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Irreversible electroporation combined with PD-L1/IL-6 dual blockade promotes anti-tumor immunity via cDC2/CD4+T cell axis in MHC-I deficient pancreatic cancer
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-09 DOI: 10.1016/j.canlet.2025.217620
Zhuozhuo Wu , Qungang Shan , Yuyue Jiang , Wei Huang , Ziyin Wang , Yaping Zhuang , Jingjing Liu , Tiankuan Li , Ziyu Yang , Chaojie Li , Tao Wei , Chenlei Wen , Wenguo Cui , Zilong Qiu , Xiaoyu Liu , Zhongmin Wang
{"title":"Irreversible electroporation combined with PD-L1/IL-6 dual blockade promotes anti-tumor immunity via cDC2/CD4+T cell axis in MHC-I deficient pancreatic cancer","authors":"Zhuozhuo Wu ,&nbsp;Qungang Shan ,&nbsp;Yuyue Jiang ,&nbsp;Wei Huang ,&nbsp;Ziyin Wang ,&nbsp;Yaping Zhuang ,&nbsp;Jingjing Liu ,&nbsp;Tiankuan Li ,&nbsp;Ziyu Yang ,&nbsp;Chaojie Li ,&nbsp;Tao Wei ,&nbsp;Chenlei Wen ,&nbsp;Wenguo Cui ,&nbsp;Zilong Qiu ,&nbsp;Xiaoyu Liu ,&nbsp;Zhongmin Wang","doi":"10.1016/j.canlet.2025.217620","DOIUrl":"10.1016/j.canlet.2025.217620","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a “cold” solid tumor with frequent Major Histocompatibility Complex I (MHC-I) deficiency, thereby making it resistant to type-1-conventional dendritic cell (cDC1)-CD8<sup>+</sup>T cell mediated anti-tumor immunity. Current studies have demonstrated the emerging compensatory role of MHC-II-mediated antigen presentation and CD4<sup>+</sup>T cell activation in anti-tumor immunity against MHC-I-deficient tumors. However, the underlying mechanism of the compensatory immune response by CD4<sup>+</sup>T cells in cancer ablation therapy remains to be elucidate. In clinical samples and murine models, we observed that irreversible electroporation (IRE) ablation therapy promoted immune infiltration and the conversion of CD4<sup>+</sup>T cells into anti-tumor IFN-γ<sup>+</sup>Th1 cells and Th17 cells in MHC-I low-expressed PDAC using scRNA-seq and flow-cytometry analyses. Furthermore, we found that PD-L1 blockade predominantly enhanced the activation of CD11b<sup>+</sup>CD103<sup>-</sup>type-2 conventional dendritic cells (cDC2s) and their antigen presentation to CD4<sup>+</sup>T cells after ablation, stimulating the anti-tumor immune response through the tumor antigen-specific IFN-γ<sup>+</sup>Th1-NK cell axis. Elevated plasma levels of IL-6 in pancreatic cancer patients receiving ablation therapy are significant indicators for impaired prognosis. IL-6 and PD-L1 dual blockade could significantly augment the ratio of IFN-γ<sup>+</sup>Th1 in CD4<sup>+</sup>T cells to boost the anti-tumor immunity of NK cells, leading to prolonged survival of mouse bearing pancreatic cancer. Collectively, we have elucidated that PD-L1 blockade activates the cDC2-CD4<sup>+</sup>T cell axis after IRE therapy, thereby playing a pivotal compensatory anti-tumor role in MHC-I low-expressed pancreatic cancer. Moreover, a combination strategy involving dual-target blockade of PD-L1/IL-6 along with ablation therapy could emerge as a novel therapeutic approach for MHC-I deficient tumors.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217620"},"PeriodicalIF":9.1,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Osteopontin promotes tumor microenvironment remodeling and therapy resistance
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-08 DOI: 10.1016/j.canlet.2025.217618
Chao Liu , Shunjin Xia , Bo Wang , Jiayong Li , Xuyan Wang , Yu Ren , Xuan Zhou
{"title":"Osteopontin promotes tumor microenvironment remodeling and therapy resistance","authors":"Chao Liu ,&nbsp;Shunjin Xia ,&nbsp;Bo Wang ,&nbsp;Jiayong Li ,&nbsp;Xuyan Wang ,&nbsp;Yu Ren ,&nbsp;Xuan Zhou","doi":"10.1016/j.canlet.2025.217618","DOIUrl":"10.1016/j.canlet.2025.217618","url":null,"abstract":"<div><div>Osteopontin (OPN) is a multifunctional secretory protein which can be expressed and secreted by a variety of tumor cells and immune cells. Tumor microenvironment remodeling provides favorable conditions for tumor progression, immune escape and therapy resistance. As a bridge molecule in crosstalk between tumor cells and tumor microenvironment, OPN can not only come from tumor cells to regulate the functions of various immune cells, promoting the formation of immunosuppressive environment, but also can be secreted by immune cells to act on tumor cells, leading to tumor progression, thus constructing a positive feedback regulatory network. Here, we summarize the molecular structure, source and receptor of OPN, and clarify the mechanism of OPN on tumor-associated macrophages, dendritic cells, myeloid-derived suppressor cells, tumor progression and therapy resistance to comprehensively understand the great potential of OPN as a tumor biomarker and therapeutic target.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217618"},"PeriodicalIF":9.1,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584851","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}
引用次数: 0
Clinical development of immuno-oncology therapeutics
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-06 DOI: 10.1016/j.canlet.2025.217616
Jianxin Wang , Qi Chen , qiang Shan , Tingbo Liang , Patrick Forde , Lei Zheng
{"title":"Clinical development of immuno-oncology therapeutics","authors":"Jianxin Wang ,&nbsp;Qi Chen ,&nbsp;qiang Shan ,&nbsp;Tingbo Liang ,&nbsp;Patrick Forde ,&nbsp;Lei Zheng","doi":"10.1016/j.canlet.2025.217616","DOIUrl":"10.1016/j.canlet.2025.217616","url":null,"abstract":"<div><div>Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217616"},"PeriodicalIF":9.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The carcinogenic metabolite acetaldehyde impairs cGAS activity to negatively regulate antiviral and antitumor immunity
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-06 DOI: 10.1016/j.canlet.2025.217615
Xiao-Yue Zhou , Nian-Chao Zhang , Xia-Nan Zhang, Xue-Dan Sun, Zi-Lun Ruan, Qing Yang, Ming-Ming Hu, Hong-Bing Shu
{"title":"The carcinogenic metabolite acetaldehyde impairs cGAS activity to negatively regulate antiviral and antitumor immunity","authors":"Xiao-Yue Zhou ,&nbsp;Nian-Chao Zhang ,&nbsp;Xia-Nan Zhang,&nbsp;Xue-Dan Sun,&nbsp;Zi-Lun Ruan,&nbsp;Qing Yang,&nbsp;Ming-Ming Hu,&nbsp;Hong-Bing Shu","doi":"10.1016/j.canlet.2025.217615","DOIUrl":"10.1016/j.canlet.2025.217615","url":null,"abstract":"<div><div>The cGAS-MITA/STING pathway plays critical roles in both host defense against DNA virus and intrinsic antitumor immunity by sensing viral genomic DNA or dis-located mitochondrial/cellular DNA. Whether carcinogenic metabolites can target the cGAS-MITA axis to promote tumorigenesis is unknown. In this study, we identified acetaldehyde, a carcinogenic metabolite, as a suppressor of the cGAS-MITA pathway. Acetaldehyde inhibits the DNA virus herpes simplex virus 1 (HSV-1)- and transfected DNA-triggered but not cGAMP-induced activation of downstream components and induction of downstream effector genes. Mechanistically, acetaldehyde impairs the binding of cGAS to DNA as well as the phase separation of the cGAS-DNA complex in cells. In mouse models, acetaldehyde inhibits antiviral cytokine production, promotes viral replication and lethality upon HSV-1 infection. In a colorectal tumor xenograft model, acetaldehyde promotes tumor growth and inhibits CD8<sup>+</sup> T cell infiltration by targeting cGAS in both the tumor cells and immune cells in mice. Bioinformatic analysis indicates that expression of acetaldehyde dehydrogenase 2 (ALDH2), which converts acetaldehyde to acetic acid, is negatively correlated with stimulatory immune signatures in clinical colorectal tumors, and higher ALDH2 expression exhibits better prognosis of colorectal cancer patients. Collectively, our results suggest that acetaldehyde impairs cGAS activity to inhibit the cGAS-MITA axis, which contributes to its effects on carcinogenesis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217615"},"PeriodicalIF":9.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584811","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}
引用次数: 0
Corrigendum to “Protein profile in urinary extracellular vesicles is a marker of malignancy and correlates with muscle invasiveness in urinary bladder cancer” [Cancer Lett. 609 (2025) 217352]
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-06 DOI: 10.1016/j.canlet.2025.217592
Loïc Steiner , Maria Eldh , Annemarijn Offens , Rosanne E. Veerman , Markus Johansson , Tammer Hemdan , Hans Netterling , Ylva Huge , Abdul-Sattar Aljabery Firas , Farhood Alamdari , Oskar Lidén , Amir Sherif , Susanne Gabrielsson
{"title":"Corrigendum to “Protein profile in urinary extracellular vesicles is a marker of malignancy and correlates with muscle invasiveness in urinary bladder cancer” [Cancer Lett. 609 (2025) 217352]","authors":"Loïc Steiner ,&nbsp;Maria Eldh ,&nbsp;Annemarijn Offens ,&nbsp;Rosanne E. Veerman ,&nbsp;Markus Johansson ,&nbsp;Tammer Hemdan ,&nbsp;Hans Netterling ,&nbsp;Ylva Huge ,&nbsp;Abdul-Sattar Aljabery Firas ,&nbsp;Farhood Alamdari ,&nbsp;Oskar Lidén ,&nbsp;Amir Sherif ,&nbsp;Susanne Gabrielsson","doi":"10.1016/j.canlet.2025.217592","DOIUrl":"10.1016/j.canlet.2025.217592","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217592"},"PeriodicalIF":9.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SLC7A5/E2F1/PTBP1/PKM2 axis mediates progression and therapy effect of triple-negative breast cancer through the crosstalk of amino acid metabolism and glycolysis pathway
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-05 DOI: 10.1016/j.canlet.2025.217612
Chengfei Jiang , Yingchen Qian , Xiaoming Bai , Shuangya Li , Liyuan Zhang , Yunxia Xie , Yifan Lu , Zhimin Lu , Bingjie Liu , Bing-Hua Jiang
{"title":"SLC7A5/E2F1/PTBP1/PKM2 axis mediates progression and therapy effect of triple-negative breast cancer through the crosstalk of amino acid metabolism and glycolysis pathway","authors":"Chengfei Jiang ,&nbsp;Yingchen Qian ,&nbsp;Xiaoming Bai ,&nbsp;Shuangya Li ,&nbsp;Liyuan Zhang ,&nbsp;Yunxia Xie ,&nbsp;Yifan Lu ,&nbsp;Zhimin Lu ,&nbsp;Bingjie Liu ,&nbsp;Bing-Hua Jiang","doi":"10.1016/j.canlet.2025.217612","DOIUrl":"10.1016/j.canlet.2025.217612","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is one of the most challenging malignancies with the highest mortality rates among women. TNBC relies on both amino acid metabolism and glycolysis to fuel its bioenergetic and biosynthetic demands. However, the potential crosstalk between these two metabolic pathways and its impact on TNBC progression remain largely unexplored. In this study, we observed that SLC7A5, a key amino acid transporter, was upregulated in TNBC and strongly associated with poor patient prognosis. We demonstrated that the elevated SLC7A5 expression activated the amino acid pathway and promoted cell proliferation, tumor growth, and therapeutic resistance by inducing the switch from PKM1 to PKM2 expression, thereby mediating the crosstalk between amino acid metabolism and glycolysis. We further identified that the upregulation of SLC7A5 resulted from miR-152 suppression, which regulates TNBC cellular function and tumor growth. In addition, the miR-152/SLC7A5 axis mediated the expression of PTBP1, which maintains the balance between PKM1 and PKM2, linking amino acid signaling with the glycolysis pathway. To further understand the mechanism of PTBP1 upregulation, we identified that E2F1 transcriptionally activated PTBP1 expression through direct binding at the seed site, while E2F1 expression was also induced by SLC7A5 in TNBC. This novel SLC7A5/E2F1/PTBP1 axis plays a crucial role in regulating the crosstalk between amino acid signaling and glycolysis in TNBC and is essential for TNBC progression and therapeutic effectiveness. Our findings offer valuable insights into the molecular mechanisms underlying TNBC metabolic reprogramming and highlight potential targets for future therapeutic interventions.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217612"},"PeriodicalIF":9.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The landscape of malignant transition: Unraveling cancer cell-of-origin and heterogeneous tissue microenvironment
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-05 DOI: 10.1016/j.canlet.2025.217591
Ruihan Luo , Jiajia Liu , Tiangang Wang , Weiling Zhao , Yanfei Wang , Jianguo Wen , Hongyu Wang , Shanli Ding , Xiaobo Zhou
{"title":"The landscape of malignant transition: Unraveling cancer cell-of-origin and heterogeneous tissue microenvironment","authors":"Ruihan Luo ,&nbsp;Jiajia Liu ,&nbsp;Tiangang Wang ,&nbsp;Weiling Zhao ,&nbsp;Yanfei Wang ,&nbsp;Jianguo Wen ,&nbsp;Hongyu Wang ,&nbsp;Shanli Ding ,&nbsp;Xiaobo Zhou","doi":"10.1016/j.canlet.2025.217591","DOIUrl":"10.1016/j.canlet.2025.217591","url":null,"abstract":"<div><div>Understanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced ANXA1 levels promoted monocyte differentiation toward M1 macrophages and inflammatory responses, whereas during malignant progression, upregulated ANXA1 fostered M2 macrophage polarization and cancer-associated fibroblast transformation by increasing TGF-β production. Our spatiotemporal analysis further provided insights into mechanisms responsible for immunosuppression and a potential target to control evolution of precancer and mitigate the risk for cancer development.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"621 ","pages":"Article 217591"},"PeriodicalIF":9.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584812","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}
引用次数: 0
Strategies for early detection and detailed characterization of oral lesions and head and neck squamous cell carcinoma in Fanconi anemia patients
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-05 DOI: 10.1016/j.canlet.2025.217529
Arnaud Beddok , Eunike Velleuer , Flore Sicre de Fontbrune , Ruud H. Brakenhoff , Jean-Hugues Dalle , Carlo Dufour , Sandrine Faivre , Carine Genet , Jerzy Klijanienko , Christine Krieg , Thierry Leblanc , Pierre Martinez , Regis Peffault de Latour , Arnaud Rigolet , Pierre Saintigny , Dominique Stoppa Lyonnet , Jean Soulier , Jordi Surralles , Martin Schramm , Juliette Thariat
{"title":"Strategies for early detection and detailed characterization of oral lesions and head and neck squamous cell carcinoma in Fanconi anemia patients","authors":"Arnaud Beddok ,&nbsp;Eunike Velleuer ,&nbsp;Flore Sicre de Fontbrune ,&nbsp;Ruud H. Brakenhoff ,&nbsp;Jean-Hugues Dalle ,&nbsp;Carlo Dufour ,&nbsp;Sandrine Faivre ,&nbsp;Carine Genet ,&nbsp;Jerzy Klijanienko ,&nbsp;Christine Krieg ,&nbsp;Thierry Leblanc ,&nbsp;Pierre Martinez ,&nbsp;Regis Peffault de Latour ,&nbsp;Arnaud Rigolet ,&nbsp;Pierre Saintigny ,&nbsp;Dominique Stoppa Lyonnet ,&nbsp;Jean Soulier ,&nbsp;Jordi Surralles ,&nbsp;Martin Schramm ,&nbsp;Juliette Thariat","doi":"10.1016/j.canlet.2025.217529","DOIUrl":"10.1016/j.canlet.2025.217529","url":null,"abstract":"<div><div>Fanconi Anemia (FA) is an inherited disorder associated with profound DNA repair defects, marked by failure to thrive, congenital malformations, progressive bone marrow failure (BMF), and an increased susceptibility to cancer. Clinical manifestations of FA vary widely, with BMF and clonal evolution predominantly affecting younger individuals, while adults are more frequently presenting with solid tumors. Individuals with FA are at a 500-fold increased risk of developing head and neck squamous cell carcinoma (HNSCC), which tends to appear at a median age of 30 years, often at advanced stages with only a 57 % two-year survival rate. The DNA repair deficiency prohibits the use of cisplatin and radiation therapy, limiting the treatment options for FA patients. Given the critical importance of early HNSCC detection in FA patients, innovative and less invasive diagnostic techniques are needed. This review discusses the role of brush biopsy-based cytology combined with molecular and morphometric analyses, as well as next-generation sequencing. Cytology alone demonstrated significant potential for detecting high-grade oral epithelial dysplasia and early-stage HNSCC, achieving sensitivities and specificities of 97.7 % and 84.5 %, respectively. Such techniques allow for stringent surveillance of the oral cavity in FA patients, essential given the aggressive nature of HNSCC in FA and the limited treatment options. In the absence of oral mucosal lesions, a six-month follow-up is recommended. For oral lesions persisting beyond three weeks, diagnostic evaluation is warranted, with clinical follow-up every three months for low-grade dysplasia and treatment of high-grade dysplasia. Integrating modern diagnostic tools within a comprehensive screening framework, alongside patient participation, is essential for personalized care, improved surveillance, and developing preventive measures to enhance FA patient care.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217529"},"PeriodicalIF":9.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584853","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}
引用次数: 0
Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-05 DOI: 10.1016/j.canlet.2025.217613
Si Lu , Qimin Zhou , Rongjie Zhao , Lei Xie , Wen-Ming Cao , Yu-Xiong Feng
{"title":"Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms","authors":"Si Lu ,&nbsp;Qimin Zhou ,&nbsp;Rongjie Zhao ,&nbsp;Lei Xie ,&nbsp;Wen-Ming Cao ,&nbsp;Yu-Xiong Feng","doi":"10.1016/j.canlet.2025.217613","DOIUrl":"10.1016/j.canlet.2025.217613","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) is the critical organelle that regulates essential cellular processes, including protein synthesis, folding, and post-translational modification, as well as lipid metabolism and calcium homeostasis. Disruption in ER homeostasis leads to a condition known as ER stress, characterized by the accumulation of misfolded or unfolded proteins. This triggers the unfolded protein response (UPR), an adaptive pathway mediated by three ER-resident sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Increasing evidence highlights sustained UPR activation in malignant and immune cells within the tumor microenvironment (TME), which promotes tumor progression and metastasis while simultaneously impairing antitumor immunity. This review explores how UPR-driven intercellular signaling influences immunotherapy resistance, focusing on the alterations occurring in tumor cells as well as in the surrounding immune environment. By providing insights into these mechanisms, we aim to highlight the therapeutic potential of targeting the UPR pathways in modulating cancer immunity.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"617 ","pages":"Article 217613"},"PeriodicalIF":9.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584813","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}
引用次数: 0
Interleukin-2-inducible T-cell kinase inhibition to block NF-κB signaling exerts anti-tumor effects and enhances chemotherapy in NK/T-cell lymphoma
IF 9.1 1区 医学
Cancer letters Pub Date : 2025-03-05 DOI: 10.1016/j.canlet.2025.217602
Jiaowu Cao , Dingyao Hu , Hui Yu , Yan Xie , Lan Mi , Yingying Ye , Mi Deng , Weimin Zhang , Miaomiao Li , Dedao Wang , Fei Qi , Jiajin Wu , Yuqin Song , Jun Zhu , Ning Ding
{"title":"Interleukin-2-inducible T-cell kinase inhibition to block NF-κB signaling exerts anti-tumor effects and enhances chemotherapy in NK/T-cell lymphoma","authors":"Jiaowu Cao ,&nbsp;Dingyao Hu ,&nbsp;Hui Yu ,&nbsp;Yan Xie ,&nbsp;Lan Mi ,&nbsp;Yingying Ye ,&nbsp;Mi Deng ,&nbsp;Weimin Zhang ,&nbsp;Miaomiao Li ,&nbsp;Dedao Wang ,&nbsp;Fei Qi ,&nbsp;Jiajin Wu ,&nbsp;Yuqin Song ,&nbsp;Jun Zhu ,&nbsp;Ning Ding","doi":"10.1016/j.canlet.2025.217602","DOIUrl":"10.1016/j.canlet.2025.217602","url":null,"abstract":"<div><div>Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma. Relapsed/refractory (R/R) NKTCL patients have dismal prognosis and lack effective treatments, novel therapeutics are urgently needed. Here we found interleukin-2-inducible T-cell kinase (ITK) expression was elevated in NKTCL cells and patient tumors. And higher <em>ITK</em> expression was associated with worse clinical outcomes. <em>In vitro</em> ITK knockdown inhibited NKTCL cell growth, induced apoptosis, cell cycle arrest and impaired its colony-forming ability while ITK overexpression accelerated cell proliferation. <em>In vivo</em> ITK knockdown greatly impeded lymphoma growth in mouse model, indicating it as a potential therapeutic target. Mechanistically, ITK knockdown inhibited NKTCL cell growth by attenuating oncogenic NF-κB signaling, which is revealed by transcriptomic profiling and further validated by <em>in vitro</em> assays and <em>in vivo</em> NKTCL models. Additionally, we showed that ITK inhibitors could inhibit NKTCL cell proliferation, promote apoptosis and suppressed tumor progression in NKTCL cell line-derived xenograft (CDX) model. Furthermore, we established a patient-derived xenograft (PDX) model from a NKTCL patient refractory to prior anti-PD-1 and asparaginase containing therapy. The primary cells from this patient highly expressed ITK and were responsive to ITK inhibitor. And ITK inhibitor effectively repressed tumor progression in PDX model. Finally, we found ITK inhibition improved the response of NKTCL cell lines to chemotherapy and overcome chemotherapy resistance in primary cells. Collectively, our results demonstrated that ITK served as an oncogene in NKTCL and represented a novel therapeutic vulnerability to be targeted or in combination with chemotherapy drugs for this disease.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"618 ","pages":"Article 217602"},"PeriodicalIF":9.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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