Cancer letters最新文献

{"title":"Corrigendum to “Identification of metastasis-associated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1” [Cancer Lett. 281 (2009) 71–81]","authors":"Jian-Wei Wang , Shu-You Peng , Jiang-Tao Li , Yong Wang , Zhi-Ping Zhang , Yan Cheng , De-Qing Cheng , Wei-Hong Weng , Xiang-Song Wu , Xiao-Zhou Fei , Zhi-Wei Quan , Ji-Yu Li , Song-Gang Li , Ying-Bin Liu","doi":"10.1016/j.canlet.2025.218201","DOIUrl":"10.1016/j.canlet.2025.218201","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218201"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773721","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":"CPE/HYOU1 axis-activated Hippo-YAP signaling pathway suppresses PANoptosis to facilitate osteosarcoma progression","authors":"Tong Zhu ,&nbsp;Hanyi Song ,&nbsp;Yifan Yu ,&nbsp;Wanjie Huang ,&nbsp;Yiqi Zhang ,&nbsp;Zhan Zhang ,&nbsp;Mingzi Tan ,&nbsp;Neili Xu ,&nbsp;Long Zhou","doi":"10.1016/j.canlet.2025.218121","DOIUrl":"10.1016/j.canlet.2025.218121","url":null,"abstract":"<div><div>PANoptotisis associates with antitumor immunity in osteosarcoma (OS). This study aims to identify PANoptosis-related prognostic biomarkers for OS and elucidate their downstream regulatory mechanisms. Therefore, open data of single-cell transcriptomics were comprehensively analyzed to identify PANoptosis-related key cells. Publicly available bulk transcriptomic data were integrated to establish prognostic signatures for OS. They were evaluated for their immune characteristics, expression specificity, downstream targets, and pathway activation patterns. Functional assays (immunofluorescence/flow cytometry/western blot/xenograft tumors) were conducted to examine effects of CPE knockdown on OS progression, PANoptosome assembly, and PANoptosis levels. Rescue experiments involving HYOU1 overexpression or Hippo-YAP activation were performed to elucidate the PANoptotic regulatory mechanisms in OS. Results of single-cell analysis revealed significant enrichment of both macrophages and osteoblasts in OS samples and particularly in the low PANoptotic score subgroup. Further integration with bulk RNA-sequencing data revealed four biomarkers (CPE, MDK, SERPINH1, and NPW) for OS prognosis. They exhibited predominant expression in osteoblasts and demonstrated potentials in predicting OS outcomes. Of which, CPE deficiency markedly suppressed OS progression while upregulating PANoptosis <em>in vitro</em> and <em>in vivo</em>. Mechanistically, CPE specifically enhanced HYOU1 protein stability by inhibiting the ubiquitin-proteasome degradation. Additionally, CPE activated the Hippo-YAP signaling pathway, promoting nuclear translocation and transcriptional activity of YAP. Overexpression of HYOU1 or addition of YAP agonist reversed the anti-tumor effects and promotion of PANoptosis mediated by CPE deficiency. To conclude, the four-gene signature demonstrated potentials to predict OS prognostic risk. Among them, CPE targets HYOU1 and activates Hippo-YAP signal to promote OS progression by blocking PANoptosis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218121"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the stromal-immune barrier: A novel strategy to overcome resistance to CLDN18.2/CD3 bispecific T-cell engager therapy in pancreatic cancer","authors":"Shiqian Liu ,&nbsp;Matthäus Felsenstein ,&nbsp;Shaokun Liu ,&nbsp;Igor Maximilian Sauer ,&nbsp;Muhammad Imtiaz Ashraf","doi":"10.1016/j.canlet.2026.218248","DOIUrl":"10.1016/j.canlet.2026.218248","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218248"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948589","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":"YTHDF2-mediated stabilization of SREBF1 promotes lipid metabolic reprogramming and ferroptosis-associated radioresistance in anaplastic thyroid carcinoma","authors":"Bao Dai ,&nbsp;Jinghua Li ,&nbsp;Lei Xu ,&nbsp;Weijian Chen ,&nbsp;Jianghong Chen ,&nbsp;Muye Song ,&nbsp;Yongchen Liu ,&nbsp;Linhe Wang ,&nbsp;Lingyun Zhang ,&nbsp;Jian Chen ,&nbsp;Zeyu Wu","doi":"10.1016/j.canlet.2025.218232","DOIUrl":"10.1016/j.canlet.2025.218232","url":null,"abstract":"<div><div>Anaplastic thyroid carcinoma (ATC) is the most aggressive endocrine malignancy and frequently resistant to radiotherapy. Lipid metabolic reprogramming has been implicated in ferroptosis evasion and therapeutic resistance in cancers; however, the specific mechanisms of lipid metabolic rewiring in regulating radioresistance in ATC remain unclear. This study employed an integrated multi-omics profiling, including RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), and RNA immunoprecipitation sequencing (RIP-seq), lipidomics profiling, and mRNA stability assays, to characterize YTHDF2- mediated regulation of metabolic pathways in ATC. Functional validation assessments were performed using Seahorse XF metabolic flux analysis, fluorescence recovery after photobleaching (FRAP) imaging, ferroptosis induction/rescue models, and radiation-exposed xenograft models. Our results demonstrated that YTHDF2 directly bound to N⁶-methyladenosine (m⁶A)-modified motifs within the 3′ untranslated region (3′UTR) of SREBF1 mRNA, thereby enhancing its stability and promoting the expression of downstream lipogenic enzymes, including stearoyl-CoA desaturase-1(SCD1). This lipid remodeling increased membrane fluidity, suppressed ferroptosis, and protected cells from lipid peroxidation while sustaining mitochondrial respiration, accompanied by maintenance of cellular homeostasis, including endoplasmic reticulum integrity. Notably, reintroduction of <em>SREBF1</em> in YTHDF2-deficient ATC cells restored radiotolerance and reversed ferroptotic susceptibility. Additionally, both pharmacologic and genetic inhibition of YTHDF2 significantly sensitized tumors to ionizing radiation and increased ferroptosis-associated cytotoxicity in vivo. Our findings reveal a novel regulatory YTHDF2–SREBF1 axis that links m⁶A-dependent post-transcriptional regulation to ferroptosis modulation through lipid metabolic remodeling. Therapeutically targeting the YTHDF2-SREBF1 pathway may represent a promising strategy to overcome radiotherapy resistance in ATC through metabolic intervention.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218232"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817601","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":"HNRNPC lactylation promotes pancreatic cancer progression through mediating the alternative splicing of PAK6","authors":"BoHao Li ,&nbsp;HanXiang Zhan ,&nbsp;Fei Gao ,&nbsp;MingXin Wen ,&nbsp;Yunhan Ma ,&nbsp;YuChen Xiu ,&nbsp;ZhenYa Liu ,&nbsp;KaiWei Huang ,&nbsp;YunShan Wang ,&nbsp;GuangWei Wei ,&nbsp;YangMiao Duan","doi":"10.1016/j.canlet.2025.218230","DOIUrl":"10.1016/j.canlet.2025.218230","url":null,"abstract":"<div><div>Pancreatic cancer (PC) is a highly malignant and lethal tumor in gastrointestinal tract. Lactate accumulation is a classical feature of metabolic reprogramming in cancers. Lactate-derived lysine lactylation (Kla) is identified as a new type of post-translational modifications (PTMs), which is confirmed to be involved in multiple biological processes. However, the cancer-specific regulation of protein Kla in PC requires further elucidation. Here, we report a range of dysregulated Kla sites specifically related to RNA splicing in human pancreatic cancer, leading to the observation that the Kla at lysine 176 of heterogeneous nuclear ribonucleoprotein C (HNRNPC K176la) is significantly elevated in PC. Blocking HNRNPC K176la dramatically inhibits pancreatic cancer growth and metastasis. Mechanistically, K176la strengthened the binding of HNRNPC with poly-U motifs in p21-activated kinase 6 (PAK6) pre-mRNA, facilitating the expression of the oncogenic isoform PAK6S. Therefore, our study identifies a number of cancer-specific Kla sites spanned on alternative splicing (AS)-related proteins and unravels the significance of HNRNPC K176la in RNA splicing and PC development.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218230"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817982","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":"Loss of branched-chain amino acid (BCAA) metabolism mediated by IGF2BP1-LPAL2-YBX1 interaction promotes malignancy in gallbladder cancer","authors":"Xuechuan Li ,&nbsp;Ke Liu ,&nbsp;Lin Li ,&nbsp;Siyuan Yan ,&nbsp;Yue Yang ,&nbsp;Yang Yang ,&nbsp;Jiahua Yang ,&nbsp;Lu Zou ,&nbsp;Weijian Li ,&nbsp;Guoqiang Li ,&nbsp;Mao Yang ,&nbsp;Liguo Liu ,&nbsp;Ziyi Wang ,&nbsp;Yajun Geng ,&nbsp;Wei Gong ,&nbsp;Yingbin Liu ,&nbsp;Xiangsong Wu","doi":"10.1016/j.canlet.2025.218208","DOIUrl":"10.1016/j.canlet.2025.218208","url":null,"abstract":"<div><div>Reprogrammed cellular metabolism plays a critical role in the development and progression of various cancers. However, the mechanisms by which these metabolic changes drive malignancy in gallbladder cancer (GBC) remain unclear. In this study, we identified significant alterations in branched-chain amino acid (BCAA) metabolism in GBC through comprehensive transcriptomic and metabolic analyses. Reduced activity of the BCAA catabolic enzymes ACADS, ACADSB, and BCKDHA was associated with poor prognosis in GBC patients. Dietary reduction of BCAAs in mouse model of GBC significantly slowed tumor growth. The lncRNA LPAL2 was found to correlate with the expression of BCAA catabolic enzymes. In vivo and in vitro assays demonstrated that LPAL2 inhibited GBC cell proliferation, downregulated intracellular BCAA levels, and suppressed mTORC1 activation. Furthermore, LPAL2 and ACADS were identified as independent prognostic factors for survival. Mechanically, IGF2BP1 maintaining LPAL2 stability through methylation. Additionally, LPAL2 decreased YBX1 stability by promoting its ubiquitination-mediated degradation, while YBX1 inhibited the transcription of certain BCAA catabolic enzymes through binding to their promoters. In summary, the LPAL2-YBX1 interaction regulates BCAA metabolism to influence GBC cell proliferation, which could be targeted for therapeutic interventions in GBC treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218208"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting ephrin receptor A10 with antibody-drug conjugates for breast cancer","authors":"Mahdieh Safaei ,&nbsp;Yi-Chuan Li ,&nbsp;Chung-Yu Chen ,&nbsp;Ping-Hua Hsieh ,&nbsp;Srimathi Venkataraman ,&nbsp;Wei-Chien Huang ,&nbsp;Wei-Chung Cheng ,&nbsp;Hirohito Yamaguchi ,&nbsp;Yu-Fu Chen ,&nbsp;Yuan-Soon Ho ,&nbsp;Wei-Chao Chang ,&nbsp;Chih-Wei Lin ,&nbsp;Mien-Chie Hung","doi":"10.1016/j.canlet.2025.218225","DOIUrl":"10.1016/j.canlet.2025.218225","url":null,"abstract":"<div><div>Despite advances in breast cancer therapy, effective treatment options remain a challenge. The Ephrin receptor A10 (EphA10), a receptor tyrosine kinase, has been reported to be overexpressed in several cancers, including breast and ovarian cancers yet absent in the majority of normal cells except for the male testis. This unique expression profile makes EphA10 an ideal therapeutic target for cancers in women. However, effective EphA10-directed therapies have yet to be developed. To investigate the therapeutic potential of targeting EphA10, we evaluated an antibody drug conjugate strategy. For this purpose, chimeric and humanized EphA10 antibodies were generated and conjugated with monomethyl auristatin E (MMAE). The results showed that EphA10-MMAE exhibited strong cytotoxic effects against EphA10-positive breast cancer cells, including those resistant to FDA-approved drugs such as trastuzumab, lapatinib, PARP inhibitors, and cyclin-dependent kinases 4 and 6 inhibitors. Taken together, these findings highlight EphA10-MMAE as a promising therapeutic strategy for breast cancer, with the potential to overcome drug resistance to existing treatments.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218225"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803233","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":"NCAPH promotes immune evasion via inhibiting PD-L1 protein degradation in head and neck squamous cell carcinoma","authors":"Baiyang Liu ,&nbsp;Xudong Xiang ,&nbsp;Yan Cheng ,&nbsp;Jimin Fei ,&nbsp;Mengge Wu ,&nbsp;Laihao Qu ,&nbsp;Xian Zhao ,&nbsp;Xing Chen ,&nbsp;Yao Li ,&nbsp;Jia Du ,&nbsp;Dengcai Mu ,&nbsp;Haoqing Zhai ,&nbsp;Qiushuo Shen ,&nbsp;Yongbin Chen ,&nbsp;Cuiping Yang","doi":"10.1016/j.canlet.2025.218218","DOIUrl":"10.1016/j.canlet.2025.218218","url":null,"abstract":"<div><div>Head and neck squamous cell carcinoma (HNSCC) is an epithelial carcinoma characterized by its distinct geographical distribution, exhibiting a higher prevalence in Southeast Asia. Despite the approval of immune checkpoint blockade (ICB) therapy for treating advanced recurrent HNSCC, the extent of patient benefit remains limited. Elucidating the molecular regulatory mechanisms of immunosuppressive tumor microenvironment in HNSCC is crucial for improving current treatment status and patient outcomes. Our findings show that knockdown of NCAPH suppresses cell proliferation, migration, and xenograft tumor growth, while enhancing radiotherapy-induced cellular apoptosis. Importantly, we found that NCAPH binds to PD-L1 and disrupts its degradation, competing with HIP1R (Huntingtin-interacting protein 1-related) and leading to the stabilization of PD-L1 protein, which contributes to the formation of immunosuppressive tumor microenvironment. To inhibit the interaction between NCAPH and PD-L1, we created a peptide known as NPIDP (NCAPH and PD-L1 Interaction Disrupting Peptide) that effectively disrupts the interaction between NCAPH and PD-L1. Furthermore, topotecan, a well-characterized topoisomerase I inhibitor, was identified to bind NCAPH and promote its proteasomal degradation. Notably, we demonstrated that NPIDP and topotecan suppress tumor immune evasion both in vitro and in vivo. In summary, our findings reveal the critical role of NCAPH in regulating tumor immune surveillance, suggesting that NCAPH could serve as a potential biomarker and therapeutic target for HNSCC in the future.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218218"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741333","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":"Extrachromosomal DNA amplifications exhibit distinct molecular characteristics and prognostic implications in gastric cancer","authors":"Seunghyun Kang ,&nbsp;Donghyeok Seol ,&nbsp;Jieun Lee ,&nbsp;Chanmi Bang ,&nbsp;Mira Yoo ,&nbsp;Soyeon Kim ,&nbsp;Sepil An ,&nbsp;Hyeongjin Cho ,&nbsp;Duyeong Hwang ,&nbsp;So Hyun Kang ,&nbsp;Young Suk Park ,&nbsp;Sang-Hoon Ahn ,&nbsp;Hyung-Ho Kim ,&nbsp;Eunhee Yi ,&nbsp;Sanghyun Kim ,&nbsp;Yun-Suhk Suh ,&nbsp;Hoon Kim","doi":"10.1016/j.canlet.2025.218214","DOIUrl":"10.1016/j.canlet.2025.218214","url":null,"abstract":"<div><div>Gastric cancer (GC) is characterized by marked molecular heterogeneity that contributes to differential patient outcomes. Focal amplification in form of extrachromosomal DNA (ecDNA) is common in multiple cancer types and is associated with poor patient outcomes, but its prevalence and clinical implications in GC remain largely unclear. In this study, we analyzed whole genome and whole transcriptome sequencing from 76 GC patients collected at a single hospital (Seoul National University Bundang Hospital) in Korea. EcDNAs were detected in 22.4 % (n = 17) of GC patients. Notably, 75.0 % (n = 12) of the patients in the ‘chromosomal instability (CIN)’ category carried ecDNAs which frequently co-occurred with chromothripsis. We found that ecDNAs were enriched for known cancer genes, and the presence of ecDNAs was associated with poor patient prognosis. Among the CIN cases, patients carrying ecDNAs showed gene expression patterns related to chromosomal instability, as also observed in patients having only non-ecDNA chromosomal amplicons (ChAmp) but exhibited more pronounced immune suppression. Our findings show that ecDNAs display distinct molecular characteristics in GC, including the high prevalence of cancer genes and pronounced characteristic of immune suppression, alongside clinical implications, suggesting that ecDNA is a key molecular factor in the clinical management of GC patients, particularly for the CIN subtype patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218214"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741202","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":"HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8+ T cell glutamine metabolism via KIR3DL3 interaction","authors":"Fei Wu ,&nbsp;Jiannan Shen ,&nbsp;Zhiting Zhao ,&nbsp;Yan Chen ,&nbsp;Binhui Ren ,&nbsp;Ming Li ,&nbsp;Rong Yin ,&nbsp;Yanyan Zhang ,&nbsp;Shaorong Yu","doi":"10.1016/j.canlet.2025.218219","DOIUrl":"10.1016/j.canlet.2025.218219","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and EGFR-mutant tumors show limited response to current immunotherapy. The immunosuppressive tumor microenvironment, particularly metabolic constraints on effector T cells, is increasingly recognized as a major barrier to effective anti-tumor responses. HHLA2, a B7 family member frequently elevated in EGFR-mutant NSCLC, has an incompletely defined role in immune escape. In this study, we demonstrate that tumor-derived HHLA2 engages the inhibitory receptor KIR3DL3 on CD8⁺ T cells, driving T cell exhaustion through metabolic reprogramming of amino acid utilization. HHLA2–KIR3DL3 signaling suppresses glutamine utilization through ERK/MAPK-dependent repression of SLC1A5, SLC38A2, and ADHFE1, key glutamine transporters and metabolic enzymes, thereby inducing metabolic insufficiency and dysfunctional cytokine production in CD8⁺ T cells, including reduced IFN-γ, TNF-α, and increased IL-10. Disruption of this axis—via HHLA2 deletion or antibody blockade—restored T cell metabolism and effector function, leading to attenuated tumor progression in humanized mouse models. Notably, HHLA2/KIR3DL3 inhibition synergized with EGFR tyrosine kinase inhibitors to enhance anti-tumor immunity and suppress tumor progression. Together, these findings identify HHLA2–KIR3DL3 as a key immunosuppressive pathway in EGFR-mutant NSCLC and may provide a rationale for therapeutic targeting to improve clinical outcomes.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218219"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145755465","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}