Cancer letters最新文献

{"title":"TMEM11 promotes cisplatin resistance by inhibiting BNIP3-mediated mitophagy in bladder cancer","authors":"Yuan Huang ,&nbsp;Chen Chen ,&nbsp;Mingqiang Su ,&nbsp;Wanteng Ye ,&nbsp;Shu Wei ,&nbsp;Kuangye Long ,&nbsp;Yunjie Huang ,&nbsp;Haiyong Chen ,&nbsp;Zhangfeng Zhong ,&nbsp;Lina Hou ,&nbsp;Jinge Zhang ,&nbsp;Wanlong Tan ,&nbsp;Fei Li","doi":"10.1016/j.canlet.2026.218271","DOIUrl":"10.1016/j.canlet.2026.218271","url":null,"abstract":"<div><div>Cisplatin-based chemotherapy stands as the first-line treatment for metastatic bladder cancer (BCa), yet only 35 % of patients show initial responsiveness, with resistance commonly developing. Therefore, investigating cisplatin-sensitizing targets is warranted for overcoming resistance. In this study, the transmembrane protein 11 (TMEM11) was explored for its role in mediating cisplatin resistance in BCa. Single-cell and bulk RNA sequencing, together with assay for transposase-accessible chromatin using sequencing were utilized. The analyses revealed that TMEM11 was upregulated in cisplatin-resistant cells and associated with mitochondrial metabolic reprogramming and poor prognosis. Spatial transcriptomics and proteomics further confirmed the spatial co-localization of TMEM11 with metabolic pathways enriched in resistant tumors. Functional experiments demonstrated that TMEM11 inhibited BNIP3-mediated mitophagy and apoptosis, thereby stabilizing mitochondrial function to promote cisplatin resistance. Mechanistically, TMEM11 suppressed BNIP3 and impaired mitophagy flux, leading to enhanced survival of cancer cells under cisplatin stress. In vivo, TMEM11 knockdown reduced tumor growth and sensitized tumors to cisplatin treatment. Furthermore, molecular docking and experimental validation identified Curcumin as a high-affinity TMEM11 inhibitor capable of restoring cisplatin sensitivity. This study uncovered the TMEM11-BNIP3 axis as a novel driver of cisplatin resistance in BCa, and proposed pharmacological targeting of TMEM11 as a precise therapeutic strategy to overcome cisplatin resistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218271"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015797","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":"Midkine (MDK) as a central regulator of the tumor microenvironment: From developmental cytokine to therapeutic target","authors":"Hareesh B. Nair ,&nbsp;Ajay Nair ,&nbsp;Ya-Guang Liu ,&nbsp;Dileep K. Vijayan ,&nbsp;Ramadevi Subramani ,&nbsp;Rajkumar Lakshmanaswamy ,&nbsp;Suryavathi Viswanadhapalli ,&nbsp;Gangadhara R. Sareddy ,&nbsp;Surinder K. Batra ,&nbsp;Ratna K. Vadlamudi","doi":"10.1016/j.canlet.2026.218258","DOIUrl":"10.1016/j.canlet.2026.218258","url":null,"abstract":"<div><div>Midkine (MDK) is an oncofetal, heparin-binding cytokine that is re-expressed across diverse cancers and correlates with aggressive disease and treatment resistance. This review synthesizes current evidence on MDK as a coordinator of tumor-intrinsic signaling and microenvironmental remodeling. We summarize MDK structural features, extracellular matrix interactions, and receptor systems that mediate MDK signaling, highlighting LRP1 and PTPRZ1 with context-dependent participation of ALK, nucleolin and integrins. Downstream, MDK engages MAPK, PI3K-AKT, STAT3 and NF-κB pathways to promote tumor cell survival, epithelial-mesenchymal plasticity, and therapeutic stress tolerance. We then focus on tumor microenvironment (TME) programs shaped by MDK, including angiogenesis, fibroblast activation and extracellular matrix remodeling, and the establishment of immunosuppressive niches. Across tumor types, MDK is linked to impaired dendritic-cell function, polarization of tumor-associated macrophages, accrual of myeloid-derived suppressor cells and reduced CD8⁺ T-cell cytotoxic fitness. Finally, we review translational opportunities and challenges, including candidate biomarkers (tumor MDK by IHC/RNA and circulating MDK by ELISA) and rational combination strategies that pair MDK blockade with MAPK-pathway inhibitors or PD-1/PD-L1 immunotherapy. Collectively, these data position MDK as a tractable node connecting tumor-intrinsic signaling with stromal and immune regulation.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218258"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028381","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":"Copper ionophores drive divergent responses to immune checkpoint inhibition across colorectal tumor models","authors":"Devon Heroux ,&nbsp;Xu Xin Sun ,&nbsp;Sijie Zhang ,&nbsp;Maryam Sharifiaghdam ,&nbsp;Ada WY. Leung ,&nbsp;Saeid Farzaneh ,&nbsp;Katy Milne ,&nbsp;Trevor MacFarlane ,&nbsp;Chantal Di Vito ,&nbsp;Brad H. Nelson ,&nbsp;Charles Walsby ,&nbsp;Marcel B. Bally","doi":"10.1016/j.canlet.2026.218281","DOIUrl":"10.1016/j.canlet.2026.218281","url":null,"abstract":"<div><div>Copper-binding agents can trigger immunogenic cell death (ICD) and modulate responses to immune checkpoint inhibitors (ICIs), but how tumor copper biology, agent chemistry, and tumor microenvironment shape these effects is unclear. We evaluated diethyldithiocarbamate [Cu(DDC)₂] and clioquinol [Cu(CQ)₂] in two syngeneic colorectal cancer models with distinct copper handling. In vitro transcriptomic and cytokine profiling showed compound-specific activation of cuproptosis and immune pathways. In vivo, copper accumulation and isotopic fractionation correlated with immune features of the tumor microenvironment, including immune cell infiltration and calreticulin exposure. In CT26 tumors, Cu(CQ)₂ transiently enhanced programmed cell death protein 1 (PD-1) blockade, then promoted immune suppression with prolonged dosing. In MC38 tumors, combination therapy showed sustained antagonism or no added benefit. These data indicate that tumor-intrinsic copper handling and ionophore identity jointly determine immune dynamics and therapeutic outcome, and they suggest copper isotopic metrics as candidate biomarkers warranting further evaluation in the context of copper-based strategies with ICIs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218281"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037429","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":"NR4A2 induces perineural invasion in head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma via CXCL5/CXCR2 signaling axis","authors":"Sanjib Chaudhary ,&nbsp;Muthamil Iniyan Appadurai ,&nbsp;Koelina Ganguly ,&nbsp;Ramesh Pothuraju ,&nbsp;Han-Jun Wang ,&nbsp;Jesse L. Cox ,&nbsp;Subodh M. Lele ,&nbsp;Mohd Wasim Nasser ,&nbsp;Imayavaramban Lakshmanan ,&nbsp;Muzafar A. Macha ,&nbsp;Surinder Kumar Batra ,&nbsp;Apar Kishor Ganti","doi":"10.1016/j.canlet.2026.218269","DOIUrl":"10.1016/j.canlet.2026.218269","url":null,"abstract":"<div><div>Perineural invasion (PNI) is associated with worse prognosis in various malignancies. Targeting PNI may hinder the tumor metastasis in head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC). We investigated the role of nuclear receptor subfamily 4 group A2 (NR4A2/Nurr1) mediated neuronal invasion in HNSCC and PDAC tumor progression. Aberrant expression of NR4A2 was observed in these tumors, and high levels of NR4A2 were associated with worse survival. The whole genome chromatin immunoprecipitation (ChIP) sequencing with NR4A2 antibody illustrated several genes associated with axonal guidance, suggesting its potential role in PNI. Treatment with conditioned-media (CM) collected from NR4A2-depleted cancer cells showed significantly decreased neurite outgrowths in dorsal root ganglion. Cytokine array analysis revealed several soluble factors, such as CXCL5, CCL2, IGBP2, and TIMP-2, that may be involved in neuritogenesis; these factors are decreased in CM of NR4A2-depleted cells. Further treatment with CXCL5 ligand significantly induced neuritogenesis, while the neurite outgrowth was abrogated when cotreated with CXCR2 (receptor for CXCL5) inhibitor SCH527123. Upregulation of Rac1 and phospho-AKT (S473) downstream signaling of CXCL5 was observed, and the CXCR2 inhibitor abrogated this effect in neuronal cells. Moreover, CM from CXCL5-depleted cells showed reduced neurite length. NR4A2 knockdown in UMSCC1 cells impaired tumor formation in vivo, and the xenograft tissues exhibited significant downregulation of CXCL5, providing direct in vivo evidence for the NR4A2–CXCL5 axis in tumor progression. NR4A2 is a key driver of CXCL5-mediated PNI and the NR4A2/CXCL5/CXCR2 signaling axis is a potential therapeutic target in HNSCC and PDAC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218269"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043552","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 “The vulnerabilities of chemotherapy resistant pancreatic cancer revealed by organoids of pre- and post- neoadjuvant therapy” [Cancer Lett. (2026), Online ahead of print]","authors":"Huan Wang ,&nbsp;Yunguang Li ,&nbsp;Shijie Tang ,&nbsp;Yikai Li ,&nbsp;Yehan Zhang ,&nbsp;Xiaoyi Yin ,&nbsp;Juan He ,&nbsp;Yiqin Zhu ,&nbsp;Yi Zhang ,&nbsp;Xiaohan Shi ,&nbsp;Maoyuan Sun ,&nbsp;Suizhi Gao ,&nbsp;Bo Li ,&nbsp;Lingyu Zhu ,&nbsp;Shuai Yuan ,&nbsp;Yaqi Pan ,&nbsp;Meilong Shi ,&nbsp;Penghao Li ,&nbsp;Chuanqi Teng ,&nbsp;Chaoliang Zhong ,&nbsp;Gang Jin","doi":"10.1016/j.canlet.2026.218298","DOIUrl":"10.1016/j.canlet.2026.218298","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218298"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130658","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 vulnerabilities of chemotherapy resistant pancreatic cancer revealed by organoids of pre- and post-neoadjuvant therapy","authors":"Huan Wang ,&nbsp;Yunguang Li ,&nbsp;Shijie Tang ,&nbsp;Yikai Li ,&nbsp;Yehan Zhang ,&nbsp;Xiaoyi Yin ,&nbsp;Juan He ,&nbsp;Yiqin Zhu ,&nbsp;Yi Zhang ,&nbsp;Xiaohan Shi ,&nbsp;Maoyuan Sun ,&nbsp;Suizhi Gao ,&nbsp;Bo Li ,&nbsp;Lingyu Zhu ,&nbsp;Shuai Yuan ,&nbsp;Yaqi Pan ,&nbsp;Meilong Shi ,&nbsp;Penghao Li ,&nbsp;Chuanqi Teng ,&nbsp;Chaoliang Zhong ,&nbsp;Gang Jin","doi":"10.1016/j.canlet.2026.218252","DOIUrl":"10.1016/j.canlet.2026.218252","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to intrinsic and acquired chemotherapy resistance, particularly after neoadjuvant therapy (NAT). To uncover therapy-induced vulnerabilities, we established matched patient-derived organoids from PDAC tissues obtained before and after NAT, creating a unique platform to track treatment-driven evolution. Comparative analysis of these organoids revealed negligible variation in key driver gene mutations but identified a transition from classical to basal-like subtype in one patient after neoadjuvant therapy. Notably, albumin-bound paclitaxel and gemcitabine (AG) treatment induced the resistance to paclitaxel, accompanied by elevated KRAS and MAPK signaling, which was confirmed by transcriptomic comparison of PDAC patient samples with (30 cases) and without (60 cases) AG treatment. Single-cell RNA sequencing of the organoid-derived xenografts revealed AG treatment promoted the emergence of resistant cell clusters characterized by KRAS and MAPK signaling activation. Importantly, EGFR/KRAS/BRAF signaling inhibitors effectively suppressed the growth of AG-resistant PDAC organoids. In a validation cohort of 29 organoids, pan-KRAS inhibitors exhibited superior efficacy against the residual organoids after AG treatment. These results provided insights into molecular changes in PDAC during treatment process and demonstrate that AG chemotherapy can activate the KRAS and MAPK signaling, presenting a potential target for therapeutic intervention.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218252"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017541","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":"Pre-treatment gut microbiome and salivary metabolome signatures associate with chemotherapy-induced cognitive decline in women with breast cancer: A prospective pilot study","authors":"Courtney B. Cross ,&nbsp;Joanne M. Bowen ,&nbsp;Wayne R. Leifert ,&nbsp;David J. Beale ,&nbsp;Maxime Francois ,&nbsp;Rohit Joshi ,&nbsp;Beverley G. Fosh ,&nbsp;Janet K. Coller ,&nbsp;Jonathan Tuke ,&nbsp;Monique Bareham ,&nbsp;Denelle J. Cosier ,&nbsp;Linh Hang To ,&nbsp;Feargal J. Ryan ,&nbsp;Hannah R. Wardill","doi":"10.1016/j.canlet.2025.218234","DOIUrl":"10.1016/j.canlet.2025.218234","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218234"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942556","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":"A novel dual-effect bimodal chip cancer research platform: Chips system interconnected vascularized tumor organoids culture with real-time exploration and detection from bench to bedside","authors":"Jinghan Ruan ,&nbsp;Chun Gao ,&nbsp;Renjie Wang ,&nbsp;Bai Hu ,&nbsp;Rui Long ,&nbsp;Ahmet Hacimuftuoglu ,&nbsp;Bingqing Liao ,&nbsp;Liang Chen ,&nbsp;Ding Ma ,&nbsp;Ling Xi ,&nbsp;Li Li ,&nbsp;Shujie Liao","doi":"10.1016/j.canlet.2025.218110","DOIUrl":"10.1016/j.canlet.2025.218110","url":null,"abstract":"<div><div>Nowadays, cancer researches widely employed organoids as research model. Organoids provide a realistic applicate scene but how to real-time detect and quantified the organoid status is still a bottleneck. To bridge this knowledge gap, we developed an all-in-one microfluidic platform that, for the first time, seamlessly integrates a vascularized tumor organoids-on-a-chip model (VOoC) with a real-time ELISA detection module for advanced tumor research and point of care testing (POCT). The platform features a unique integration of two cutting-edge technologies: (1) VOoC consists of a perfusable self-forming vessel network throughout the tumor organoid, emulates <em>in vivo</em> tumor angiogenesis, and (2) a real-time microfluidic diagnostic chip equipped with ELISA for simultaneously monitoring of tumor biomarker expression levels. We demonstrated the platform's capabilities using cervical cancer organoids and evaluated the drug efficacy of cisplatin and bevacizumab. This coupled system enables simultaneous tumor microenvironment modeling and continuous, real-time monitoring of secreted biomarkers, a capability not achievable with conventional disconnected systems. By combining these two systems, our dual-effect bimodal chip platform holds great promise for advancing personalized medicine and cancer research, offering a powerful tool for both drug screening and quick diagnosis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218110"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457681","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 clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in Multiple Myeloma by modulating mitochondrial metabolism","authors":"Chenggong Tu ,&nbsp;Arne Van der Vreken ,&nbsp;Sylvia Faict ,&nbsp;Gamze Ates ,&nbsp;Ann Massie ,&nbsp;Kim De Veirman ,&nbsp;Elke De Bruyne ,&nbsp;Karin Vanderkerken ,&nbsp;Eline Menu","doi":"10.1016/j.canlet.2026.218245","DOIUrl":"10.1016/j.canlet.2026.218245","url":null,"abstract":"<div><div>Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells residing in the bone marrow. Despite advancements in treatment, including proteasome inhibitors (PIs) such as bortezomib (Bz), drug resistance remains a major challenge. Metabolic reprogramming supports MM survival and drug resistance, with mitochondria emerging as promising therapeutic targets through their control of OXPHOS and mitochondrial reactive oxygen species (Mito-ROS). Using metabolic flux analyses, flow cytometry, and Western blot analysis, we identified pyruvate as a central metabolic intermediate, which not only enhances mitochondrial respiration and Mito-ROS production, but also the Integrated Stress Response (ISR) pathway. Conversely, metformin, an inhibitor of OXPHOS, was still able to activate the ISR pathway, but rather reduced Bz-induced cytotoxicity by decreasing both protein synthesis, and ROS production. Results were confirmed on primary murine and patient samples. Moreover, analysis of the CoMMpass study revealed that patients with prolonged progression-free survival under PI treatment showed enrichment in OXPHOS-related genes, highlighting the importance of mitochondrial metabolism in regulating MM responses to Bz. These data suggest that targeting pyruvate metabolism to increase ROS production could offer a strategy to enhance Bz activity in MM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218245"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942577","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":"Programmable Smart CAR-T design: A new paradigm in precision immunotherapy driven by logic gates, conditional activation, allogeneic strategies, and artificial intelligence","authors":"Peizhen Wen ,&nbsp;Qi Ai ,&nbsp;Xiang Fan ,&nbsp;Zhangyuan Gu ,&nbsp;Bo Chen ,&nbsp;Hui Qian","doi":"10.1016/j.canlet.2026.218257","DOIUrl":"10.1016/j.canlet.2026.218257","url":null,"abstract":"<div><div>Chimeric antigen receptor T-cell (CAR-T) therapy has achieved unprecedented success in hematological malignancies but faces formidable challenges in solid tumors. These limitations include severe “on-target, off-tumor” toxicity, antigen heterogeneity, and the immunosuppressive tumor microenvironment, where the dense extracellular matrix acts as a physical barrier hindering T-cell infiltration. To address these hurdles, this review proposes a comprehensive Efficacy, Safety, and Accessibility (ESA) framework for engineering next-generation “Smart” CAR-T cells. We explore the implementation of programmable Boolean logic gates (AND, OR, NOT) and conditional activation systems (e.g., synNotch, focused ultrasound) that allow T cells to compute antigen patterns and precisely sense tumor-specific cues. Furthermore, we examine the development of off-the-shelf allogeneic platforms that utilize advanced gene editing technologies—such as CRISPR-Cas9 and base editing—to eliminate endogenous receptors and prevent graft-versus-host disease. Crucially, we highlight the transformative potential of Artificial Intelligence/Machine Learning in accelerating the “Design-Build-Test-Learn” cycle, from optimizing single-chain variable fragment (scFv) affinity to predicting clinical toxicity risks. By integrating these multi-dimensional strategies, we outline a new paradigm in precision immunotherapy, aiming to transform CAR-T cells into intelligent, controllable, and universally accessible living drugs capable of eradicating complex solid tumors.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218257"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974636","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}