Cancer Biology & Medicine最新文献

{"title":"Comprehensive microbiome profiling reveals mucosal microbiome heterogeneity in patients with left- and right-sided colorectal neoplasia.","authors":"Sunny H Wong, Thomas N Y Kwong, Ru Zhang, Thomas Y T Lam, Andrew M Y Ho, Wing Wah Leung, Xing Kang, Harry C H Lau, Eagle S H Chu, Marc T L Wong, Louis H S Lau, Rashid N S Lui, Raymond S Y Tang, James Y W Lau, Simon S M Ng, Jun Yu, Joseph J Y Sung","doi":"10.20892/j.issn.2095-3941.2025.0846","DOIUrl":"10.20892/j.issn.2095-3941.2025.0846","url":null,"abstract":"<p><strong>Objective: </strong>Left- and right-sided colorectal cancer (CRC) exhibit distinct molecular and clinicopathologic features. However, little is known about the spatial heterogeneity of microbial signatures. In this study the profiles and ecologic patterns of disease-associated intestinal microbiome were investigated in patients with an adenoma(s) or CRC at different anatomic locations.</p><p><strong>Methods: </strong>A total of 690 stool, colonic aspirate, and mucosal biopsy samples were prospectively collected from 32 healthy, 30 adenoma, and 31 CRC patients.</p><p><strong>Results: </strong>CRC was associated with alterations in fecal and mucosal microbiomes. Furthermore, the overall composition of the mucosal microbiome, stratified by metacommunities, differed between the patients with left- and right-sided neoplastic lesions. Patients with right-sided CRC had an elevated inter-phylum ecologic network, while patients with left-sided CRC had an enriched abundance of <i>Fusobacterium</i>. Interestingly, rectal neoplasia harbored a tumor microbiome that was distinctly different from the tumor microbiome at other anatomic sites.</p><p><strong>Conclusions: </strong>The mucosal microbiome of right-sided CRC was distinctly different from the mucosal microbiome of left-sided CRC patients, suggesting distinct microbial ecology and heterogeneous host-microbial ecologic relationships that may contribute to differences in the tumor microenvironment between left- and right-sided CRC.</p>","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of first-line osimertinib in Chinese patients with EGFR-mutated advanced non-small cell lung cancer: a prospective, multicenter, non-interventional study (FLOURISH).","authors":"Lisha Shen, Dongqing Lv, Ke-Jing Tang, Jun Zhao, Dan Zhu, Yanqiu Zhao, Ke Wang, Yan Wang, Zhigang Cai, Ligang Xing, Ke Xie, Jiuwei Cui, Lin Mu, Chao Cao, Liren Ding, Peifeng Chen, Jun Liang, Yongmin Ding, Liqin Lu, Jiliang Zhang, Xinmin Yu, Li Chen, Jing Zheng, Jianya Zhou, Jianying Zhou","doi":"10.20892/j.issn.2095-3941.2025.0566","DOIUrl":"10.20892/j.issn.2095-3941.2025.0566","url":null,"abstract":"<p><strong>Objective: </strong>Osimertinib has demonstrated superior efficacy as a first-line treatment for epidermal growth factor receptor (<i>EGFR</i>)-mutated non-small cell lung cancer (NSCLC) in clinical trials. This study was aimed at providing real-world evidence of osimertinib treatment in Chinese populations.</p><p><strong>Methods: </strong>This prospective, multicenter, non-interventional study was conducted from July 27, 2020, to April 27, 2022. Treatment-naïve adults (≥18 years of age) with locally advanced or metastatic <i>EGFR</i>-mutated NSCLC scheduled to receive first-line osimertinib were included. Of 507 patients screened, 481 were eligible in the full analysis set. The primary endpoint was time to treatment discontinuation (TTD). Secondary endpoints included real-world progression-free survival (rwPFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.</p><p><strong>Results: </strong>Among 481 patients (median age 64.1 years; 62.2% women), the median follow-up was 31.3 months. The mTTD was 24.6 months (95% CI, 22.4-26.7), the median rwPFS was 19.4 months (95% CI, 16.2-20.4), and the mOS was 41.0 months [95% CI, 39.7 to not reached (NR)]. The mOS was 43.1 months (95% CI, 39.7 to NR) in FLAURA-eligible patients <i>vs</i>. 33.5 months (95% CI, 26.8 to NR) in FLAURA-ineligible patients. The mOS was 29.3 months (95% CI: 25.4 to NR) in patients with co-mutations <i>vs</i>. NR (95% CI: 32.9 to NR) in the cohort with <i>EGFR</i>-only mutations. Adverse events occurred in 71.7% of patients, and grade ≥3 events occurred in 11.4%. The safety profiles were similar between FLAURA-eligible and ineligible patients.</p><p><strong>Conclusions: </strong>First-line osimertinib demonstrated robust effectiveness and manageable safety in real-world Chinese patients with <i>EGFR</i>-mutated advanced NSCLC, including those ineligible for clinical trials. Patients with co-mutations showed diminished clinical benefit, thus suggesting a potential need for intensified treatment strategies in this population.</p>","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13498878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferumoxytol triggers cancer ferroptosis via an NF-κB-driven IRONKILL mechanism.","authors":"Tao Luo, Meng Li, Shijie Zhang, Kang Ding, Feng Gu, Qinguo Huang","doi":"10.20892/j.issn.2095-3941.2026.0149","DOIUrl":"10.20892/j.issn.2095-3941.2026.0149","url":null,"abstract":"","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment implications of T cell DNA damage in anti-tumor immunity.","authors":"Xiaofei Jiao, Yiyang Shen, Yixuan Tang, Jiahao Liu, Qinglei Gao","doi":"10.20892/j.issn.2095-3941.2026.0020","DOIUrl":"https://doi.org/10.20892/j.issn.2095-3941.2026.0020","url":null,"abstract":"<p><p>T cell activity is fundamental to effective immunotherapies and sustained tumor control. Recent studies have demonstrated that the therapeutic potential of T cells is notably affected by DNA damage dynamics. Notably, DNA damage within T cells is both a predictive biomarker for therapeutic responses and a druggable vulnerability whose modulation enhances the anti-tumor efficacy of immunotherapies and targeted treatments. This review is aimed at assessing current understanding of the origins of DNA damage in T cells, its consequences, and therapeutic implications within the tumor microenvironment and during anticancer treatment. By elucidating the mechanisms through which DNA damage dictates T cell fate and function, we highlight its dual role as a biomarker and a therapeutic target. Our goal is to accelerate the optimization of immunotherapeutic regimens and the development of combinatorial approaches leveraging a dynamically regulated immune microenvironment by integrating T cell-intrinsic DNA damage response into patient stratification and trial design, together with rational optimization of genotoxic therapies and immunotherapy, to enable a durable response while minimizing immune toxicity.</p>","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial reprogramming of immunogenic cell death: a new paradigm in tumor immunotherapy.","authors":"Yilin Li, Huiyue Zhang, Yun Feng, Kun Fang, Yue Wang, Yuhang Zhou, Tao Sun, Junnan Xu","doi":"10.20892/j.issn.2095-3941.2025.0769","DOIUrl":"10.20892/j.issn.2095-3941.2025.0769","url":null,"abstract":"<p><p>Immunogenic cell death (ICD), a special form of cell death, transforms \"cold\" tumors into \"hot\" tumors by fulfilling the following three key conditions: antigenicity; adjuvanticity; and a suitable tumor microenvironment (TME). Tumor cells release damage-associated molecular patterns (DAMPs) during ICD, thereby activating the dendritic-cytotoxic T cell axis to elicit systemic antitumor immune responses. However, drug resistance and immune-related adverse effects often limit traditional ICD inducers, including chemotherapy and radiotherapy. Notably, microbiota and microbial metabolites can trigger ICD in tumor cells, leading to the release of DAMPs, modulation of immune cell functions, and TME remodeling. This study comprehensively reviews the mechanisms underlying ICD regulation <i>via</i> microbiota and microbial metabolites. In addition, this review examines emerging strategies, including engineered microbiota, microbial-based combination therapies (such as incorporating immune checkpoint inhibitors or chemotherapy), and dietary interventions. Despite challenges associated with individual microbiota variability and mechanistic complexity, this study highlights the potential of microbiota-mediated ICD modulation as a novel paradigm for personalized cancer therapy, thereby providing insights for future directions of scientific research.</p>","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HBx-mediated GPT2 suppression promotes liver cancer development by downregulating ADH1A.","authors":"Hongjuan You, Xing Wang, Ruyu Liu, Yuxin Wang, Huanyang Zhang, Lihong Ma, Ensi Bao, Yujie Zhong, Xiangye Liu, Delong Kong, Xiucheng Pan, Xiaocui Li, Suping Qin, Kuiyang Zheng, Chen Li, Renxian Tang, Fanyun Kong","doi":"10.20892/j.issn.2095-3941.2025.0236","DOIUrl":"10.20892/j.issn.2095-3941.2025.0236","url":null,"abstract":"<p><strong>Objective: </strong>Hepatitis B virus (HBV) is the primary driver of liver cancer (LC), a malignancy characterized by extensive metabolic reprogramming. However, the specific mechanisms linking viral oncoproteins to metabolic dysregulation in LC remain incompletely understood. This study was aimed at investigating the function of the metabolic enzyme GPT2 in hepatocarcinogenesis, focusing on its regulation by HBV X protein (HBx) and its effects on downstream signaling pathways.</p><p><strong>Methods: </strong>We combined analysis of multiple patient cohorts with <i>in vitro</i> and <i>in vivo</i> functional assays to determine the clinical relevance and function of GPT2. Co-immunoprecipitation, ubiquitination assays, and targeted pharmacological or genetic manipulations were used to delineate the signaling cascade.</p><p><strong>Results: </strong>GPT2 was significantly downregulated in LC, and its low expression correlated with poor patient survival. Functionally, GPT2 loss promoted LC cell proliferation, migration, and lipid accumulation. Mechanistically, GPT2 was found to suppress the mTOR pathway by disrupting the AKT-mTOR interaction and leading to upregulation of ADH1A. In turn, ADH1A facilitates CBL-mediated ubiquitination and degradation of LSD1, a key driver of lipogenesis. Critically, the HBV oncoprotein HBx functions as a molecular adaptor that recruits TRIM25 to GPT2, thus leading to GPT2 ubiquitination and proteasomal degradation. Moreover, HBx-mediated loss of GPT2 was found to drive tumor progression by modulating the mTOR-ADH1A-LSD1 axis and enhancing lipid synthesis.</p><p><strong>Conclusions: </strong>Our study delineated a novel HBx-TRIM25-GPT2-ADH1A-LSD1 signaling axis promoting virus-associated hepatocarcinogenesis. GPT2 was identified as a critical metabolic tumor suppressor hijacked by HBV and a promising therapeutic target for treating HBV-associated LC.</p>","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13326605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAMK2D isoform 15 facilitates gefitinib resistance <i>via</i> AKT phosphorylation in lung adenocarcinoma.","authors":"Lingmei Li, Danyang Ren, Yutian Wang, Jiaojiao Zhang, Chenhui Yan, Tongyuan Qu, Ruimin He, Wenshuai Zhang, Wanghao Li, Ningrui Feng, Yalei Wang, Yuhong Guo, Lisha Qi, Lu Cao, Qianru Guo, Qiang Zhao, Zhaoxiang Ye, Wenfeng Cao","doi":"10.20892/j.issn.2095-3941.2025.0710","DOIUrl":"https://doi.org/10.20892/j.issn.2095-3941.2025.0710","url":null,"abstract":"<p><strong>Objective: </strong>Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge in the treatment of lung adenocarcinoma (LUAD). Our previous study demonstrated that EGFR signaling activates calcium/calmodulin-dependent protein kinase 2 (CAMK2). However, the relationship between this mechanism and TKI resistance has not been fully elucidated.</p><p><strong>Methods: </strong>In this study the role of calcium/calmodulin-dependent protein kinase IIδ (CAMK2D) splice variants in gefitinib resistance was investigated using clinical specimens and chronically TKI-exposed cell lines. The biological effects of CAMK2D isoform 15 were evaluated using <i>in vitro</i> assays and <i>in vivo</i> xenograft models. In addition, integrative multi-omics analysis was applied to identify potential upstream regulators of CAMK2D splicing 15.</p><p><strong>Results: </strong>Analysis of clinical samples and cell models revealed that CAMK2D overexpression, particularly isoform 15 containing exon 7, was strongly associated with resistance to EGFR-TKIs. Upregulation of isoform 15 enhanced gefitinib resistance, while knockdown of isoform 15 restored drug sensitivity <i>in vitro</i>. Upregulation of isoform 15 significantly increased tumor growth in xenograft models. Mechanistically, isoform 15 directly interacted with AKT and promoted phosphorylation of AKT at Thr308, thereby activating anti-apoptotic signaling. Multi-omics analysis further identified small nuclear ribonucleoprotein polypeptide A1 (SNRPA1) as a key upstream splicing regulator. Downregulation of SNRPA1 promoted isoform 15 expression and induced a high-resistance phenotype.</p><p><strong>Conclusions: </strong>Our findings revealed a novel mechanism underlying EGFR-TKI resistance in which SNRPA1-controlled alternative splicing drives the expression of CAMK2D isoform 15, leading to activation of AKT signaling and gefitinib resistance. These results identified CAMK2D isoform 15 as a potential prognostic biomarker and therapeutic target, providing a rationale for splicing-directed strategies to overcome EGFR-TKI resistance in LUAD.</p>","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VAMP2/SNAP25 promotes the aggressive progression of head and neck cancer by regulating the fate of multivesicular bodies.","authors":"Suwen Bai, Hexing Sun, Rong Liu, Wenjun Zhang, Yuan Wei, Yumei Luo, Minghua Wang, Jing Wu, David W Chan, Juan Du","doi":"10.20892/j.issn.2095-3941.2025.0522","DOIUrl":"https://doi.org/10.20892/j.issn.2095-3941.2025.0522","url":null,"abstract":"<p><strong>Objective: </strong>Tumor-secreted exosomes are essential in driving tumor progression by releasing multivesicular bodies (MVBs), which are endosome organelles containing intraluminal vesicles (ILVs), as exosomes. However, the mechanisms controlling MVB biosynthesis, trafficking, and exosome exocytosis are not fully understood.</p><p><strong>Methods: </strong>We examined the expression of vesicle-associated membrane protein 2 (VAMP2) and synaptosome-associated protein 25 (SNAP25) in head and neck cancer (HNC) tumor tissues using clinical analysis. Techniques, like nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and exosome quantification, were used to study the roles of VAMP2 and SNAP25 in exosome secretion. Experiments involving overexpression or depletion of VAMP2 and SNAP25 were performed to observe effects on exosome release, MVB trafficking, and cellular behavior.</p><p><strong>Results: </strong>Clinical data showed that VAMP2 and SNAP25 were significantly upregulated in HNC tissues and linked to tumor progression. Increased expression of these proteins boosted exosome secretion and enhanced HNC cell tumorigenicity. Conversely, depleting VAMP2 or SNAP25 impaired MVB release, causing intracellular buildup of MVBs and ILVs, and reduced exosome secretion, which was reversible by exosome degradation methods. Blocking exosome secretion by inhibiting MVB-plasma membrane fusion weakened tumorigenic capacities but triggered a compensatory Ras-related protein Rab-11A-myosin9-phosphatidylserine (PS) externalization pathway, releasing MVB-like extracellular vesicle (EV) clusters.</p><p><strong>Conclusions: </strong>VAMP2 and SNAP25 are key to exosome secretion and HNC tumor progression. Suppressing this pathway activated a compensatory Rab11a-myosin9-PS mechanism that sustained EV release. A dual-targeting strategy that blocks both VAMP2/SNAP25-mediated exosome secretion and the Rab11a-myosin9-PS pathway may improve tumor cell eradication, offering a potential treatment for HNC and other cancers.</p>","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction immunochemotherapy followed by definitive radiotherapy in patients with limited-stage small cell lung cancer: a multicenter study.","authors":"Junxu Wen, Qian Wang, Xinrui Yu, Yang Liu, Xiaoyan Yin, Shanshan Li, Heng Zhao, Zhaoqin Huang, Yu Chen, Xiangjiao Meng","doi":"10.20892/j.issn.2095-3941.2025.0800","DOIUrl":"https://doi.org/10.20892/j.issn.2095-3941.2025.0800","url":null,"abstract":"","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lenvatinib triggers an EGR1-ZNF768-SLC7A11 adaptive response to limit ferroptosis-mediated therapeutic efficacy in hepatocellular carcinoma.","authors":"Jialei Hua, Shuya Zhao, Changsen Bai, Ranliang Cui, Yichao Wang, Yang Liu, Yueguo Li, Dong Dong","doi":"10.20892/j.issn.2095-3941.2025.0814","DOIUrl":"https://doi.org/10.20892/j.issn.2095-3941.2025.0814","url":null,"abstract":"<p><strong>Objective: </strong>Adaptive therapeutic tolerance frequently limits first-line lenvatinib efficacy in hepatocellular carcinoma (HCC). This study explored the C2H2-type zinc finger (ZNF) protein family (the largest class of transcription factors) and hypothesized that specific members of the ZNF protein family are hijacked by cancer cells to orchestrate pro-survival defenses against lenvatinib-induced ferroptosis.</p><p><strong>Methods: </strong>We implemented a hypothesis-driven integrative multi-omics strategy to identify clinically relevant ZNF drivers. The top candidate, ZNF768, was functionally investigated using lentiviral modulation in HCC cell lines and subcutaneous xenograft models. Mechanistic elucidation was performed through ChIP-qPCR, luciferase reporter assays, and upstream signaling pathway analysis. The therapeutic synergy of an AAV-shZNF768 vector combined with lenvatinib was evaluated <i>in vivo</i>.</p><p><strong>Results: </strong>ZNF768 was identified as a potent transcriptional driver of pro-survival programs in HCC; high expression correlated with poor patient prognosis. ZNF768 knockdown suppressed proliferation and robustly sensitized HCC cells to ferroptosis, which was marked by uncontrolled lipid peroxidation and GSH depletion. ZNF768 directly transactivated the <i>SLC7A11</i> promoter, reinforcing the cellular antioxidant shield. We uncovered a paradoxical therapy-induced feedback loop in which lenvatinib inhibits AKT signaling, leading to EGR1 accumulation and transcriptional activation of <i>ZNF768</i>. This adaptive response limits the efficacy of lenvatinib. Consequently, disrupting this loop <i>via</i> ZNF768 knockdown synergizes with lenvatinib to trigger robust ferroptosis and profoundly suppress tumor growth <i>in vivo</i>.</p><p><strong>Conclusions: </strong>The EGR1-ZNF768-SLC7A11 axis constitutes a critical adaptive shield limiting lenvatinib efficacy in HCC. ZNF768 serves as a predictive biomarker and a high-value therapeutic target. Disrupting this axis offers a rational strategy to overcome therapeutic resistance and maximize the clinical potential of lenvatinib.</p>","PeriodicalId":9611,"journal":{"name":"Cancer Biology & Medicine","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}