Cancer letters最新文献

{"title":"Lactylation enhances YTHDF3 stability to promote cisplatin resistance via m6A-dependent KDM6B decay in bladder cancer","authors":"Kai Yu ,&nbsp;Jiazhu Sun ,&nbsp;Jiawei Zhang ,&nbsp;Yuchen Shi ,&nbsp;Junyan Wang ,&nbsp;Yuqing Wu ,&nbsp;Dingheng Lu ,&nbsp;Xinyang Niu ,&nbsp;Yuxiao Li ,&nbsp;Suyuelin Huang ,&nbsp;Jihuan Yuan ,&nbsp;Zhixiang Qi ,&nbsp;Fenghao Zhang ,&nbsp;Jiangfeng Li ,&nbsp;Hong Chen ,&nbsp;Ben Liu","doi":"10.1016/j.canlet.2026.218282","DOIUrl":"10.1016/j.canlet.2026.218282","url":null,"abstract":"<div><div>Acquired resistance to cisplatin remains a major therapeutic challenge in muscle-invasive bladder cancer. Here, we demonstrate for the first time that lactate accumulation induces AARS2-dependent lactylation of the m6A reader YTHDF3, establishing lactylation as a previously unrecognized regulatory layer of this epitranscriptomic factor. YTHDF3 lactylation stabilizes the protein by antagonizing ubiquitin-mediated degradation. Importantly, a lactylation-deficient YTHDF3 mutant fails to confer cisplatin resistance, underscoring the functional importance of this modification. Mechanistically, lactylated YTHDF3 enhances its m6A-dependent recognition and decay of KDM6B RNA. The resulting downregulation of KDM6B suppresses CDKN1A transcription through impaired H3K27me3 demethylation, representing an epigenetic mechanism that weakens the DNA damage response and promotes chemoresistance. Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate–AARS2–YTHDF3–KDM6B–CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218282"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099886","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":"Treg-driven magnetic resonance radiomics in glioblastoma: a multicenter and cross-species model for prognostic biomarker discovery","authors":"Xuezhen Wang ,&nbsp;Minghuan Yang ,&nbsp;Jinxin Li ,&nbsp;Yufan Wu ,&nbsp;Qiuyuan Yue ,&nbsp;Xinkai Wang ,&nbsp;Hailin Lan ,&nbsp;Xiaoxia Li ,&nbsp;Junjun Li ,&nbsp;Yang Wang ,&nbsp;Qichun Wei ,&nbsp;Jinsheng Hong ,&nbsp;Mingwei Zhang","doi":"10.1016/j.canlet.2026.218303","DOIUrl":"10.1016/j.canlet.2026.218303","url":null,"abstract":"<div><div>Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. This study aimed to develop and validate a regulatory T cell (Treg)-associated magnetic resonance imaging (MRI) radiomics model and assess its prognostic value, cross-species similarity, and interpretability across multicenter cohorts. Tregs retained prognostic significance for patients with GBM under World Health Organization CNS 5 classification. In murine models, Treg depletion suppressed tumor growth and reduced the infiltration of myeloid-derived suppressor cells, tumor-associated macrophages, and exhausted CD8⁺T cells. The <em>in vitro</em> co-culture of Tregs with GL261 cells significantly reduced radiation-induced apoptosis. We constructed a Treg-associated radiomics model comprising six features and validated the prognostic value of the radiomics score (RS) across multicenter clinical imaging cohorts (First Affiliated Hospital of Fujian Medical University, <em>n</em> = 111, hazard ratio [HR] = 2.178, 95% confidence interval [CI]: 1.269–3.740; Second Affiliated Hospital of Zhejiang University School of Medicine, <em>n</em> = 126, HR = 1.664, 95% CI: 1.049–2.640; The Cancer Genome Atlas, <em>n</em> = 86, HR = 1.811, 95% CI: 1.089–3.010). Treg depletion experiments also confirmed causal associations between two radiomic features and Treg infiltration. RS stratification correlated with hypoxia, glycolysis, interleukin (IL)–2/signal transducer and activator of transcription (STAT) 5, and IL-6/Janus kinase/STAT3 signaling pathways and immune checkpoints and genomic alterations. The MRI radiomics model enables noninvasive prediction of Treg infiltration and serves as a robust, generalizable prognostic biomarker for GBM. These findings provide evidence for biological causal associations and cross-species similarities between radiomics features and Treg infiltration.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218303"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141146","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":"Burden of primary liver cancer and underlying etiologies among young adults from 1990 to 2021 and modelled Projection to 2050","authors":"Qi Liu ,&nbsp;Huawei Zhang ,&nbsp;Senyan Wang ,&nbsp;Cheng Ye ,&nbsp;Wenjuan Wei ,&nbsp;Jing Fu ,&nbsp;Hongyang Wang ,&nbsp;Xiaofang Zhao","doi":"10.1016/j.canlet.2026.218272","DOIUrl":"10.1016/j.canlet.2026.218272","url":null,"abstract":"<div><div>This study analyzes the global burden of primary liver cancer among young adults (15–49 years) from 1990 to 2021, revealing a 46.0% rise in incidence and 59.0% increase in prevalence, yet declining age-standardized mortality (Estimated Annual Percentage Change-EAPC = −1.27). Middle-SDI regions faced the highest burden, with East Asia accounting for 66,472 prevalent cases and stark national disparities (e.g., Mongolia ASR = 1846.83/100,000 vs. Morocco ASR = 16.73). Population growth drove 42.8–47.8% of case increases, while metabolic risks and alcohol use (surpassing smoking in 2021) emerged as dominant factors. Males showed a 3.5-fold higher smoking-related risk than females. Deaths rose notably among those ≥30 years, with a 20.6% increase in 30–34-year-olds, signaling earlier onset. A shift from hepatitis B to metabolic/behavioral risks underscores evolving etiology. Projections suggest 133,561 cases by 2050, urging prioritized early screening and equitable resource allocation beyond traditional viral hepatitis frameworks.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218272"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103869","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":"Exosomal circUBR5 drives metastasis and chemoresistance in gastric signet-ring cell carcinoma by reprogramming cholesterol metabolism through the hsa-miR-1208/CYP19A1 axis and ACAT1 upregulation","authors":"Yujuan Jiang ,&nbsp;Zitong Zhao ,&nbsp;Liying Ma ,&nbsp;Xinxin Shao ,&nbsp;Peng Wang ,&nbsp;Yongmei Song ,&nbsp;Yantao Tian","doi":"10.1016/j.canlet.2026.218279","DOIUrl":"10.1016/j.canlet.2026.218279","url":null,"abstract":"<div><div>Gastric signet-ring cell carcinoma (GSRCC) exhibits a poor prognosis because of its aggressive behavior and chemoresistance, which is strongly associated with dysregulated cholesterol metabolism. This study investigated the role of circUBR5 in GSRCC progression. CircUBR5 was identified by transcriptome sequencing of gastric cancer tissues and validated. CircUBR5 was upregulated in GSRCC and correlated with advanced stage, metastasis, and poor survival. Functionally, circUBR5 promoted the proliferation, metastasis, and cisplatin resistance of GSRCC cells <em>in vitro and in vivo.</em> Mechanistically, cytoplasmic circUBR5 functions as a sponge for miR-1208, thereby relieving miR-1208-mediated suppression of CYP19A1, a key estrogen synthesis-related enzyme, and activating estrogen signaling. Concurrently, circUBR5 directly binds to the cholesterol esterification enzyme ACAT1 and recruits the deubiquitinase PSMD14 to stabilize it, promoting cholesterol metabolic reprogramming. CircUBR5 can also be packaged into exosomes, which mediates chemoresistance transfer to recipient gastric adenocarcinoma cells. Notably, combining circUBR5-targeting antisense oligonucleotides with cisplatin synergistically inhibited tumor growth and reversed chemoresistance <em>in vivo.</em> Thus, circUBR5 promotes GSRCC progression through dual pathways coordinating estrogen signaling and cholesterol metabolism, and its exosomal dissemination facilitates chemoresistance induction within the tumor microenvironment, highlighting its potential as a prognostic biomarker and therapeutic target.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218279"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043601","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":"IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function","authors":"Yaning Yang ,&nbsp;Chengming Liu ,&nbsp;Lu Yang ,&nbsp;Sufei Zheng ,&nbsp;Haiyan Xu ,&nbsp;Shuyang Zhang ,&nbsp;Linyan Tian ,&nbsp;Nan Sun ,&nbsp;Jie He ,&nbsp;Yan Wang","doi":"10.1016/j.canlet.2026.218259","DOIUrl":"10.1016/j.canlet.2026.218259","url":null,"abstract":"<div><div>Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, we retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression or inhibition and treated them with anti-PD-1 therapy ± chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (&gt;7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P = 0.001) and OS (median: 15.63 vs. 32.80 months, P = 0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR = 2.42, P &lt; 0.001) and OS (HR = 2.96, P &lt; 0.001) and was correlated with progressive disease (PD, P = 0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8⁺ T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8⁺ T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218259"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003281","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":"Recent advances in the management of pancreatic neuroendocrine tumors: From diagnosis, treatment to biology","authors":"Senjie Dai ,&nbsp;Wuhu Zhang ,&nbsp;Heli Gao ,&nbsp;Yan Wang ,&nbsp;Junfeng Xu ,&nbsp;Xiaowu Xu ,&nbsp;Xianjun Yu ,&nbsp;Shunrong Ji","doi":"10.1016/j.canlet.2026.218285","DOIUrl":"10.1016/j.canlet.2026.218285","url":null,"abstract":"<div><div>Pancreatic neuroendocrine tumors (PNETs) are relatively rare and highly heterogeneous tumors. Early diagnosis is a critical step in improving patient prognosis, but there is still a lack of circulating biomarkers with both high specificity and high sensitivity. The development of liquid biopsy technologies (such as CTCs and NETest) has opened new avenues for the early diagnosis of PNETs. Considerable heterogeneity among PNETs represents a major challenge to their effective clinical management. Radiomics, however, has demonstrated significant potential in predicting the malignant behavior of these tumors. For PNETs patients after radical resection, accurate postoperative risk stratification is a key basis for formulating individualized follow-up strategies and selecting adjuvant therapies. Molecular feature-based classification systems will be a major research focus in this field in the future. In the treatment of advanced PNETs, therapeutic strategies have become increasingly diverse. Advances in targeted therapy and immunotherapy have expanded the range of available treatment options for PNETs. However, numerous challenges remain, including limited efficacy, susceptibility to drug resistance, and the lack of standardized treatment sequences. Moreover, in response to these clinical difficulties, significant progress has been made in developing preclinical models that simulate the development and progression of PNETs. Therefore, this review systematically summarized the latest research advances in the diagnosis, treatment, and research models of PNETs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218285"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146084417","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":"Cutting-edge AI technologies in skin cancer applications","authors":"Yueqin Diao ,&nbsp;Xiao Chen ,&nbsp;Ziyan Huang ,&nbsp;Qian Tan ,&nbsp;Meng Yang ,&nbsp;Hanyi Yu ,&nbsp;Yanwu Xu ,&nbsp;Xing Hu","doi":"10.1016/j.canlet.2026.218256","DOIUrl":"10.1016/j.canlet.2026.218256","url":null,"abstract":"<div><div>The rapid development of multimodal large language models (LLMs) such as GPT and Med-PaLM is reshaping medical practice. Skin cancer, one of the most prevalent malignancies, encompasses diverse subtypes and early signs that often resemble benign lesions, making timely detection and accurate diagnosis challenging. Traditional diagnostic methods are hindered by subjectivity, sampling bias, and low efficiency. Skin cancer diagnosis is largely constrained by strong subjectivity, sampling bias, and low diagnostic efficiency regularly. Although immunotherapy and targeted therapy aimed at the tumor microenvironment have brought new therapeutic possibilities to patients, tumor heterogeneity and immune evasion remain major unresolved challenges. Artificial intelligence techniques based on deep learning and complex neural networks can integrate dermoscopic images, histopathological information, and genetic databases through multimodal fusion strategies, enabling the extraction of richer and complementary features and thereby significantly improving diagnostic accuracy and robustness. Moreover, tailoring treatment strategies according to individual patient characteristics facilitates truly personalized therapy and prognostic assessment. In the field of drug development, artificial intelligence accelerates the screening and simulation of candidate compounds, substantially reducing development time and expenditure. This review summarizes recent advances in AI for skin cancer, with emphasis on early detection, individualized therapy, and patient management. We further discuss challenges related to data quality and model interpretability, emphasizing the importance of dermatology-specific foundation models and collaboration between clinicians and engineers<strong>.</strong></div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218256"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988121","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":"FIG4 downregulation-arrested autophagy-lysosomal degradation of IL-18 drives lipid-associated macrophage polarization and immunotherapy resistance in triple-negative breast cancer","authors":"Fada Xia ,&nbsp;Xudong Zhu ,&nbsp;Xiaoyan Li ,&nbsp;Qiaoli Yi ,&nbsp;Shangjun Zhou ,&nbsp;Jiayu Wang ,&nbsp;Xia Wang ,&nbsp;Kejing Zhang ,&nbsp;Cheng Zhan ,&nbsp;Hailin Tang ,&nbsp;Zhijie Xu ,&nbsp;Huiting Zhang ,&nbsp;Anli Yang ,&nbsp;Yuanliang Yan","doi":"10.1016/j.canlet.2026.218278","DOIUrl":"10.1016/j.canlet.2026.218278","url":null,"abstract":"<div><div>Factor-induced gene 4 (FIG4) has been recently identified as a lipid-modifying enzyme that plays an important role in controls autophagolysosomal activity. However, the regulatory mechanisms and biological functions of FIG4 in cancer therapeutic resistance are not well defined. In this study, we identify that FIG4 as a regulator of IL-18 autophagy–lysosomal degradation, participating in the immunotherapy response in triple-negative breast cancer (TNBC). FIG4 overexpression markedly facilitate the autophagy–lysosomal degradation of IL-18 in the LAMP2A-dependent manner. Ubiquitinated IL-18 induced by FIG4 overexpression reduces its secretion, inhibiting the tumor infiltration of immune-suppressive lipid-associated macrophages (LAMs) and re-sensitizing TNBC to immune-checkpoint blockade. Notably, the combination of FIG4 overexpression or IL-18 neutralizing antibody (aIL-18) with PD-1 inhibitor (aPD-1) produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches in TNBC. In conclusion, these findings underscore a novel mechanism underlying the roles of FIG4-IL-18 axis in immunotherapy resistance. Targeting FIG4–IL-18 axis offers a tractable strategy to dismantle LAM-mediated immunotherapy resistance in TNBC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218278"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040188","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 TFAM accelerates pentose phosphate pathway by unleashing G6PD oligomerization to drive hepatocarcinogenesis","authors":"Xiaoxiao Zhu,&nbsp;Wanli Ma,&nbsp;Xiaoying Ji,&nbsp;Jinli He,&nbsp;Jiao Luo,&nbsp;Xiangbing Kong,&nbsp;Honghui Guo,&nbsp;Linran Zhang,&nbsp;Yaxin Ju,&nbsp;Lin Xu,&nbsp;Yuan Jin,&nbsp;Dianke Yu,&nbsp;Kunming Zhao","doi":"10.1016/j.canlet.2026.218275","DOIUrl":"10.1016/j.canlet.2026.218275","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, characterized by complex pathogenesis and limited early diagnostic markers. Multi-omics analyses of mice and patients with primary liver tumors reveal significant depletion of oxidative phosphorylation (OXPHOS), despite increased tumor development. However, how this metabolic reprogramming supports tumor growth remains unclear. Here, we uncover the novel tumor-suppressive function of mitochondrial transcription factor A (TFAM), which is consistently downregulated in human HCC and correlates with poor prognosis. Hepatocyte-specific TFAM depletion promotes hepatocarcinogenesis by enhancing glucose-6-phosphate dehydrogenase (G6PD) activity, the rate-limiting enzyme of pentose phosphate pathway (PPP). Cytosolic TFAM directly binds G6PD and blocks its dimerization, restricting metabolism toward PPP, inhibiting nucleotide biosynthesis and slowing down tumor growth. Genetic or pharmacological inhibition of G6PD with 6-aminonicotinamide (6AN) reverses the tumorigenic effects of TFAM deficiency, highlighting a critical metabolic reprogramming in HCC progression. We further show silent mating type information regulation2 homolog-3 (SIRT3)-mediated deacetylation stabilizes TFAM, whereas SIRT3 downregulation promotes TFAM degradation via polyubiquitination. Together, our study reveals a novel mode of metabolic reprogramming due to the loss of TFAM and identifies the TFAM-G6PD axis as a metabolic vulnerability, offering a promising synthetic lethal therapeutic strategy for liver cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218275"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040107","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":"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}