Cancer letters最新文献

{"title":"Mechanistic Study of Pharmacodynamic Regulation in Tumorigenesis: Epigenetic Targeting of Key Enzymes by Active Ginsenoside Components.","authors":"Jinglai Zhu, Fei Kong, Dean Guo, Tong Zhang, Zizhao Yang, Tao Yang","doi":"10.1016/j.canlet.2026.218559","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218559","url":null,"abstract":"<p><p>Epigenetic dysregulation drives tumor progression and therapeutic resistance, creating a critical need for targeted modulators. Protopanaxadiol (PPD) type ginsenosides, triterpenoid saponins from Panax ginseng, emerged as promising natural epigenetic regulators, but their clinical translation is limited by poor bioavailability and context dependent activity. Here, we synthesize preclinical and early clinical evidence to define their mechanistic and translational potential. Structurally distinct ginsenosides converge on conserved epigenetic enzyme families with tumor specific isoform selectivity: one ginsenoside inhibits DNA methyltransferases (DNMTs) across ovarian, renal, and liver cancers; another selectively targets DNMTs and histone deacetylases (HDACs) in colorectal cancer (CRC); a third modulates HDACs and RNA modifiers in leukemia and breast cancer. These interventions reactivate silenced tumor suppressors, suppress epithelial mesenchymal transition (EMT), reverse metabolic reprogramming, and remodel the tumor immune microenvironment. Highly-glycosylated ginsenosides act indirectly via upstream signaling, while low-glycosylated metabolites exhibit superior bioavailability. Key mechanistic principles include family level epigenetic convergence, multi-enzyme co-regulation, and functional complementarity. Clinical translation is hindered by subtherapeutic intratumoral accumulation, lack of biomarker guided studies, and RNA modifier dependency variability. Ginsenosides represent a pharmacologically unique class of epigenetic modulators, with precision oncology potential when paired with delivery optimization and epigenetic biomarker stratification.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218559"},"PeriodicalIF":10.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863905","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":"Human neural stem cell-derived extracellular vesicles improve cognitive function following glioma chemoradiation therapy.","authors":"Casey Hudson, Robert P Krattli, Sanad M El-Khatib, Arya R Vagadia, An H Do, Shreya Madan, Manal T Usmani, Tracy Nguyen, Devyani Swami, Katja M Piltti, Leslie M Thompson, Brian J Cummings, Aileen J Anderson, Munjal M Acharya","doi":"10.1016/j.canlet.2026.218564","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218564","url":null,"abstract":"<p><p>Cranial radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ; Stupp protocol) prolongs glioma survival but frequently results in persistent cognitive impairment. Human neural stem cell (hNSC)-derived extracellular vesicles (EVs) are a promising acellular therapy whose bioactive cargo can modulate neuroinflammation and synaptic integrity. We evaluated two EVs derived from GMP-grade hNSCs (Shef6 and UCI-191) in syngeneic glioma-bearing and non-tumor adult mice treated with fractionated cranial RT (3 × 8.67 Gy) together with concomitant low-dose (25 mg/kg) and adjuvant high-dose (66.7 mg/kg, intraperitoneal) TMZ. EV administration improved memory performance in RT-TMZ-exposed mice and, notably, Shef6-EVs also extended survival in glioma-bearing mice in the absence of chemoradiotherapy. Immunofluorescence analyses demonstrated attenuated gliosis and preservation of synaptic integrity in EV-treated RT-TMZ-exposed brains, while bulk transcriptomic profiling identified distinct neuroprotective gene expression pathways associated with each EV source. Critically, neither Shef6 nor UCI-191 EVs diminished or interfered with the anti-tumor efficacy of RT-TMZ. These data support hNSC-derived EVs as a translational strategy to mitigate treatment-related neurotoxicity while preserving oncologic benefit in a clinically relevant glioma model.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218564"},"PeriodicalIF":10.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856055","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":"Dynamic Responses of Cancer-Associated Fibroblasts to Therapy in Primary Liver Cancer.","authors":"Qi Ruan, Ying Rong Tan, Minwoo Kim, Damon Li, Kim Bridle, Thomas O'Rourke, Darrell Crawford, Xiaowen Liang","doi":"10.1016/j.canlet.2026.218566","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218566","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are central players in the tumour microenvironment (TME) of primary liver cancer, influencing both cancer progression and treatment response. Studies involving single-cell RNA sequencing and spatial multi-omics have significantly expanded our understanding of CAF heterogeneity and functional diversity, although consolidated markers to identify CAF subtypes and therapy-dependent plasticity remain largely unknown. In this review, CAF subpopulations, including their markers and functions, are comprehensively summarised in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The spatial distribution of CAF subtypes from tumour core to boundary correlates with their phenotypes and functions. We focus on mapping dynamic changes of CAF subtypes in response to therapy, including chemotherapy and immunotherapy, and how these changes influence treatment response and prognosis in liver cancer. Finally, we discuss key challenges in targeting specific CAF subtypes and general CAF activation pathways in current clinical trials. This review provides a holistic view of the current and future landscape of CAF-targeting and CAF-regulating strategies in combination with standard-of-care treatments for liver cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218566"},"PeriodicalIF":10.1,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834036","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":"Cigarette smoke induces FASN-dependent fatty acid metabolic rewiring to drive bladder cancer progression.","authors":"Chandra Sekhar Amara, Danthasinghe Waduge Badrajee Piyarathna, Abu Hena Mostafa Kamal, Yuen San Chan, Karthik Reddy Kami Reddy, Chandra Shekar R Ambati, Mohammed Khurshidul Hassan, Pratik Shriwas, Tanmay Gandhi, Antrix Jain, Tanja Gangnus, Pooja Popli, Roshan Borkar, Sung Wook Kang, Silvia L Summers, Vasanta Putluri, Sandra L Grimm, Sharan Venkatesh, Ningxin Song, Erin H Seeley, Jenna Hedlich-Dwyer, Shu-Hsia Chen, Nupam P Mahajan, Abhinav K Jain, Lacey Elizabeth Dobrolecki, Gabrielle A Wells, Hugo Villanueva, Jenny Li, Xuefeng Liu, Roni J Bollag, Anna Malovannaya, Sung Yun Jung, Hyun-Sung Lee, Irfan A Asangani, Martha K Terris, Chad J Creighton, Leomar Y Ballester, Balasubramanyam Karanam, Suyu Liu, MinJae Lee, Rajeeva R Raju, M Minhaj Siddiqui, Livia S Eberlin, Ramakrishna Kommagani, Arun Sreekumar, Jianjun Gao, Nicolas L Young, H Courtney Hodges, Cristian Coarfa, Natalie R Gassman, Seth P Lerner, Yair Lotan, Nagireddy Putluri","doi":"10.1016/j.canlet.2026.218562","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218562","url":null,"abstract":"<p><p>Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via FASN. Genetic and pharmacological inhibition of FASN significantly reduced tumor growth in a Chicken embryo Chorio-allantoic Membrane model exposed to smoke. FASN inhibitors such as TVB-2640, currently in clinical trials, may represent an effective therapeutic strategy for smokers with bladder cancer exhibiting high FASN levels.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218562"},"PeriodicalIF":10.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833998","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":"Angiotensin II Type 1 Receptor Blockade Inhibits Gastric Cancer Metastasis Through Tight Junction Restoration.","authors":"Sooraj Kakkat, Prabhat Suman, Sandeep Goswami, Brusi Kola, Kira A Bruno, Wendy L Frankel, Sujit Basu, Elba A Turbat-Herrera, Veronica Ramirez-Alcantara, Martin J Heslin, Joel F Andrews, Paramahansa Pramanik, Chandrani Sarkar, Debanjan Chakroborty","doi":"10.1016/j.canlet.2026.218530","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218530","url":null,"abstract":"<p><p>Cell-Cell adhesion maintained by tight junctions (TJs) is essential for epithelial integrity; loss of TJs correlates with poor prognosis, metastasis, and adverse clinical outcome in gastric cancer (GC). Restoring TJ integrity is therefore considered a promising therapeutic strategy in GC. The study identifies the stomach renin angiotensin system (stRAS) as a crucial regulator of TJ function in GC. Using integrative analysis of GC patient tissues, human GC cell lines, and orthotopic GC xenograft models, here we show that angiotensin II (ATII), the principal effector peptide of stRAS, drives TJ disassembly through an autocrine loop involving angiotensin receptor type 1 (AT1R) expressed on GC cells. Both ATII and AT1R are overexpressed in GC, where they suppress the expression of key TJ proteins. By analyzing global RNA-sequencing (RNA-seq) data and performing CRISPR/Cas9 gene deletion, chromatin immunoprecipitation, and functional assays, we mechanistically reveal that ATII, which is predominantly produced by cancer cells within the tumor microenvironment (TME), inhibits the expression of krüppel-like factor 4 (KLF4), a transcription factor crucial for the transcription of key TJ genes (CLDN1, 3, 4, and TJP1), leading to reduced synthesis of TJ proteins via AT1R expressed on cancer cells. Notably, the study demonstrates the effectiveness of pharmacological inhibition of AT1R with clinically established AT1R antagonists in preventing GC growth and metastasis by restoring TJ stability in vivo. These findings delineate a previously unrecognized role for ATII in governing TJ disassembly in GC and highlight the ATII/AT1R axis as a promising therapeutic target.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218530"},"PeriodicalIF":10.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834010","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":"Challenges in Triple Negative Breast Cancer Treatment and Therapeutic Potential of the Mitogen Activated Protein Kinase Pathway.","authors":"Prettisha K Nand, David R Croucher, Levon M Khachigian","doi":"10.1016/j.canlet.2026.218556","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218556","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterised by the lack of progesterone receptor, oestrogen receptor and HER2 expression, and is typically associated with high rates of metastasis, recurrence and mortality. Despite recent advances, such as the use of PARP inhibitors, immune checkpoint inhibitors and antibody-drug conjugates, lasting clinical benefit is limited, particularly in advanced disease. A key driver of relapse in TNBC is extensive inter- and intratumoral heterogeneity, largely sustained by self-renewing cancer stem cell (CSC) populations. These cells exhibit enhanced plasticity, immune evasion and resistance to cytotoxic drugs, enabling treatment failure and relapse. Growing evidence implicates aberrant activation of mitogen activated protein kinase (MAPK) signalling in CSC maintenance, epithelial-mesenchymal transition (EMT) and resistance to therapy in TNBC. While MAPK pathway inhibitors show limited efficacy in monotherapy, preclinical and clinical data suggest that their integration with existing treatment strategies may enhance therapeutic robustness, delay resistance and reduce recurrence. Targeting MAPK, in combination with other drugs that restrain CSC plasticity could represent a promising strategy to improve long-term outcomes in TNBC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218556"},"PeriodicalIF":10.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834006","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":"The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.","authors":"Xiaofeng Kang, Guanglin Lei, Xiaobo Hou, Yimeng Du, Minghao Xu, Chunyuan Xue, Donghui Liu, Songhao Jia, Jingbo Shan, Chuanhao Tang, Xiaojie Xu, An Xu","doi":"10.1016/j.canlet.2026.218557","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218557","url":null,"abstract":"<p><p>Cancer stemness drives malignant progression and drug resistance in hepatocellular carcinoma (HCC). Although mitochondrial dynamics are known to influence HCC development, the precise mechanisms linking mitochondrial function to stemness remain largely elusive. Integrating bulk and single-cell transcriptomics, we identified Butyrophilin Subfamily 3 Member A3 (BTN3A3) as a novel oncogene driving HCC stemness. BTN3A3 depletion markedly reduced sphere formation, stemness-related gene expression, and the percentage of CD90+/EpCAM+ cancer stem cells. Rescue experiments confirmed that BTN3A3 promotes HCC cell proliferation, migration, and invasion. Furthermore, BTN3A3 depletion sensitized HCC cells to sorafenib by inducing ROS accumulation and apoptosis. Mechanistically, mass spectrometry and Co-IP identified TOMM22 as a key mitochondrial interactor of BTN3A3. Crucially, sorafenib stress actively promotes BTN3A3 mitochondrial translocation, where it shields TOMM22 from ubiquitin-proteasome-dependent degradation. BTN3A3 deficiency led to TOMM22 depletion, mitochondrial fragmentation, and impaired oxidative phosphorylation (OXPHOS) and ATP production. Importantly, silencing TOMM22 reversed BTN3A3-mediated stemness and sorafenib resistance. In vivo orthotopic xenograft models and patient-derived organoids (PDOs) further validated that BTN3A3 correlates with stemness and malignant tumor growth. Utilizing 5E08, a pan-BTN3 monoclonal antibody, markedly suppressed tumor growth and concurrently downregulated TOMM22 expression in vivo. In conclusion, our study unveils a previously unrecognized non-immunological role for BTN3A3 in mitochondrial reprogramming. We demonstrate that BTN3A3 drives HCC stemness and drug resistance by preventing TOMM22 ubiquitination to maintain mitochondrial homeostasis. These findings position BTN3A3 as a promising therapeutic target, with the pan-BTN3 monoclonal antibody 5E08 offering a potential strategy to overcome stemness-driven malignancy and resistance in HCC patients.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218557"},"PeriodicalIF":10.1,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811381","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":"Necrosis, microbial cues and macrophage-driven immune escape in pancreatic cancer.","authors":"Marco Cordani","doi":"10.1016/j.canlet.2026.218553","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218553","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218553"},"PeriodicalIF":10.1,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811402","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":"TRIM21 drives glioblastoma malignancy via ubiquitination-mediated PDGFRA degradation.","authors":"Qu-Jing Gai, Chuan Wang, Si-Di Li, Bing Pang, Qiang Sun, Hong Zhou, Xin-Yue Yao, Yan Qin, Qian Yan, Yue-Xi Zhu, Zi-Dong Liu, Shuai Zhang, Yan-Xia Wang, Hui-Min Lu, Xiao-Xue Yao, Si-Yu Zhang, Hong Zhang, Mei-Hua Qu, Yang Luo, Xiu-Wu Bian, Yan Wang","doi":"10.1016/j.canlet.2026.218551","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218551","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains a lethal brain tumor with limited therapeutic efficacy from current standard care. The platelet-derived growth factor receptor alpha (PDGFRA) is a major oncogenic driver frequently amplified in gliomas. However, its high expression is paradoxically associated with improved prognosis in lower-grade gliomas, indicating a context-dependent role that is not fully understood. The regulatory mechanisms controlling PDGFRA protein stability represent a significant knowledge gap. In this study, we identify tripartite motif-containing 21 (TRIM21) as a previously uncharacterized E3 ubiquitin ligase for PDGFRA. We demonstrated that TRIM21 catalyzed K48-linked polyubiquitination specifically at lysine 606 of PDGFRA, directing PDGFRA for proteasomal degradation. Surprisingly, the oncogenic activity of TRIM21 was strictly dependent on PDGFRA expression. TRIM21 promoted malignant phenotypes specifically in PDGFRA-positive GBM cells, while exhibiting minimal or opposite effects in PDGFRA-negative cells. Mechanistically, TRIM21-mediated degradation of PDGFRA relieved a constitutive tumor-restraining function and simultaneously activated key downstream oncogenic pathways, including ERK, STAT3, and NF-κB, driving aggressive tumor progression. Clinically, elevated TRIM21 expression correlated with poor patient survival and confers resistance to both conventional radio-chemotherapy and the PDGFRA-targeted tyrosine kinase inhibitor imatinib in PDGFRA-high GBM. Our integrated analysis revealed an inverse correlation between TRIM21 and PDGFRA protein levels in patient specimens and highlighted TRIM21 upregulation as a feature of advanced disease. Collectively, these findings unveiled a crucial regulatory axis wherein TRIM21 switched PDGFRA from a context-dependent protective factor to an oncogenic driver and revealed TRIM21 as a prognostic biomarker and a therapeutic target for the PDGFRA-amplified subset of GBM.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218551"},"PeriodicalIF":10.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811360","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":"Protein kinase Cι-driven macrophage infiltration mediates immunosuppression in non-small cell lung cancer","authors":"Shichuan Hu ,&nbsp;Zichen Zhao ,&nbsp;Jing Zhao ,&nbsp;Yilin Liang ,&nbsp;Lingye Zeng ,&nbsp;Yifei Xia ,&nbsp;Haoya Guo ,&nbsp;Lili Jiang ,&nbsp;Yan Zhang","doi":"10.1016/j.canlet.2026.218330","DOIUrl":"10.1016/j.canlet.2026.218330","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer-related mortality. Immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-1/PD-L1) axis can induce durable tumor regression in a subset of NSCLC patients; however, most exhibit resistance to ICIs therapy. Here, we identify the protein kinase Cι (PKCι)) as a biomarker and critical mediator of poor ICIs responsiveness in NSCLC. High PKCι expression correlates with resistance to anti-PD-1 antibody (αPD1) therapy, whereas low PKCι expression are highly sensitive. PKCι-dependent resistance to αPD1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, PKCι regulated Yap1-dependent transcription of CCL7, which recruits TAMs and fosters an immunosuppressive microenvironment. In contrast, Overexpression of PKCι or CCL7 in PKCι-knockdown tumors restores TAMs infiltration and αPD1 resistance. Pharmacological inhibition of PKCι with auranofin (AF) reduces TAMs accumulation and promotes CD8+T cell infiltration by inhibiting the PKCι-Yap1-CCL7 axis. Combination therapy with AF and αPD1 triggers a CD8+T cell-dependent antitumor immune response, thereby controlling tumor growth in situ or subcutaneously. In summary, our study reveals a PKCι-mediated immunosuppressive pathway driving ICIs resistance and support PKCι inhibition as a promising strategy to enhance immunotherapy efficacy in NSCLC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218330"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257643","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}