Cancer letters最新文献_第5页

Unraveling the potential of targeting methionine metabolism in cancer 揭示靶向蛋氨酸代谢在癌症中的潜力。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-02-19 DOI: 10.1016/j.canlet.2026.218338

Bang-Qi Wang , Xu-Chu Li , Zhenyu Huo , Kai Zeng , Shen Chen , Yuning Wang , Yiming Zhu , Yuyang Huang , Jiatong Ding , Yuanting Cai , Ning Li , Yu Tang

{"title":"Unraveling the potential of targeting methionine metabolism in cancer","authors":"Bang-Qi Wang , Xu-Chu Li , Zhenyu Huo , Kai Zeng , Shen Chen , Yuning Wang , Yiming Zhu , Yuyang Huang , Jiatong Ding , Yuanting Cai , Ning Li , Yu Tang","doi":"10.1016/j.canlet.2026.218338","DOIUrl":"10.1016/j.canlet.2026.218338","url":null,"abstract":"<div><div>Methionine metabolism is a central axis of cellular homeostasis, integrating protein synthesis, redox regulation, and epigenetic control. Cancer cells exhibit a heightened dependence on methionine to sustain proliferation, primarily through enhanced flux into S-adenosylmethionine (SAM) synthesis, which fuels aberrant DNA and histone methylation and maintains oncogenic transcriptional programs. The SAM-producing enzyme methionine adenosyltransferase 2A (MAT2A) is frequently overexpressed in tumors, linking nutrient availability to epigenetic reprogramming and tumor progression. Beyond intrinsic tumor growth, dysregulated methionine metabolism reshapes the tumor microenvironment (TME) by modulating nutrient competition and impairing antitumor immunity—promoting T cell exhaustion and functional suppression. In this review, we synthesize current insights into methionine metabolism in cancer, emphasizing its roles in epigenetic plasticity, stemness, regulated cell death and metabolic crosstalk, with particularly focus on MAT2A as a metabolic vulnerability by discussing its potential for synthetic lethality-based targeting. We further evaluate methionine-restricted (MR) strategies and MAT2A inhibition as emerging interventions capable of reconditioning the TME and synergizing with immunotherapy. Finally, from a novel and integrative perspective, we map the evolving clinical landscape of methionine-targeted therapies and outline future translational directions, aiming to provide a comprehensive framework for understanding its therapeutic potential in cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218338"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776129","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}

引用次数: 0

The histone-modified landscape: Core mechanisms of osimertinib resistance in EGFR-mutant lung cancer 组蛋白修饰景观：egfr突变肺癌中奥西替尼耐药的核心机制。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-02-19 DOI: 10.1016/j.canlet.2026.218321

Jingyi Yang , Minpu Zhang , Chundi Gao , Xiaoyu Yao , Changgang Sun , Jing Zhuang

{"title":"The histone-modified landscape: Core mechanisms of osimertinib resistance in EGFR-mutant lung cancer","authors":"Jingyi Yang , Minpu Zhang , Chundi Gao , Xiaoyu Yao , Changgang Sun , Jing Zhuang","doi":"10.1016/j.canlet.2026.218321","DOIUrl":"10.1016/j.canlet.2026.218321","url":null,"abstract":"<div><div>Despite the transformative impact of osimertinib as a cornerstone targeted therapy for advanced EGFR-mutant non-small cell lung cancer, the emergence of acquired resistance ultimately limits its long-term efficacy. While genetic alterations, tumor microenvironment dynamics, and cancer stem cells contribute to resistance, they inadequately explain its rapid adaptive evolution. This critical knowledge gap points to an underexplored dimension of resistance: the dynamic reprogramming of the epigenetic landscape. This review establishes dynamic histone plasticity--driven by imbalances in key epigenetic modifications such as acetylation and methylation, along with newly recognized marks including lactylation--as a pivotal epigenetic driver of resistance. Evidence demonstrates that these modifications remodel chromatin architecture, reprogram transcriptional networks, compromise DNA damage repair, and stabilize a drug-tolerant persister state, collectively accelerating tumor adaptation during therapeutic pressure. Beyond mechanism, distinct histone-modification signatures are emerging as promising predictive biomarkers for resistance, simultaneously revealing novel, pharmacologically targetable epigenetic vulnerabilities. Leveraging next-generation technologies, we propose an integrated strategy: multimodal epigenetic therapies combined with real-time liquid biopsy profiling to shift from reactive management toward predictive prevention of resistance. By bridging deep epigenomic mechanistic understanding with innovative diagnostic and therapeutic tools, this roadmap provides a proactive, adaptive framework designed to circumvent tumor evolutionary pathways, overcome therapeutic resistance, and prolong patient survival.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218321"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776152","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}

引用次数: 0

Corrigendum to “Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-152” [Cancer Lett. 2015 Apr 1;359(1):75-86] “敲低长链非编码RNA XIST通过上调miR-152在人胶质母细胞瘤干细胞中发挥肿瘤抑制功能”的更正[Cancer Lett. 2015, Apr 1;359(1):75-86]。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-03-02 DOI: 10.1016/j.canlet.2026.218273

Yilong Yao , Jun Ma , Yixue Xue , Ping Wang , Zhen Li , Jing Liu , Liangyu Chen , Zhuo Xi , Hao Teng , Zhenhua Wang , Zhiqing Li , Yunhui Liu

引用次数: 0

Unraveling stress-adaptation pathways in cancer: Functional dissection through CRISPR-based genetic screens 揭示癌症中的应激适应途径：通过基于crispr的基因筛选进行功能解剖。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-01-06 DOI: 10.1016/j.canlet.2026.218246

Fatemeh Mokhles , Mohammad Amin Moosavi , Alvaro Gutierrez-Uzquiza , Guillermo Velasco , Min Li , Marco Cordani

{"title":"Unraveling stress-adaptation pathways in cancer: Functional dissection through CRISPR-based genetic screens","authors":"Fatemeh Mokhles , Mohammad Amin Moosavi , Alvaro Gutierrez-Uzquiza , Guillermo Velasco , Min Li , Marco Cordani","doi":"10.1016/j.canlet.2026.218246","DOIUrl":"10.1016/j.canlet.2026.218246","url":null,"abstract":"<div><div>Cancer cells face a hostile microenvironment characterized by hypoxia, nutrient deprivation, endoplasmic reticulum (ER) stress, and oxidative imbalance. To cope with these challenges, they activate an interconnected network of adaptive pathways including autophagy, the unfolded protein response, metabolic reprogramming, and the integrated stress response., which promote cell survival, therapy resistance, immune evasion, and metastasis. CRISPR-based functional genomics has emerged as a powerful strategy to systematically dissect these stress-adaptive networks, enabling the identification of key regulators and vulnerabilities across diverse contexts. In this review, we first summarize tumor progression in major stress conditions and then highlight how CRISPR screening strategies ranging from genome-wide loss-of-function studies to single-cell and combinatorial platforms, are unraveling critical stress regulators. We further discuss emerging tools, model systems, and translational perspectives, underscoring how the integration of CRISPR technologies with multi-omics, artificial intelligence, and advanced preclinical models is reshaping our understanding of cancer stress biology and guiding the development of novel therapeutic strategies. Finally, we addressed how these novel dissection technologies influence translational opportunities, specifically in the context of combining stress-pathway modulators with immunotherapy and targeted therapy drugs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218246"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931597","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}

引用次数: 0

IGSF3 binds to TNFR2 on Treg to facilitate immunosuppression in cervical cancer IGSF3结合Treg上的TNFR2促进宫颈癌的免疫抑制。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-02-12 DOI: 10.1016/j.canlet.2026.218307

Guangping He , Xinyu Qu , Ziyang Ding , Jiali Liang , Tong Wu , Fanghua Chen , Keqin Hua , Junjun Qiu

{"title":"IGSF3 binds to TNFR2 on Treg to facilitate immunosuppression in cervical cancer","authors":"Guangping He , Xinyu Qu , Ziyang Ding , Jiali Liang , Tong Wu , Fanghua Chen , Keqin Hua , Junjun Qiu","doi":"10.1016/j.canlet.2026.218307","DOIUrl":"10.1016/j.canlet.2026.218307","url":null,"abstract":"<div><div>The clinical success of immune checkpoint blockades has revolutionized oncology; however, their efficacy in cervical cancer remains limited, primarily due to intricate tumor immune evasion mechanisms. Here, we identify elevated IGSF3 expression on tumor cells as a key driver enhancing regulatory T cell (Treg) infiltration and function. Crucially, we reveal a previously unrecognized ligand-receptor pair: IGSF3 on cervical cancer cells binds to TNFR2 on Tregs, activating NF-κB pathway and thereby amplifying Treg-mediated immunosuppression. Through structure-based virtual screening and rigorous multi-level validation, we developed purpurogallin, a conventionally recognized antioxidant compound, as a novel IGSF3 inhibitor, which effectively disrupts the IGSF3-TNFR2 interaction, reduces Treg abundance, suppresses tumor growth, and synergizes with anti-PD-1/anti-CTLA-4 antibodies. Notably, pretreatment with purpurogallin followed by PD-1 blockade yields prominent therapeutic efficacy. This study establishes IGSF3 as a pivotal regulator of the immunosuppressive microenvironment and unveils a promising sequential immunotherapy strategy for cervical cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218307"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197546","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}

引用次数: 0

Starvation-induced LHFPL3-AS2 promotes MAPKAP K2-dependent phosphorylation of hnRNPA0 and progression of esophageal squamous cell carcinoma 饥饿诱导的LHFPL3-AS2促进MAPKAP k2依赖性hnRNPA0磷酸化和食管鳞状细胞癌的进展。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-02-16 DOI: 10.1016/j.canlet.2026.218332

Yuan Xu , Ziqi Zhang , Yanting Yang , Minxin Li , Haipeng Wang , Long Zhang , Shouyu Wang , Chuanli Ren , Nasha Zhang , Zengjun Li , Ming Yang

{"title":"Starvation-induced LHFPL3-AS2 promotes MAPKAP K2-dependent phosphorylation of hnRNPA0 and progression of esophageal squamous cell carcinoma","authors":"Yuan Xu , Ziqi Zhang , Yanting Yang , Minxin Li , Haipeng Wang , Long Zhang , Shouyu Wang , Chuanli Ren , Nasha Zhang , Zengjun Li , Ming Yang","doi":"10.1016/j.canlet.2026.218332","DOIUrl":"10.1016/j.canlet.2026.218332","url":null,"abstract":"<div><div>Esophageal squamous cell carcinoma (ESCC) remains a leading cause of cancer-related mortality worldwide. Long non-coding RNAs (lncRNAs) play essential roles in ESCC progression. In this study, we profiled lncRNA expression in ESCC cells following serum deprivation and identified LHFPL3-AS2 as a serum starvation-inducible, oncogenic lncRNA. LHFPL3-AS2 could promote invasion and metastasis of ESCC cells <em>in vitro</em> and <em>in vivo</em>. Mechanistically, LHFPL3-AS2 directly binds to hnRNPA0 protein, enhances its interaction with its kinase MAPKAP-K2 (MK2), and promotes MK2-mediated phosphorylation of hnRNPA0 at serine 84. The phosphorylated hnRNPA0 binds to several oncogenic transcripts, such as the <em>BMP7</em> mRNAs, stabilizes these mRNAs and elevates their expression in ESCC cells. Importantly, LHFPL3-AS2 enhances polarization of macrophages toward an immunosuppressive M2 phenotype via upregulating BMP7 secretion by cancer cells, thereby facilitating tumor immune evasion and ESCC progression. Overall, our study identified a previously unappreciated LHFPL3-AS2-MK2-hnRNPA0-BMP7 axis in cancer progression under serum starvation conditions and provides mechanistic insight for ESCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218332"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218848","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}

引用次数: 0

SLC5A11 mediates metformin-induced PD-L1 suppression to enhance cancer immunotherapy through AMPK–IRF1 signaling SLC5A11介导二甲双胍诱导的PD-L1抑制，通过AMPK-IRF1信号传导增强癌症免疫治疗

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-02-12 DOI: 10.1016/j.canlet.2026.218311

Yarui Ma , Xue Wang , Zhewen Wei , Qi Zhang , Fangqing Yuan , Chungui Xu , Chang Liu , Xiaobing Wang , Lin Li , Yuchen Jiao

{"title":"SLC5A11 mediates metformin-induced PD-L1 suppression to enhance cancer immunotherapy through AMPK–IRF1 signaling","authors":"Yarui Ma , Xue Wang , Zhewen Wei , Qi Zhang , Fangqing Yuan , Chungui Xu , Chang Liu , Xiaobing Wang , Lin Li , Yuchen Jiao","doi":"10.1016/j.canlet.2026.218311","DOIUrl":"10.1016/j.canlet.2026.218311","url":null,"abstract":"<div><div>Metformin exhibits immunomodulatory properties in cancer treatment, but the underlying mechanisms remain elusive. Using genome-wide CRISPR screening, we identified SLC5A11 as an essential mediator of metformin sensitivity. Molecular docking and dynamics simulations revealed direct metformin-SLC5A11 binding at the pocket containing Asn78 and Glu102 residues. Metformin suppressed PD-L1 expression across multiple cancer models through SLC5A11-dependent activation of AMPK and subsequent JAK2-STAT1-IRF1 downregulation. SLC5A11 knockout abolished these effects, while reconstitution restored metformin responsiveness. In syngeneic mouse models of lung and pancreatic cancer, combining metformin with anti-PD1 therapy produced synergistic antitumor effects, enhanced T cell infiltration, and potentiated immunotherapy efficacy. Metformin pretreatment significantly enhanced PBMC-mediated cytotoxicity against tumor cells and patient-derived organoids in ex vivo co-culture systems. Our findings establish the SLC5A11-AMPK-PD-L1 axis as a novel mechanism linking metformin to tumor immunity, providing a molecular rationale for combining metformin with checkpoint inhibitors in cancer immunotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218311"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197602","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}

引用次数: 0

A tumor-derived mitochondrial tsRNA drives vascular invasion of lung adenocarcinoma by promoting ribosomal assembly in endothelial cells 肿瘤来源的线粒体tsRNA通过促进内皮细胞核糖体组装驱动肺腺癌血管侵袭。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-02-17 DOI: 10.1016/j.canlet.2026.218324

Si Liang , Qinglin Wang , Minhao Zhang , Xuming Song , Yijian Zhang , Hui Wang , Yipeng Feng , Rutao Li , Wenjie Xia , Lin Xu , Gaochao Dong , Qixing Mao , Feng Jiang

{"title":"A tumor-derived mitochondrial tsRNA drives vascular invasion of lung adenocarcinoma by promoting ribosomal assembly in endothelial cells","authors":"Si Liang , Qinglin Wang , Minhao Zhang , Xuming Song , Yijian Zhang , Hui Wang , Yipeng Feng , Rutao Li , Wenjie Xia , Lin Xu , Gaochao Dong , Qixing Mao , Feng Jiang","doi":"10.1016/j.canlet.2026.218324","DOIUrl":"10.1016/j.canlet.2026.218324","url":null,"abstract":"<div><div>Vascular invasion is associated with metastasis and poor prognosis in patients with lung adenocarcinoma (LUAD). Recent studies have highlighted the role of intercellular mitochondrial transfer, mediated by both contact-dependent and contact-independent mechanisms, in tumor progression. Here, we reveal an abnormal accumulation of mitochondria in vascular endothelial cells invaded by tumor cells. Further <em>in vivo</em> and <em>in vitro</em> experiments demonstrated that tumor cells can transfer mitochondria with highly expressed mitochondrial tRNA-derived small RNAs (tsRNAs), mt-5′tiRNA-34-GlnTTG, to endothelial cells. Mechanistic investigations indicated that mt-5′tiRNA-34-GlnTTG binds to FUBP3 and facilitates its translocation, ultimately enhancing ribosomal assembly efficiency and translation rates in endothelial cells. This molecular cascade leads to increased endothelial cell proliferation and migration, thereby promoting LUAD metastasis. Moreover, we demonstrated the potential clinical translational value of lipid nanoparticles(LNPs) encapsulating mt-5′tiRNA-34-GlnTTG inhibitors in animal experiments. Utilizing LNPs encapsulating mt-5′tiRNA-34-GlnTTG inhibitors effectively suppressed lung cancer metastasis in <em>in vivo</em> models. These findings reveal a novel mechanism of LUAD progression mediated by mitochondrial tsRNA transfer and highlight a promising therapeutic strategy for limiting metastatic spread.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218324"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218863","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}

引用次数: 0

Pharmacological inhibition of histone deacetylase 6 and DNA damage repair enhances radiosensitivity in melanoma 药物抑制组蛋白去乙酰化酶6和DNA损伤修复增强黑色素瘤的放射敏感性。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-02-17 DOI: 10.1016/j.canlet.2026.218322

Yidian Fu , Caoyan Jiang , Ying Chen , Fang Li , Xiaoyu He , Liang Ma , Shuer Xie , Lin Ye , Shengfang Ge , Jie Yu , Zhi Yang , Xianqun Fan

{"title":"Pharmacological inhibition of histone deacetylase 6 and DNA damage repair enhances radiosensitivity in melanoma","authors":"Yidian Fu , Caoyan Jiang , Ying Chen , Fang Li , Xiaoyu He , Liang Ma , Shuer Xie , Lin Ye , Shengfang Ge , Jie Yu , Zhi Yang , Xianqun Fan","doi":"10.1016/j.canlet.2026.218322","DOIUrl":"10.1016/j.canlet.2026.218322","url":null,"abstract":"<div><div>Melanoma, a malignant tumour originating from melanin-producing melanocytes, poses a significant threat to human health, including cutaneous melanoma and uveal melanoma (UM). Although surgical resection remains a primary treatment modality, radiotherapy has emerged as another therapeutic option, particularly for UM. Nevertheless, the adverse effects induced by radiotherapy are considerably pronounced. In this study, we identified WT-161, a selective histone deacetylase 6 (HDAC6) inhibitor, as a potent radiosensitizer for melanoma therapy through high-throughput drug screening. Mechanistically, inhibition of HDAC6 disrupted its interaction with DNA damage repair proteins (DDB2 and DEK) and suppressed gene expression in the DNA damage repair pathway, leading to the accumulation of irradiation-induced DNA damage and tumour regression. Our findings establish HDAC6 as a predictive biomarker for radiation response in melanoma and demonstrate that pharmacological inhibition of HDAC6 with WT-161 could expand the clinical utility of radiotherapy in patients with UM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218322"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225684","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}

引用次数: 0

PPP4C restores YAP1 activity by modulating MST4 phosphorylation to enhance immunosuppression and augment tumor growth in non-small cell lung cancer PPP4C通过调节MST4磷酸化来增强非小细胞肺癌的免疫抑制和促进肿瘤生长，从而恢复YAP1活性。

IF 10.1 1区医学

Cancer letters Pub Date : 2026-04-28 Epub Date: 2026-02-12 DOI: 10.1016/j.canlet.2026.218306

Zhengshui Xu , Jiani Gao , Changchun Ye , Yu Li , Danwen Zhao , Liang Li , Liangzhang Sun , Yao Cheng , Wendeng Li , Jiantao Jiang , Shiyuan Liu

{"title":"PPP4C restores YAP1 activity by modulating MST4 phosphorylation to enhance immunosuppression and augment tumor growth in non-small cell lung cancer","authors":"Zhengshui Xu , Jiani Gao , Changchun Ye , Yu Li , Danwen Zhao , Liang Li , Liangzhang Sun , Yao Cheng , Wendeng Li , Jiantao Jiang , Shiyuan Liu","doi":"10.1016/j.canlet.2026.218306","DOIUrl":"10.1016/j.canlet.2026.218306","url":null,"abstract":"<div><div>Abnormal expression of mammalian sterile 20-like kinase 4 (MST4) has been frequently linked to cancer development. This study explores the function of MST4 in non-small cell lung cancer (NSCLC) and delves into its functional mechanism. The expression and clinical indicative values of MST4 in NSCLC were analyzed using tissue microarrays. Gain- and loss-of-function experiments of MST4 were conducted in NSCLC cell lines to identify its effects on cell growth <em>in vitro</em>. Transfected NSCLC cells were co-cultured with natural killer (NK) cells to analyze immune resistance. Mouse NSCLC cells 3LL were transplanted into C57BL/6 mice to generate subcutaneous or orthotopic isograft tumor models. Upstream and downstream factors of MST4 were identified using bioinformatics. MST4 was under-expressed in NSCLC tissue microarrays and human NSCLC cells. MST4 overexpression suppressed growth activity of NSCLC cells <em>in vitro</em>, reduced expression of immune checkpoint genes, and reduced cell resistance to NK cell cytotoxicity. Reverse trends were observed in MST4-silenced cells. <em>In vivo</em>, MST4 overexpression inhibited tumorigenic activity of 3LL cells in mice and reduced immunosuppressive factors in tumor tissues. Regarding the mechanism, MST4 induced phosphorylation and cytoplasmic degradation of YAP1 by influencing the MAP4K2-LATS1/2 cascade. Protein phosphatase 4 catalytic subunit (PPP4C) was found to interact with MST4 and reduce its function, thus promoting growth and immunosuppression in NSCLC by activating YAP1. This study demonstrates that PPP4C-mediated MST4 degradation contributes to growth activity and immunosuppression in NSCLC by restoring YAP1 activity, suggesting PPP4C and MST4 as potential targets for NSCLC management.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"644 ","pages":"Article 218306"},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197458","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}

引用次数: 0