Cancer letters最新文献

{"title":"Tumor endothelial cells as vascular immune gatekeepers: reprogramming the vascular-immune interface for cancer immunotherapy.","authors":"Tianming Zhang, Chu Zhang, Chao Wang, Mingzhong Sun, Jianming Wei, Jian Yu, Linlin Sui, Wenxue Ma","doi":"10.1016/j.canlet.2026.218908","DOIUrl":"10.1016/j.canlet.2026.218908","url":null,"abstract":"<p><p>Despite durable clinical responses to immunotherapy in a subset of patients, most solid tumors remain refractory owing to an immune-excluded phenotype characterized by limited trafficking, infiltration, and function of effector immune cells within the tumor microenvironment (TME). Tumor endothelial cells (TECs) function as vascular immune gatekeepers that orchestrate this process. Driven by persistent pro-angiogenic signaling and metabolic stress, TECs establish a multilayered immune barrier through structurally abnormal, poorly perfused vasculature, endothelial anergy, and active immunosuppressive programs. TECs directly suppress effector T-cell and natural killer (NK)-cell function through checkpoint-like ligands, death-ligand pathways, and immunometabolic mechanisms involving adenosine production and tryptophan catabolism. Simultaneously, they recruit, retain, and reprogram immunosuppressive leukocytes, thereby reinforcing immune exclusion and therapeutic resistance. Here, we propose a TEC-centric vascular immune gatekeeping framework and review strategies to reprogram tumor vessels from immune barriers into conduits for effective immune-cell trafficking and activation. We discuss endothelial-directed monotherapies that transiently normalize or reset TEC states, together with combination strategies integrating vascular modulation with immune checkpoint blockade, adoptive and innate immune-cell therapies, cancer vaccines, oncolytic viruses, STING agonists, and multifunctional antibodies. We also highlight key translational considerations, including biomarker-guided patient stratification, pharmacodynamic monitoring using mechanism-based endpoints, and optimization of treatment dose and scheduling within the vascular normalization window. Overall, this review establishes endothelial reprogramming as a central strategy for overcoming vascular immune gatekeeping and provides a mechanistic framework for biomarker-guided vascular-immune combination therapies in solid tumors.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218908"},"PeriodicalIF":11.8,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219947","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":"Profiling circulating tumor DNA for recurrence prediction and prevention in hepatocellular carcinoma following liver transplantation.","authors":"De-Zhen Guo, Shi-Yu Zhang, Xiang-Yu Zhang, Xia-Hui Lin, Ling Aye, Han-Cheng Liu, Xin-Yin Wang, Zhu-Jun Gu, Xiu-Tao Fu, Guo-Huan Yang, Qi-Man Sun, Yi-Feng He, Kang Song, Xiao-Wu Huang, Wei-Ren Liu, Zhen-Bin Ding, Ying-Hong Shi, Xin-Rong Yang, Jia Fan, Ao Huang, Jian Zhou","doi":"10.1016/j.canlet.2026.218880","DOIUrl":"10.1016/j.canlet.2026.218880","url":null,"abstract":"<p><p>Sensitive biomarkers for recurrence risk stratification, recurrence surveillance and adjuvant therapy guidance are of unmet need for patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). Herein, we explored the potential of profiling circulating tumor DNA (ctDNA) for prediction and prevention of recurrence in HCC after LT. HCC patients (n = 91) who underwent LT were prospectively enrolled. ctDNA was assayed using next-generation sequencing from perioperative plasma (n = 408). Associations between ctDNA status with clinicopathological parameters, tumor recurrence, and adjuvant treatment effect were analyzed. Higher preoperative ctDNA burden correlated with microvascular invasion (median: 45.0 vs 5.1 MTM/mL, P = 0.003) and recurrence (156.2 vs 7.7 MTM/mL, P < 0.001). ctDNA clearance was noted in 87.7% patients after LT and patients who kept positive postoperative ctDNA showed higher recurrence risk (HR = 8.86, P < 0.001), especially early recurrence (within 1 year; 75.0% vs 10.1%, P < 0.001). During follow-up, positive longitudinal ctDNA was similarly predictive of recurrence (HR = 36.50, P < 0.001). The AUC of longitudinal ctDNA for predicting recurrence was 0.930-significantly higher than alpha-fetoprotein (0.655, P < 0.001). Longitudinal ctDNA detected radiologically evidenced recurrence with a median lead time of 5.1 months compared to standard-of-care surveillance. Among patients who received adjuvant therapy, those with positive postoperative ctDNA could benefit (HR = 0.11, P = 0.003) and those with decreased ctDNA burden following treatment experienced longer interval from ctDNA positivity to recurrence (HR = 0.17, P = 0.006). Serial ctDNA analysis demonstrates strong prognostic value, capable of heralding tumor recurrence prior to radiological recurrence and measuring treatment efficacy. Its integration into clinical practice of HCC provides unique opportunities for adjuvant therapy decision-making following LT.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218880"},"PeriodicalIF":11.8,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206606","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":"2-Hydroxyisobutyrylation of SRSF9 regulates CD44 alternative splicing to promote colorectal cancer liver metastasis.","authors":"Mengrou Zhang, Jinming Song, Shuhui Yu, Huolian Liu, Zhun Li, Tiantian Nie, Jiali Qi, Saiqi He, Chuanjie Zhang, Xunhua Liu, Su Yao, Wen Ni, Jianming Li","doi":"10.1016/j.canlet.2026.218900","DOIUrl":"10.1016/j.canlet.2026.218900","url":null,"abstract":"<p><p>Colorectal cancer liver metastasis (CRLM) remains a major cause of cancer mortality, yet the metabolic mechanisms that remodel metastatic RNA-splicing programs are poorly defined. Here, integrated quantitative proteomics and lysine 2-hydroxyisobutyrylation (Khib) proteomics of patient-matched normal mucosa, primary CRCs, and liver metastases revealed a progressive increase in global Khib, with enrichment on RNA-splicing proteins. Serine/arginine-rich splicing factor 9 (SRSF9) emerged as a Khib-modified splicing factor whose expression and K155 Khib levels increased from normal tissue to primary tumors and liver metastases. Gain and loss of function studies in CRC cell lines, patient-derived organoids, subcutaneous xenografts, and splenic injection liver metastasis models showed that SRSF9 promotes proliferation, invasion, tumor growth, and liver colonization. Mechanistically, K155 Khib stabilized SRSF9 protein; the K155R mutation accelerated degradation and abolished SRSF9-driven malignant phenotypes. KAT7 and SIRT6 act as regulators of Khib modification, which positively and negatively modulate the K155 Khib modification of SRSF9, respectively. SRSF9 bound CD44 pre-mRNA through its RRM1 domain and promoted alternative splicing toward the oncogenic CD44V8-10 isoform, which was elevated in patient tumors and metastases and rescued the impaired proliferation and metastatic capacity caused by SRSF9 loss. Finally, a CD44V8-10-targeting antisense oligonucleotide suppressed CRC growth and liver metastasis in preclinical models. These findings define a KAT7/SIRT6-regulated Khib-SRSF9-CD44V8-10 axis that couples metabolic acylation to metastatic splicing and nominate CD44V8-10 as a therapeutic vulnerability in CRC liver metastasis.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218900"},"PeriodicalIF":11.8,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215040","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":"Central neuroendocrine governance as a unifying framework for host-tumor interaction: From afferent sensing to therapeutic modulation.","authors":"Yi-Fei Wang, Mei-Ling Zhang, Wei-Lin Jin","doi":"10.1016/j.canlet.2026.218906","DOIUrl":"10.1016/j.canlet.2026.218906","url":null,"abstract":"<p><p>Cancer is not biologically confined to the tumor bed. Cachexia, fatigue, metabolic dysfunction, circadian disruption, and immune dysfunction reflect disturbances that local models alone cannot fully explain. The brain is well positioned to participate in these processes because it continuously samples circulating signals and coordinates endocrine and autonomic responses. Yet the afferent side of this communication has received less attention than its downstream consequences. Here, we synthesize evidence showing that cytokines, hormones, metabolites, and cargo carried by extracellular vesicles can engage central sensory interfaces and integrative regions, particularly circumventricular organs and hypothalamic and brainstem circuits. We use the term Endocriception to describe afferent humoral sensing and early central decoding of circulating biochemical signals, and focus here on how tumor- and host-associated changes engage this process in cancer. Central neuroendocrine governance refers to the subsequent integration of this information and the generation of autonomic and endocrine outputs. Persistent inflammation, stress, circadian disruption, and impaired feedback may gradually reconfigure this regulatory system. The resulting changes can affect systemic immunity, metabolism, behavior, and host tolerance of cancer. Evidence is strongest for a limited number of pathways, whereas many proposed links remain incomplete or dependent on tumor type and experimental context. We therefore present central neuroendocrine governance as a working framework for organizing current evidence and guiding mechanistic studies, biomarker development, and interventions aimed at restoring host physiology.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218906"},"PeriodicalIF":11.8,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206587","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":"Tumor-like alterations in brain tissue adjacent to glioblastoma: an integrated analysis based on continuous en bloc resection strategy.","authors":"Yuan Xie, Wanming Hu, Changyu Wang, Al-Nahari Fuad, Xiangheng Zhang, Ke Sai, Yinsheng Chen, Zhenghe Chen, Ruhua Liu, Zhi Li, Sheng Zhong, Jie Lu, Yunzhi Zou, Chang Li, Yuanzhong Yang, Jing Zeng, Xiaoxuan Wang, Zhouyu Wang, Xing Zhang, Xiao Luo, Yadi Yang, Chuanmiao Xie, Shaoxiong Wu, Meiling Deng, Yuanyuan Chen, Xiaojing Du, Zhenqiang He, Hao Duan, Yonggao Mou","doi":"10.1016/j.canlet.2026.218907","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218907","url":null,"abstract":"<p><p>The prognosis for glioblastoma (GBM) is correlated with the extent of resection. Continuous en bloc resection (CEBR) is a surgical strategy that involves the removal of the gross tumor along with its normal adjacent tissue (NAT) as \"one whole block\". However, its impact on the survival of patients with GBM in non-eloquent areas is unknown. We found that CEBR significantly prolongs both overall survival and progression-free survival in patients with GBM in non-eloquent areas. We further reported that the molecular drivers, transcriptomic abnormalities, and microenvironmental alterations akin to those found in tumors were detected in the NAT. These tumor-like molecular and microenvironmental alterations were predominantly present in the NAT within 10 mm around the tumor, despite the absence of identifiable tumor cells on rigorous histological examination. Overall, CEBR improved survival in patients with GBM in non-eloquent areas, while tumor-like alterations were present in brain tissue adjacent to the tumor. These findings provide the rationale to incorporate NAT into the extent of resection in the CEBR strategy and support further investigation of the association between its resection and patient prognosis.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218907"},"PeriodicalIF":11.8,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215017","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 \"Chinese guidelines for the diagnosis and treatment of Craniopharyngioma in children (2025)\" [Cancer Lett. 659 (2026) 218784].","authors":"Zhixiong Lin, Jie Ma, Yonggao Mou, Songtao Qi, Xuejun Yang, Jianguo Xu, Yi Lin, Yi Liu, Chuan Zhao, Wenhao An, Feng Wan, Songbai Gui, Gao Zeng, Ping Liang, Yiguang Chen, Yang Zhao, Mingwang Zhu, Chunde Li, Jian Gong, Yongxin Wang, Yaming Wang, Jie Zhao, Yan Ju, Ye Song, Xiaosheng He, Xingfu Wang, Xiaofang Yan, Xianxin Qiu, Hao Li, Yang Wang, Rong Zhang, Jie Gong, Xueling Qi, Ming Ge, Julei Wang, Qingguo Li, Jun Fan, Xiaobing Jiang, Shibin Sun, Wenzhong Mei, Zheming Fang, Song Han, Bo Zhang","doi":"10.1016/j.canlet.2026.218898","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218898","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218898"},"PeriodicalIF":11.8,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149214987","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":"Verbascoside inhibits ovarian cancer proliferation via IRAK4-CXCL5 axis-mediated suppression of neutrophil infiltration and neutrophil extracellular trap formation.","authors":"Yu Ren, Tianyi Yu, Zhijie Wang, Yuzhen Ma, Jinying He","doi":"10.1016/j.canlet.2026.218901","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218901","url":null,"abstract":"<p><p>The specific mechanisms of Verbascoside (VB) in ovarian cancer (OC) remain insufficient. This study aimed to explore the anti-tumor mechanisms of VB in OC, focusing on its ability to modulate the immunosuppressive tumor microenvironment (TME), particularly through targeting neutrophil infiltration and neutrophil extracellular traps (NETs). The anti-tumor and anti-NETosis efficacy of VB was evaluated in vivo using subcutaneous, orthotopic, and pulmonary metastasis mouse models of OC. Microproteomics and bioinformatics analysis identified the direct molecular target of VB and the key neutrophil chemoattractant. The underlying mechanisms were validated in vitro and in vivo (using SKOV3, ID8, and neutrophils), alongside loss-of-function approaches. The combination of VB with anti-PD-1 immunotherapy was also assessed. VB inhibited OC proliferation/metastasis, promoted anti-tumor immunity, and suppressed neutrophil infiltration and NETosis. Neutrophil depletion attenuated VB's anti-metastatic effect. Microproteomics and bioinformatics screening identified IRAK4 as a direct molecular target of VB and CXCL5 as a key neutrophil chemoattractant. SPR confirmed the direct binding between VB and IRAK4, and molecular docking revealed specific hydrogen bond interactions. Mechanistically, VB treatment or IRAK4 knockdown suppressed CXCL5 expression, and consequently reduced neutrophil infiltration and NETosis. Consistently, CXCL5 overexpression abrogated the inhibitory effects of VB on neutrophil NETosis and recruitment. Furthermore, VB synergized with anti-PD-1 therapy, thereby achieving superior tumor growth inhibition, reduced Ki67 expression, and enhanced CD8⁺ T cell infiltration. In conclusion, VB exerts potent anti-tumor effects in OC by targeting the IRAK4/CXCL5 axis, thereby inhibiting neutrophil infiltration and NETosis, reshaping the immunosuppressive TME, and restoring anti-tumor immunity.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218901"},"PeriodicalIF":11.8,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206611","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":"Macrophage-derived WNT regulates tumor immune microenvironment to reduce colitis-associated colon cancer.","authors":"Payel Bhanja, Rishi Man Chugh, Shujah Rehman, Stacey Krepel, Amrita Mitra, Pooja Gupta-Saraf, Ximena Diaz Olea, Tanu Arora, Harsh Pathak, Anup Kasi, Subhrajit Saha","doi":"10.1016/j.canlet.2026.218879","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218879","url":null,"abstract":"<p><p>Prolonged colonic inflammation and ulcerative colitis lead to colon cancer. The rapid growth and treatment-resistant nature of these tumors are primarily influenced by an immunosuppressive tumor microenvironment, which is led by tumor-associated macrophages (TAMs). However, factors influencing or regulating the immunosuppressive nature of TAMs have not been sufficiently studied. In this manuscript, we use a mouse model of colitis-associated colorectal cancer (CRC) to demonstrate that WNT expression in TAMs regulates their immunosuppressive function by inhibiting Glycogen synthase kinase-3 beta (GSK-3β) within the macrophages, possibly through an autofeedback loop. GSK3β is a positive regulator of PD-1 and PD-L1 expression in macrophages and promotes an immunosuppressive microenvironment. Therefore, GSK-3β inhibition alters the immunosuppressive nature of the immune microenvironment and effectively controls tumor growth. In Csf1r.iCre; Porcn^fl/fl mice, the absence of macrophage-derived WNT promotes tumor growth in the model of colitis-associated colon cancer. Absence of macrophage-derived WNT stabilizes GSK-3β in macrophages and promotes an immunosuppressive tumor microenvironment. We also show that pharmacological inhibition of GSK-3β in a macrophage-specific manner, achieved by systemic delivery of a lipo-GSK3β inhibitor, effectively inhibits tumor growth. Therefore, this manuscript demonstrates for the first time that the macrophage-specific modulation of GSK3β can be a potential target to treat colitis-associated colon cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218879"},"PeriodicalIF":11.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179500","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":"Repurposing antimalarial drug atovaquone in combination with radiation and PD-L1 checkpoint blockade to enhance antitumour response in head and neck squamous cell carcinoma (HNSCC).","authors":"Abul Azad, Rebecca Carter, Wu Yu-Ching, Selvam Thavaraj, Ifigenia Vasiliadou, Rumi Mustafa, Tony Ng, Tammy Kalber, Anthony Kong","doi":"10.1016/j.canlet.2026.218894","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218894","url":null,"abstract":"<p><p>Atovaquone is an approved antimalarial drug which could sensitise tumours to radiation and may modulate tumour immune microenvironment. Here we evaluated the triple combination of radiation with atovaquone plus anti-PD-L1 in HNSCC syngeneic mouse tumour models. We observed significant tumour growth delay induced by the triple combination treatment with differential responses in three different mouse models. There was complete tumour eradication in 6 of 12 mice in the MOCL1 model but not in the other two murine models. The triple combination was associated with increased populations of CD8⁺-T Granzyme B+ cells as well as decreased populations of Tregs, CD11b⁺Gr1⁺ granulocytic MDSCs and CD11b⁺ Ly.6G⁺ neutrophils. Atovaquone inhibited EGFR and its downstream signalling as well as reduced PD-L1 expression. The differential antitumour effects of the triple combination may be due to different basal and post-treatment levels of PD-L1, pERK1/2 and pS6, in particular, their levels were reduced by atovaquone +/- RT in MOCL1 models and not in the other two murine models. Radiotherapy plus atovaquone combination increased cell cycle arrest in G2/M phase, which led to inhibition of DNA damage repair by homologous recombination and increased cell death. We also observed increased activation of CD8⁺-T cells that led to enhanced killing in our HNSCC patient-derived organoid models treated with the triple combination of radiotherapy and atovaquone plus PD-1/PD-L1 blockade. Overall, our results suggest that the triple combination of radiotherapy and atovaquone plus PD-1/PD-L1 blockade has the potential to increase the efficacy of radiotherapy and/or immunotherapy. Thus, this may provide a rationale to further validate this triple combination of radiotherapy and atovaquone plus PD-1/PD-L1 blockade in clinical trials to improve treatment outcomes.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218894"},"PeriodicalIF":11.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179452","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":"MDK⁺ cancer-associated fibroblasts promote immunotherapy resistance through mitochondrial reprogramming in breast cancer.","authors":"Wei Deng, Yidan Fan, Hanqi Zhang, Song Wu, Kaiying Zhang, Yongzhou Luo, Wenwen Tian, Huajie Guan, Hailin Tang, Lewei Zhu, Zikun Ma, Rongfang He, Yutian Zou","doi":"10.1016/j.canlet.2026.218884","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218884","url":null,"abstract":"<p><p>Immunotherapy has improved outcomes for patients with breast cancer, yet therapeutic resistance remains a major clinical challenge. Therefore, we integrated single-cell and spatial transcriptomic data from breast cancer cohorts treated with immune checkpoint inhibitors to identify resistance-associated cellular populations and pathways, with validation across eight independent bulk RNA-seq immunotherapy cohorts. Cancer-associated fibroblasts (CAFs) were isolated from anti-PD-1-resistant breast tumors for functional studies, including in vitro co-culture and in vivo models. Mitochondrial function and metabolic alterations were assessed by flow cytometry, transmission electron microscopy, ATP and adenosine quantification, and JC-1 staining. Tumor mitochondrial metabolism was markedly upregulated in anti-PD-1 non-responders and consistently associated with poor therapeutic response across validation cohorts. MDK-expressing CAFs were enriched in resistant tumors, exhibited strong interactions with tumor cells, and were negatively associated with intratumoral CD8+ T cell infiltration. Single-cell source contribution and depletion analyses identified CAF-derived MDK as the major paracrine mediator linking stromal signaling to tumor metabolic adaptation and immune suppression. Mechanistically, MDK activated SDC1-dependent PI3K/AKT/mTOR signaling in cancer cells, promoting mitochondrial metabolic reprogramming, ATP production, and CD38/CD73-dependent extracellular adenosine accumulation, thereby suppressing CD8+ T cell cytotoxicity. Receptor-depletion experiments further identified SDC1 as the principal functional receptor mediating these effects. Importantly, CAF-specific MDK depletion or pharmacological MDK inhibition enhanced anti-PD-1 efficacy and restored CD8+ T cell effector activity in vivo. Collectively, MDK+ CAFs facilitate anti-PD-1 resistance via mitochondrial rewiring and adenosine-mediated immunosuppression, supporting the MDK-SDC1 axis as a potential therapeutic target for overcoming resistance and improving immunotherapy efficacy in breast cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218884"},"PeriodicalIF":11.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179477","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}