drives epithelial‒mesenchymal transition (EMT) through autocrine activation of the JAK2/STAT5 signaling axis, subsequently increasing the expression of EMT-related transcription factors. Notably, the oncogenic activity of NPFF was also dependent on immune microenvironment modulation, as NPFF orchestrated the polarization of tumor-associated macrophages toward the M2-like phenotype while upregulating protumorigenic genes, which encode growth factors, chemokines, and matrix metalloproteinases, in macrophages. Our study reveals the SMARCA1–NPFF axis as a dual regulator of metastatic progression and immune microenvironment reprogramming in CRC, identifying the NPFF as a novel therapeutic vulnerability factor for the management of metastatic CRC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217933"},"PeriodicalIF":9.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673977","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":"Corrigendum to \"Sublethal heat treatment of hepatocellular carcinoma promotes intrahepatic metastasis and stemness in a VEGFR1-dependent manner\" [Cancer Lett. (460), 28 September 2019, Pages 29-40].","authors":"Li Tan, Shuling Chen, Guangyan Wei, Yue Li, Junbin Liao, Huilin Jin, Ying Zou, Manling Huang, Zhenwei Peng, Yu Guo, Sui Peng, Lixia Xu, Ming Kuang","doi":"10.1016/j.canlet.2025.217893","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217893","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217893"},"PeriodicalIF":9.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667236","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 associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer","authors":"Jiahua He ,&nbsp;Weihao Li ,&nbsp;Song Wang ,&nbsp;Jin Lan ,&nbsp;Xuanlin Hong ,&nbsp;Leen Liao ,&nbsp;Da Kang ,&nbsp;Weifeng Wang ,&nbsp;Ruowei Wang ,&nbsp;Weili Zhang ,&nbsp;Long Yu ,&nbsp;Qingjian Ou ,&nbsp;Yujing Fang ,&nbsp;Xiaojun Wu ,&nbsp;Junzhong Lin ,&nbsp;Peirong Ding ,&nbsp;Chi Zhou ,&nbsp;Zhizhong Pan ,&nbsp;Jianhong Peng","doi":"10.1016/j.canlet.2025.217917","DOIUrl":"10.1016/j.canlet.2025.217917","url":null,"abstract":"<div><div>Oxaliplatin is widely used in chemotherapy for patients with advanced colorectal cancer (CRC). However, frequent drug resistance limits its therapeutic efficacy in patients. Here, we found that a subset of cancer associated fibroblasts (CAFs) with activated glycolysis induced CRC resistance to oxaliplatin. Lactate derived from CAFs promoted the transcription of ANTXR1 through histone lactylation and induced ANTXR1 lactylation at lysine 453 residue. The increased expression of ANTXR1 and ANTXR1 K453la in CRC cells was correlated with oxaliplatin resistance in CRC cells and the poor prognosis of CRC patients. Mechanistically, lactylation promoted ANTXR1 stability and activated the RhoC/ROCK1/SMAD5 signal pathway, subsequently contributed to CRC stemness and oxaliplatin resistance. Genetic or pharmacologic inhibition of the lactate shuttle between CAFs and cancer cells improved chemotherapy efficiency in vitro and in cell/patient-derived xenograft models. These findings contribute to a better understanding of oxaliplatin resistance and indicates that inhibition of tumor-stromal interactions might be an attractive strategy for enhancing the efficacy of oxaliplatin.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217917"},"PeriodicalIF":9.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667234","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":"MYB and HIF1α crosstalk drives hypoxia-induced transcriptional reprogramming and adaptive signaling alterations in pancreatic cancer","authors":"Shashi Anand ,&nbsp;Kunwar Somesh Vikramdeo ,&nbsp;Mohammad Aslam Khan ,&nbsp;Seema Singh ,&nbsp;Ajay Pratap Singh","doi":"10.1016/j.canlet.2025.217916","DOIUrl":"10.1016/j.canlet.2025.217916","url":null,"abstract":"<div><div>Pancreatic cancer is an aggressive malignancy, characterized by extensive desmoplasia and a hypoxic tumor microenvironment that contributes to therapy resistance. MYB, a proto-oncogene encoding a transcription factor, plays a crucial role in pancreatic tumor growth and metastasis. Recently, we also revealed a role of MYB in hypoxic survival of pancreatic cancer cells by promoting metabolic reprogramming through interaction with HIF1α, modulating its expression and binding to glycolytic gene promoters. In this study, we investigated how hypoxia influences the genome-wide occupancy of MYB using chromatin immunoprecipitation sequencing (ChIP-seq), and whether this effect is modulated by its interaction with HIF1α. In addition, we examined the genomic distribution of HIF1α in presence and absence of MYB and the impact of their crosstalk on the transcriptional output and associated signaling alterations by RNA sequencing (RNA-seq) and pathway analyses. Our findings show that hypoxia induces significant changes in the genomic distribution of MYB, which is partly dependent on HIF1α. We also demonstrate a significant impact of MYB on HIF1α genomic binding, identifying a subset of hypoxia-induced genes, co-regulated by MYB and HIF1α. These genes are involved in key metabolic and oncogenic signaling pathways critical for hypoxic adaptation. Together, these findings highlight the functional significance of reciprocal crosstalk between MYB and HIF1α, providing novel mechanistic insights into pancreatic cancer pathobiology.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217916"},"PeriodicalIF":9.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662116","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":"CircRHOBTB3 suppresses MAOA by promoting cytoplasmic retention of NONO to inhibit prostate cancer proliferation and metastasis","authors":"Yufeng Song ,&nbsp;Cong Zhang ,&nbsp;Dingchang Shao ,&nbsp;Xiaoming Song ,&nbsp;Dunsheng Han ,&nbsp;Jinke Liu ,&nbsp;Xuefeng Xie ,&nbsp;Mingkun Zhao ,&nbsp;Ziwei Wei ,&nbsp;Guoxiong Xu ,&nbsp;Shiyu Wang ,&nbsp;Gang Chen","doi":"10.1016/j.canlet.2025.217910","DOIUrl":"10.1016/j.canlet.2025.217910","url":null,"abstract":"<div><div>Prostate cancer (PCa) is one of the most prevalent malignant tumors affecting men. Metastatic PCa is generally considered incurable. Circular RNA (circRNA) is a distinct class of RNA implicated in the tumorigenesis and development of various cancers, including PCa. However, the specific role and underlying molecular mechanisms of circRNA in PCa remain poorly understood. This study identifies hsa_circ_0007444, generated from the back-splicing of exons 6–7 of the <em>Rho Related BTB Domain Containing 3 (RHOBTB3)</em> gene and named as circRHOBTB3, as being downregulated in PCa. Low expression of circRHOBTB3 correlates with elevated pathological T stage, clinical M stage, and D'Amico grade. Functionally, circRHOBTB3 inhibits PCa cell proliferation and metastasis both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, circRHOBTB3 binds to the non-POU domain-containing octamer-binding protein (NONO), a transcription factor for monoamine oxidase A (MAOA), sequestering NONO in the cytoplasm and preventing it from upregulating MAOA transcription. This results in decreased MAOA expression, ultimately suppressing PCa cell proliferation and metastasis. Furthermore, the RNA binding protein serine/arginine-rich splicing factor 9 specifically interacts with AluSx and AluJb, inhibiting circRHOBTB3 circularization. In conclusion, this study identifies circRHOBTB3 as a tumor suppressor with potential to be a promising clinical biomarker and therapeutic target for metastatic PCa.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217910"},"PeriodicalIF":9.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667235","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":"Extracellular vesicle proteomics identify neutrophils as potential mediators of bladder radiotoxicity in prostate cancer","authors":"Ryan D. Molony ,&nbsp;Md. Mahmudul Hasan Akash ,&nbsp;Sarah L. Kerns ,&nbsp;Brian Marples ,&nbsp;Angela Groves ,&nbsp;Chrysolite Dhinakaran ,&nbsp;Lauren E. Nichols ,&nbsp;Yi-Fen Lee","doi":"10.1016/j.canlet.2025.217931","DOIUrl":"10.1016/j.canlet.2025.217931","url":null,"abstract":"<div><div>Radiation cystitis (RC) is a chronic debilitating complication that impacts 8–11% of patients with prostate cancer (PCa) after radiotherapy (RT), reducing quality of life and contributing to decisional regret. Reliable treatments to alleviate the symptoms of RC, which include gross hematuria, are lacking, emphasizing the need for predictive biomarkers of RC to support therapeutic decision-making. We performed paired liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses of the protein cargos in extracellular vesicles (EVs) from the urine of PCa patients who did or did not develop late hematuria following standard-of-care RT. We identified a 60-protein RT-toxicity-associated signature enriched for neutrophil-related proteins, several of which, including myeloperoxidase (MPO), were elevated even before RT in urinary EVs from patients who later developed hematuria. In healthy mice, focal bladder irradiation was sufficient to elicit a localized neutrophil response in the bladder, while <em>in vitro</em> co-culture assays confirmed the ability of neutrophils to induce urothelial cell killing following irradiation, a process that was abrogated by the CRISPR/Cas9-mediated deletion of MPO or the EV release regulator Rab27α. Serum EV proteomics from these same patients further validated the neutrophil-related RC risk signature, and enzyme-linked immunosorbent assays (ELISAs) gave additional support to <span>MPO</span> and other neutrophil-related proteins, including defensin α3 (DEFA3) and neutrophil elastase (ELANE), as possible predictors of late hematuria development following RT in a larger cohort of PCa patients. Neutrophils may thus at least partially mediate bladder radiotoxicity in PCa patients. The multi-protein risk signatures and specific biomarkers identified herein may provide an opportunity for risk stratification in PCa.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217931"},"PeriodicalIF":9.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667237","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":"Lectin-affinity glycosylation pattern analysis of plasma extracellular vesicles: An all-in-one clinical assessment for gastric cancer diagnosis and treatment","authors":"Fanqin Bu ,&nbsp;Guangyu Ding ,&nbsp;Lin Yang ,&nbsp;Yunzi Wu ,&nbsp;Chenjie Xu ,&nbsp;Liyi Bai ,&nbsp;Ruixuan Chen ,&nbsp;Lan Sun ,&nbsp;Xintao Qiu ,&nbsp;Pengfei Yu ,&nbsp;Jingxin Meng ,&nbsp;Meng Fan ,&nbsp;Yibin Xie ,&nbsp;Li Min","doi":"10.1016/j.canlet.2025.217929","DOIUrl":"10.1016/j.canlet.2025.217929","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) exhibit extensive glycosylation modifications, which are promising biomarkers for gastric cancer (GC). However, EV glycomics and the potential application of EV glycosylation patterns in liquid biopsy remain largely unexplored. This study aims to elucidate the heterogeneity of EV glycosylation in the initiation and progression of GC and to identify specific EV glycosylation markers for clinical assessment. We developed a novel platform for analyzing EV glycosylation patterns via a lectin microarray for EV glycosyl-lectin affinity assessment and antibody-based EV subgroup annotation. The lectin-affinity glycosylation pattern (LAGP) of plasma EVs was profiled across 84 plasma samples, encompassing cases from different stages of GC, benign gastric diseases (BD), and non-disease control (NC). We uncovered heterogeneous LAGPs in different patient groups, identified group-specific LAGPs, and employed them in modeling with the assistance of machine learning algorithms. The linear discriminant analysis (LDA) distinguished advanced GC, early GC, BD, and NC samples with 100 % accuracy. A LAGP-based nomogram was established to predict survival outcomes within 200, 300, and 500 days, achieving area under the ROC curve (AUC) of 0.793, 0.914, and 0.988, respectively. We also tested LAGP for immunotherapeutic response prediction, obtaining AUC values of 0.866–1.000 with various supervised machine-learning algorithms. In conclusion, we represented heterogeneous LAGPs during the occurrence and progression of GC and developed an all-in-one clinical assessment tool for screening cancer patients, monitoring survival outcomes, and predicting immunotherapeutic responses.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217929"},"PeriodicalIF":9.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665513","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":"Multimodal radiopathomics signature for prediction of response to immunotherapy-based combination therapy in gastric cancer using interpretable machine learning","authors":"Weicai Huang ,&nbsp;Xiaoyan Wang ,&nbsp;Rou Zhong ,&nbsp;Zhe Li ,&nbsp;Kangneng Zhou ,&nbsp;Qing Lyu ,&nbsp;James Edward Han ,&nbsp;Tao Chen ,&nbsp;Md Tauhidul Islam ,&nbsp;Qingyu Yuan ,&nbsp;M. Usman Ahmad ,&nbsp;Sitong Chen ,&nbsp;Chuanli Chen ,&nbsp;Jiongqiang Huang ,&nbsp;Jingjing Xie ,&nbsp;Yunhao Shen ,&nbsp;Wenjun Xiong ,&nbsp;Lin Shen ,&nbsp;Yikai Xu ,&nbsp;Fan Yang ,&nbsp;Yuming Jiang","doi":"10.1016/j.canlet.2025.217930","DOIUrl":"10.1016/j.canlet.2025.217930","url":null,"abstract":"<div><div>Immunotherapy has become a cornerstone in the treatment of advanced gastric cancer (GC). However, identifying reliable predictive biomarkers remains a considerable challenge. This study demonstrates the potential of integrating multimodal baseline data, including computed tomography scan images and digital H&amp;E-stained pathology images, with biological interpretation to predict the response to immunotherapy-based combination therapy using a multicenter cohort of 298 GC patients. By employing seven machine learning approaches, we developed a radiopathomics signature (RPS) to predict treatment response and stratify prognostic risk in GC. The RPS demonstrated area under the receiver-operating-characteristic curves (AUCs) of 0.978 (95 % CI, 0.950–1.000), 0.863 (95 % CI, 0.744–0.982), and 0.822 (95 % CI, 0.668–0.975) in the training, internal validation, and external validation cohorts, respectively, outperforming conventional biomarkers such as CPS, MSI-H, EBV, and HER-2. Kaplan-Meier analysis revealed significant differences of survival between high- and low-risk groups, especially in advanced-stage and non-surgical patients. Additionally, genetic analyses revealed that the RPS correlates with enhanced immune regulation pathways and increased infiltration of memory B cells. The interpretable RPS provides accurate predictions for treatment response and prognosis in GC and holds potential for guiding more precise, patient-specific treatment strategies while offering insights into immune-related mechanisms.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217930"},"PeriodicalIF":9.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144655050","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":"Neuroimmunology-driven CAR T-cell therapeutics for gliomas: translational challenges and clinical trial paradigm innovation","authors":"Zhipeng Li ,&nbsp;Fan Yang ,&nbsp;Siyuan Lu ,&nbsp;Xinhao Wu ,&nbsp;Shenglong Li ,&nbsp;Minghao Wang","doi":"10.1016/j.canlet.2025.217928","DOIUrl":"10.1016/j.canlet.2025.217928","url":null,"abstract":"<div><div>Glioma, a category of the most lethal primary brain tumors, remains incurable despite multimodal therapy combining maximal resection, radiation, and temozolomide. These interventions invariably fail due to residual invasive cells, molecular heterogeneity, and an immunosuppressive tumor microenvironment (TME) reinforced by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). The blood-brain barrier (BBB) further limits therapeutic access, while antigen escape and T-cell exclusion mechanisms drive relapse. Chimeric antigen receptor (CAR) T-cell therapy, transformative in relapsed B-cell malignancies with sustained remission rates, faces formidable yet surmountable barriers in solid tumors. Recent advances in CAR-T trials targeting glioma-associated antigens demonstrate partial intracranial activity, albeit with transient efficacy, underscoring the need for neuroimmunology-informed engineering. This review critically evaluates CAR-T strategies countering glioma-specific resistance: bispecific antigen targeting combats tumor plasticity, cytokine-armored designs neutralize immunosuppression, and innovative delivery routes enhance CNS bioavailability. Early clinical outcomes reveal critical divergence points from hematologic success, including antigen loss due to glioma's evolutionary capacity and T-cell exhaustion within hypoxic niches. Emerging solutions integrate CRISPR-edited allogeneic platforms with combinatorial immunomodulation (e.g., myeloid-targeting) and delivery innovations to address these barriers. We further dissect translational priorities including neurotoxicity mitigation and scalable manufacturing for infiltrative glioma phenotypes. By converging advances in immune-engineering, TME remodeling, and biomarker-driven trial designs, this work proposes a roadmap to achieve durable CAR-T efficacy in GBM. The synthesis bridges mechanistic insights into glioma-immune interactions with clinical translation strategies, aiming to transcend current limitations of transient cytoreduction and establish CAR-T therapy as a cornerstone of neuro-oncologic practice.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217928"},"PeriodicalIF":9.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648668","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}