Cancer letters最新文献

{"title":"The IRE1α/XBP1-mediated upregulation of LMTK2 attenuates endoplasmic reticulum stress by enhancing autophagic activity","authors":"Jie Lun ,&nbsp;Xiuxiu Li ,&nbsp;Rongjing Zhang ,&nbsp;Chenyao Wang ,&nbsp;Yanqing Qin ,&nbsp;Yu Li ,&nbsp;Zhiqiang Ling ,&nbsp;Mengchao Yu ,&nbsp;Jing Fang","doi":"10.1016/j.canlet.2025.217993","DOIUrl":"10.1016/j.canlet.2025.217993","url":null,"abstract":"<div><div>Lemur tyrosine kinase 2 (LMTK2), a transmembrane protein, is not well characterized regarding its biological functions and regulatory mechanisms. Herein, we demonstrate that LMTK2 functions as an ER stress-induced protein that plays a crucial role in regulating ER stress and safeguarding cells through autophagy pathway. Our study reveals that ER stressors thapsigargin (Tg) and tunicamycin (Tm) upregulate LMTK2 expression via IRE1α-XBP1s signaling in colon cancer cells. LMTK2 overexpression ameliorates Tm-induced ER stress, whereas its knockdown did the opposite. LMTK2 depletion impairs Tg-induced autophagy. The protective effect of LMTK2 against ER stress is autophagy-dependent, evidenced by LMTK2's inability to mitigate ER stress when autophagy was pharmacologically inhibited. These findings establish that LMTK2-mediated ER stress alleviation is dependent on its facilitation of autophagic processes. Importantly, LMTK2 demonstrates a protective role against ER stress-induced apoptosis that is abolished upon autophagy inhibition. Xenograft experiments reveal that LMTK2-deficient tumors exhibited increased apoptotic cells, elevated GRP78 expression, and reduced LC3 levels. Analyses of clinical colon cancer specimens indicate that LMTK2 expression levels correlate with tumor grades and poor patients' survival. These results provide compelling evidence that LMTK2 functions as an ER stress-responsive protein that maintains ER homeostasis and promotes cell survival via autophagy-dependent mechanisms.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 217993"},"PeriodicalIF":10.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896578","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 “Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma” [Cancer Lett. (2017) 410, 20–31]","authors":"Chang Liu ,&nbsp;Yi-Fan Ren ,&nbsp;Jian Dong ,&nbsp;Meng-Yun Ke ,&nbsp;Feng Ma ,&nbsp;Satdarshan P.S. Monga ,&nbsp;Rongqian Wu ,&nbsp;Yi Lv ,&nbsp;Xu-Feng Zhang","doi":"10.1016/j.canlet.2025.217982","DOIUrl":"10.1016/j.canlet.2025.217982","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217982"},"PeriodicalIF":10.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882265","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":"Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress","authors":"Akash Sabarwal ,&nbsp;Marc Machaalani ,&nbsp;Laxminarayan Rawat ,&nbsp;Johannes Wedel ,&nbsp;Saba Tabasum ,&nbsp;Yuzuru Sasamoto ,&nbsp;Florian Buerger ,&nbsp;Josie Ascione ,&nbsp;Marc Eid ,&nbsp;Karl Semaan ,&nbsp;Eddy Saad ,&nbsp;Yifan Yang ,&nbsp;Dongwon Lee ,&nbsp;F. Stephen Hodi ,&nbsp;Matthew L. Freedman ,&nbsp;Gwo-Shu Mary Lee ,&nbsp;Murugabaskar Balan ,&nbsp;Toni K. Choueiri ,&nbsp;Soumitro Pal","doi":"10.1016/j.canlet.2025.217984","DOIUrl":"10.1016/j.canlet.2025.217984","url":null,"abstract":"<div><div>The mechanisms underlying therapeutic resistance to c-Met/receptor tyrosine kinase (RTK) inhibitors in renal cancer remain unexplored. In renal cell carcinoma (RCC) cells, both AXL and c-Met are highly upregulated. Notably, we found that prolonged treatment with the c-Met/RTK inhibitor, cabozantinib (Cabo), a standard treatment for advanced-stage RCC, markedly increased total c-Met levels and promoted renal cancer cell proliferation. This effect was confirmed not only <em>in vitro</em> but also in murine models and renal tumor tissues from Cabo-treated patients. At lower concentrations (1 nM and 10 nM), Cabo treatment failed to inhibit HGF (c-Met ligand)-induced c-Met phosphorylation. Instead, it further enhanced receptor phosphorylation and downstream signaling events for tumor growth. Additionally, Cabo treatment induced AXL-c-Met association and disrupted the physiological degradation of c-Met. However, inhibition or knockout of AXL could significantly overcome therapeutic resistance to c-Met inhibitor(s). It triggered apoptotic cell death through increased oxidative stress and inhibition of the redox-sensitive transcription factor, Nrf2 and its effector molecule, heme oxygenase-1 (HO-1). We also generated Cabo-resistant RCC cells and observed a marked upregulation of both c-Met and AXL in these cells. Epigenomic profiling revealed significant differences between Cabo-resistant and Cabo-sensitive RCC cells. Importantly, inhibition of AXL either using a potent inhibitor, TP-0903, or through genetic silencing resensitized the resistant cells to Cabo-induced cell death. Together, our findings highlight AXL as a key driver of therapeutic resistance to c-Met inhibitors. A combination therapy targeting both c-Met and AXL in renal cancer could be a promising strategy to overcome the acquired resistance to c-Met inhibitors through increased oxidative stress.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 217984"},"PeriodicalIF":10.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882266","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 “Survival of the fittest: Cancer challenges T cell metabolism” [Cancer Lett. 412 (2018) 216–223]","authors":"Davide G. Franchina ,&nbsp;Feng Q. HeFeng ,&nbsp;Dirk Brenner","doi":"10.1016/j.canlet.2025.217974","DOIUrl":"10.1016/j.canlet.2025.217974","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217974"},"PeriodicalIF":10.1,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871630","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":"Inhibition of CPT1A activates the cGAS/STING pathway to enhance neutrophil-mediated tumor abrogation in triple-negative breast cancer","authors":"Chenglong Li ,&nbsp;Tingfang Gao ,&nbsp;Qiuling Zhao ,&nbsp;Zhi Li ,&nbsp;Zhidong Wang ,&nbsp;Shuaishuai Ding ,&nbsp;Mengsi Zhang ,&nbsp;Yan Qin ,&nbsp;Xinwen Xue ,&nbsp;Xiao Zhang ,&nbsp;Gan Tian ,&nbsp;Xiu-wu Bian ,&nbsp;Yi Yang","doi":"10.1016/j.canlet.2025.217991","DOIUrl":"10.1016/j.canlet.2025.217991","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) remains a challenging malignancy to treat, underscoring the urgent need to explore novel and effective therapeutic targets. In this study, we found that carnitine palmitoyltransferase 1A (CPT1A), the central and rate-limiting enzyme for fatty acid oxidation (FAO) in lipid metabolism, is significantly correlates with poor survival outcomes in TNBC patients and is highly expressed in TNBC patient samples. Inhibition of CPT1A greatly suppresses TNBC tumor growth. Mechanistically, we discovered that beyond disruption of the canonical metabolic functions for tumor cell survival, <em>CPT1A</em> depletion markedly triggers cGAS/STING activation due to lipid accumulation-induced elevation of mitochondrial reactive oxygen species (ROS), leading to mitochondrial damage and subsequent mtDNA cytosolic release, which ultimately promotes neutrophil intratumoral infiltration and acquisition of a tumor-killing phenotype, thereby effectively inhibiting tumor growth. Our current findings suggest that inhibition of CPT1A potently activates the cGAS/STING pathway, significantly enhancing the engagement of neutrophils for tumor abrogation.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 217991"},"PeriodicalIF":10.1,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871631","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":"Single-cell profiling identifies biomarkers for immunochemotherapy in esophageal squamous cell carcinoma","authors":"Changchun Wang ,&nbsp;Guanglei Xie ,&nbsp;Mingming Jia ,&nbsp;Liwei Xu ,&nbsp;Rongwei Ruan ,&nbsp;Chang Yu ,&nbsp;Xianjin Kan ,&nbsp;Yiding Feng ,&nbsp;Jianghua Ying ,&nbsp;Yueyu Huang ,&nbsp;Weitian Wei ,&nbsp;Qian Chen ,&nbsp;Youhua Jiang ,&nbsp;Yuqian Hu ,&nbsp;Lei Cai ,&nbsp;Hongyang Lu ,&nbsp;Ge Song ,&nbsp;Lei Shi ,&nbsp;Weimin Mao ,&nbsp;Jian Hu ,&nbsp;Xi Wang","doi":"10.1016/j.canlet.2025.217988","DOIUrl":"10.1016/j.canlet.2025.217988","url":null,"abstract":"<div><div>Esophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with limited therapeutic options. While immune checkpoint blockade (ICB) combined with chemotherapy has improved outcomes, resistance mechanisms and predictive biomarkers are poorly understood. This study aims to characterize the dynamic changes in the tumor microenvironment (TME) during ICB treatment and identify cell populations and molecular programs associated with therapeutic response. We performed scRNA-seq, scTCR-seq, and scBCR-seq on 174,223 cells from 27 samples (22 paired pre- and post-treatment tumors, 2 unpaired tumors, and 3 adjacent tissues) treated with neoadjuvant camrelizumab (<em>anti</em>-PD-1) plus chemotherapy. ICB treatment reshaped the TME, increasing <em>CXCL12</em>+ inflammatory fibroblasts and <em>CD1C</em>+ dendritic cells while reducing neutrophils and plasma cells. Resistance-associated features included malignant cells with partial epithelial-mesenchymal transition (p-EMT) programs, <em>DES</em>+ myofibroblasts, <em>FOLR2</em>+ macrophages, and clonally expanded CD8+ T cells exhibiting terminal exhaustion. On the other hand, responders harbored more <em>RGS13</em>+ germinal center B cells. This study reveals the cellular and molecular reprogramming of the TME during ICB therapy and identifies biomarkers of response and resistance in ESCC. These insights could potentially guide patient stratification and the development of targeted strategies to overcome ICB resistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 217988"},"PeriodicalIF":10.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862086","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":"Epithelial-YAP activation promotes wound-induced SCC in a TLR3-dependent microenvironment","authors":"Yingchao Xue ,&nbsp;Ru Dai ,&nbsp;Elizabeth Winnicki ,&nbsp;Amy van Ee ,&nbsp;Charles Kirby ,&nbsp;Chaewon Lee ,&nbsp;Sashank K. Reddy ,&nbsp;Luis A. Garza","doi":"10.1016/j.canlet.2025.217985","DOIUrl":"10.1016/j.canlet.2025.217985","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217985"},"PeriodicalIF":10.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858044","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":"Comparison of Food and Drug Administration expedited approvals and guideline updates: A case study of immune checkpoint inhibitors in colon cancer care","authors":"Danea M. Horn ,&nbsp;Kathryn A. Phillips ,&nbsp;Kevin A. Schulman","doi":"10.1016/j.canlet.2025.217979","DOIUrl":"10.1016/j.canlet.2025.217979","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217979"},"PeriodicalIF":10.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854615","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":"Anti-tumor activity of CDYL2b in prostate cancer","authors":"Ruicai Gu ,&nbsp;Julia Janknecht ,&nbsp;Sangphil Oh ,&nbsp;Hanlin Jiang ,&nbsp;Ralf Janknecht","doi":"10.1016/j.canlet.2025.217987","DOIUrl":"10.1016/j.canlet.2025.217987","url":null,"abstract":"<div><div>Prostate cancer is a leading cause of death among men, yet the molecular underpinnings of this malignancy are still not fully understood. We discovered that two histone demethylases driving prostate tumorigenesis, the JMJD2A and JMJD2B enzymes, suppressed transcription of the <em>CDYL2</em> epigenetic reader gene. Bioinformatic analyses showed that low <em>CDYL2</em> expression in prostate tumors was associated with more metastasis and disease recurrence as well as reduced survival. Out of the four predicted CDYL2 isoforms, all of which were capable of forming homo- and heteromers, only CDYL2b was appreciably expressed in prostate cancer cells and tightly associated with chromatin. Overexpression of CDYL2b in human DU145 and 22Rv1 prostate cancer cells decreased their growth and clonogenic activity <em>in vitro</em> as well as tumor expansion in nude mice, while CDYL2b downregulation stimulated LNCaP cell growth. RNA sequencing exposed that CDYL2b induced upregulation of transcription factor genes <em>HES7</em>, <em>KLF17</em> and <em>TBX6</em> and overexpression of those factors phenocopied to various degrees the anti-oncogenic effects of CDYL2b. Further JMJD2B, but not JMJD2A, robustly formed complexes with CDYL2b and antagonized CDYL2b in upregulating <em>HES7</em> transcription. In conclusion, our data highlight that CDYL2b can suppress prostate tumorigenesis, while JMJD2A and JMJD2B may exert their pro-oncogenic functions in part through stifling <em>CDYL2b</em> transcription or CDYL2b activity. In addition, our study revealed that the developmental transcription factors TBX6 and HES7 may also suppress tumorigenesis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217987"},"PeriodicalIF":10.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144827083","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":"Chimeric antigen receptor-engineered (CAR)-T cell therapy for metastatic prostate cancer","authors":"Leah Tharian ,&nbsp;Shiv Verma ,&nbsp;Daniel Feinberg ,&nbsp;Reshmi Parameswaran ,&nbsp;Sanjay Gupta","doi":"10.1016/j.canlet.2025.217986","DOIUrl":"10.1016/j.canlet.2025.217986","url":null,"abstract":"<div><div>Metastatic prostate cancer is associated with a significantly reduced survival rate, often indicating a more aggressive disease phenotype with diminished responsiveness to conventional therapies. Several FDA-approved treatments have demonstrated improved overall survival in men with metastatic disease. These include androgen receptor signaling inhibitors such as enzalutamide and abiraterone acetate, taxane-based chemotherapies including docetaxel and cabazitaxel, and bone-targeting radiopharmaceuticals like radium-223. Immunotherapeutic agents have also contributed to expanding treatment options with Sipuleucel-T, a dendritic cell-based vaccine, and pembrolizumab, a PD-1 immune checkpoint inhibitor approved for select patient populations. Furthermore, the introduction of poly (ADP-ribose) polymerase inhibitors like olaparib and rucaparib, has transformed the therapeutic landscape, particularly for patients with DNA repair deficiencies in metastatic prostate cancer. More recently, prostate-specific membrane antigen (PSMA)-targeted immunotherapies have shown promise for the treatment of advanced-stage malignancy. Ongoing developments in immunotherapy, particularly those targeting the tumor microenvironment, are expected to significantly reshape the management of metastatic prostate cancer. Among these, chimeric antigen receptor T-cells (CAR-Ts) have revolutionized the treatment of hematologic malignancies, are now being extensively evaluated in solid tumors. In this review, we highlight adoptive cellular therapies utilizing CAR-T cells engineered to recognize prostate cancer–specific antigens, aiming to overcome immune evasion mechanisms. We summarize current CAR-T modalities with their limitations and prospects being evaluated in both preclinical and clinical settings of metastatic prostate cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217986"},"PeriodicalIF":10.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841576","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}