Cancer letters最新文献

{"title":"CDC34 suppresses macrophage phagocytic activity and predicts poor response to immune checkpoint inhibitor in cancers","authors":"Xiao-Liang Jie ,&nbsp;Jia-Cong Wei ,&nbsp;Di Wang ,&nbsp;Xiang-Wei Zhang ,&nbsp;Meng-Yao Lv ,&nbsp;Yong-Fang Lin ,&nbsp;Yi-Shuai Tan ,&nbsp;Zheng Wang ,&nbsp;Aikede Alifu ,&nbsp;Lei Ji ,&nbsp;Yu-Ke Shen ,&nbsp;Cong Wang ,&nbsp;Bing-Qing Xu ,&nbsp;Zheng Liu ,&nbsp;Si-Chong Han ,&nbsp;Zi-Hao Wang ,&nbsp;Xiao-Wan Tong ,&nbsp;Lin Feng ,&nbsp;Jian-Ming Ying ,&nbsp;Guang-Biao Zhou ,&nbsp;Gui-Zhen Wang","doi":"10.1016/j.canlet.2025.217822","DOIUrl":"10.1016/j.canlet.2025.217822","url":null,"abstract":"<div><div>The Cell Division Cycle 34 (CDC34) is an E2 ubiquitin-conjugating enzyme that is required for proteasomal degradation of substrate proteins, and is able to stabilize proteins including the epidermal growth factor receptor to promote lung carcinogenesis. Here, we conducted a pan-cancer analysis of CDC34 in The Cancer Genome Atlas datasets, and found its high expression in breast cancer and negative association with patient outcomes. Analysis of single-cell RNA-sequencing data revealed a negative role of CDC34 in macrophage phagocytotic activity for cancer cells. CDC34 stabilized hypoxia-inducible factor 1α (HIF1α) and transcriptionally upregulated CD47 in cancer cells to evade phagocytosis by macrophages. Inhibition of CDC34 inhibited tumor growth and synergized with anti-PD-L1 antibody in murine models. CDC34 was positively associated with CD47 and negatively associated with CD8⁺ granzyme B⁺ T-cell infiltration in patient samples, and patients with co-overexpression of CDC34 and CD47 had markedly poorer prognosis compared to those with high expression of either marker alone. In pre-treatment tumor samples, non-responders to immunotherapy exhibited significantly higher CDC34 levels and reduced CD8⁺ T-cell infiltration compared to responders. These findings indicated that CDC34 is critical to immune evasion and could be a potential therapeutic target for those resistant to immune checkpoint inhibitors.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217822"},"PeriodicalIF":9.1,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149260","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":"Therapeutic targeting of circTNK2 with nanoparticles restores tamoxifen sensitivity and enhances NK cell-mediated immunity in ER-positive breast cancer","authors":"Runxin Wu ,&nbsp;Shubin Yu ,&nbsp;Aiwei Bi ,&nbsp;Yingliang Li ,&nbsp;Deanna Tiek ,&nbsp;Kuai Yu ,&nbsp;Haiwei Xiong ,&nbsp;Qingfeng Shi ,&nbsp;Zhaohong Mo ,&nbsp;Xiaozhou Yu ,&nbsp;Xiao Song ,&nbsp;Fang Yin ,&nbsp;Yu Wang ,&nbsp;Wang Yi ,&nbsp;Mengting Liu ,&nbsp;Penghui Li ,&nbsp;Bo Hu ,&nbsp;Aiping Le ,&nbsp;Shi-Yuan Cheng ,&nbsp;Boxuan Zhou","doi":"10.1016/j.canlet.2025.217823","DOIUrl":"10.1016/j.canlet.2025.217823","url":null,"abstract":"<div><div>Endocrine resistance is a leading cause of relapse in patients with estrogen receptor (ER)-positive breast cancer (ER⁺ BC), with tamoxifen resistance being the most prevalent form. circTNK2, a circular RNA, is overexpressed in tamoxifen-resistant BC tissues and is correlated with poor prognosis. circTNK2 encodes a novel 487-amino acid protein, termed C-TNK2-487aa, which inhibits the recruitment of natural killer (NK) cells into BC tumors. Mechanistically, C-TNK2-487aa interacts with STAT3 and promotes STAT3 phosphorylation (p-STAT3) in ER⁺ BC cells. The increased p-STAT3 competes with STAT1 binding, inhibiting the formation of STAT1 homodimers that induces CXCL10 expression, ultimately leading to immune evasion. Additionally, circTNK2 RNA binds to SRSF1 and promotes tamoxifen resistance and BC tumorigenicity by activating AKT-mTOR signaling. Delivery of BC-targeting ZIF-8 nanoparticles loaded with circTNK2 antisense oligonucleotides (ASOs) and a CXCL10-encoding plasmid DNA markedly suppresses the growth of BC tumor xenografts, restores tamoxifen sensitivity, and increases CD56⁺ NK cell infiltration into BC tumors. Our data describe a critical role of the circTNK2-encoded peptide and its RNA in ER⁺ BC resistance to tamoxifen and immune evasion, providing a therapeutic vulnerability in treating tamoxifen-resistant breast cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"627 ","pages":"Article 217823"},"PeriodicalIF":9.1,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149286","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":"Role of artificial intelligence in cancer drug discovery and development","authors":"Sruthi Sarvepalli ,&nbsp;ShubhaDeepthi Vadarevu","doi":"10.1016/j.canlet.2025.217821","DOIUrl":"10.1016/j.canlet.2025.217821","url":null,"abstract":"<div><div>The role of artificial intelligence (AI) in cancer drug discovery and development has garnered significant attention due to its potential to transform the traditionally time-consuming and expensive processes involved in bringing new therapies to market. AI technologies, such as machine learning (ML) and deep learning (DL), enable the efficient analysis of vast datasets, facilitate faster identification of drug targets, optimization of compounds, and prediction of clinical outcomes. This review explores the multifaceted applications of AI across various stages of cancer drug development, from early-stage discovery to clinical trial design, development.</div><div>In early-stage discovery, AI-driven methods support target identification, virtual screening (VS), and molecular docking, offering precise predictions that streamline the identification of promising compounds. Additionally, AI is instrumental in de novo drug design and lead optimization, where algorithms can generate novel molecular structures and optimize their properties to enhance drug efficacy and safety profiles. Preclinical development benefits from AI's predictive modeling capabilities, particularly in assessing a drug's toxicity through in silico simulations. AI also plays a pivotal role in biomarker discovery, enabling the identification of specific molecular signatures that can inform patient stratification and personalized treatment approaches. In clinical development, AI optimizes trial design by leveraging real-world data (RWD), improving patient selection, and reducing the time required to bring new drugs to market.</div><div>Despite its transformative potential, challenges remain, including issues related to data quality, model interpretability, and regulatory hurdles. Addressing these limitations is critical for fully realizing AI's potential in cancer drug discovery and development. As AI continues to evolve, its integration with other technologies, such as genomics and clustered regularly interspaced short palindromic repeats (CRISPR), holds promise for advancing personalized cancer therapies. This review provides a comprehensive overview of AI's impact on the cancer drug discovery and development and highlights future directions for this rapidly evolving field.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"627 ","pages":"Article 217821"},"PeriodicalIF":9.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141539","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":"Effective leukemia-to-granulocyte induction by a cocktail of RUNX1, SPI1 and CEBPE","authors":"Guiqiyang Xiang ,&nbsp;Ping Zhu ,&nbsp;Liuqingqing Zhang ,&nbsp;Shuting Yu ,&nbsp;Fangying Jiang ,&nbsp;Shuai Wang ,&nbsp;Jinzeng Wang ,&nbsp;Yao Dai ,&nbsp;Shengyue Wang ,&nbsp;Yun Tan ,&nbsp;Feng Liu","doi":"10.1016/j.canlet.2025.217820","DOIUrl":"10.1016/j.canlet.2025.217820","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"626 ","pages":"Article 217820"},"PeriodicalIF":9.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138471","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":"Evolutionary adaptation and asymmetric inheritance of polyploid giant cancer cells in esophageal squamous cell carcinoma.","authors":"Qiqin Song, Mingwei Gao, Yongjia Weng, Xuehan Zhuang, Yueguang Wu, Heyang Cui, Ning Ding, Longlong Wang, Shanshan Bi, Li Zhang, Weimin Zhang, Yongping Cui","doi":"10.1016/j.canlet.2025.217818","DOIUrl":"10.1016/j.canlet.2025.217818","url":null,"abstract":"<p><p>Polyploid Giant Cancer Cells (PGCCs) play a critical role in tumor progression due to their distinctive biological behaviors. However, the mechanisms by which PGCCs regulate their composition and structure to adapt to dynamic environments during their formation remain poorly understood. In this study, we used multicolour labeling of major organelles in esophageal squamous cell carcinoma (ESCC) cells combined with high- and super-resolution time-lapse imaging to monitor induced PGCCs in three dimensions. In addition to abnormal PGCC division, we observed nuclear dynamics and transient cell-in-cell formations. PGCCs exhibited cell cycle abnormalities, including prolonged G1/S transitions, asynchronous micronuclei, and intranuclear mitosis. Notably, early progeny continued dividing despite cell cycle dysregulation, resulting in asymmetric offspring. Quantitative analysis of subcellular structures revealed asymmetric inheritance of organelles, particularly mitochondria and the Golgi apparatus, in recurrent cells. These adaptive mechanisms in PGCCs may also be relevant in the context of anticancer treatments, contributing to the heterogeneity of recurrent tumours arising from early PGCC progeny populations.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217818"},"PeriodicalIF":9.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141514","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":"Fusobacterium nucleatum enhances cholesterol biosynthesis in colorectal cancer via miR-130a-3p-mediated AMPK inhibition, a process counteracted by butyrate","authors":"Yuting Sun ,&nbsp;Jiawei Lu ,&nbsp;Effie Yin Tung Lau ,&nbsp;Yao Zeng ,&nbsp;Sarah Wing Lam Li ,&nbsp;Ting Hei Au ,&nbsp;Silin Ye ,&nbsp;Tingyu Zhou ,&nbsp;Francis KL. Chan ,&nbsp;Jessie Qiaoyi Liang","doi":"10.1016/j.canlet.2025.217810","DOIUrl":"10.1016/j.canlet.2025.217810","url":null,"abstract":"<div><div><em>Fusobacterium nucleatum</em> (<em>Fn</em>) has been implicated in various diseases, including colorectal cancer (CRC). This study elucidates <em>Fn</em>'s contribution to cholesterol synthesis and the underlying link with CRC, as well as butyrate's counteracting effects in this process. Cells and mouse models were treated with <em>Fn</em> followed/accompanied by butyrate treatments to investigate the interplay between butyrate and <em>Fn</em>'s oncogenic properties. Transcriptomics analysis pinpointed <em>Fn</em>'s profound impact on cholesterol biosynthesis genes and pathways. <em>Fn</em> treatment upregulated the expression of genes involved in cholesterol synthesis (FDPS, FDFT1, and SQLE) and increased SREBF2 activity in cells and mouse intestines, elevating cholesterol levels in cells, intestines, and sera. <em>Fn</em> upregulated miR-130a-3p, identified through transcriptomics and target prediction, through nuclear factor-κB activation. miR-130a-3p subsequently downregulated AMPKα/β1 expression to activate SREBF2 and upregulate cholesterol biosynthesis genes. These effects were predominantly mitigated by butyrate. Notably, analysis of TCGA data revealed that fusobacterial abundance correlated significantly with the expression of FDPS, FDFT1, SQLE, and AMPKα/β1 in CRC. <em>Fn</em> abundance and miRNA expression in human stools were quantified using qPCR and RT-qPCR. Fecal miR-130a-3p levels increased progressively from normal subjects through adenoma patients to CRC patients, correlating significantly with fecal <em>Fn</em> abundance. Additionally, heightened fecal <em>Fn</em> abundance was associated with an increased incidence of hypercholesterolemia in CRC patients. <em>Fn</em> promotes cholesterol biosynthesis by upregulating miR-130a-3p, which downregulates AMPK proteins and activates SREBF2. This study highlights the influence of gut bacteria on host cholesterol synthesis. Targeted modulation of gut microbiota to reduce cholesterol may represent a promising preventive strategy for CRC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"627 ","pages":"Article 217810"},"PeriodicalIF":9.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141532","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":"Harnessing exosomes: From tumor immune escape to therapeutic innovation in gastric cancer immunotherapy","authors":"Zhao Jin,&nbsp;Cheng Zhang,&nbsp;Lin Shen,&nbsp;Yanshuo Cao","doi":"10.1016/j.canlet.2025.217792","DOIUrl":"10.1016/j.canlet.2025.217792","url":null,"abstract":"<div><div>Gastric cancer ranks fifth among the most prevalent cancers globally, with a dismal prognosis. In recent years, immunotherapy, particularly immune checkpoint inhibitors, has emerged as a glimmer of hope for advanced gastric cancer patients. However, not all patients can benefit from this treatment modality, as the tumor microenvironment significantly influences treatment efficacy. Exosomes, pivotal mediators of intercellular communication, exert intricate and diverse effects in shaping and regulating the tumor microenvironment. This review provides a comprehensive overview of the functional mechanisms of exosomes within the gastric cancer tumor microenvironment. It delves into their biogenesis, functions, and impact on innate and adaptive immune cells (such as dendritic cells, myeloid-derived suppressor cells, and T cells) and cancer-associated fibroblasts. Additionally, the potential applications of exosomes in gastric cancer immunotherapy are explored, including their use as biomarkers to predict responses to immune checkpoint inhibitors, and drug delivery vectors, and in the development of exosome-based vaccines and gene therapy. Notably, this review emphasizes the dual nature of exosomes: they can facilitate tumor immune escape, yet they also serve as promising targets for innovative therapeutic strategies. It also compares potential exosome-based strategies with existing immunotherapies like ICIs and emerging CAR-T cell therapies. Finally, insights into the future of exosomes in precision immunotherapy for gastric cancer are offered, presenting a forward-looking perspective on this emerging field.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"626 ","pages":"Article 217792"},"PeriodicalIF":9.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132199","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":"Polo-like kinase 1 inactivation enhances PI3K inhibition-mediated apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma","authors":"Pooja A. Shah ,&nbsp;Tuhina Mazumdar ,&nbsp;Soma Ghosh ,&nbsp;Lacin Yapindi ,&nbsp;Reid T. Powell ,&nbsp;Yong S. Park ,&nbsp;Li Shen ,&nbsp;Anne M. Fernandez ,&nbsp;Clifford C. Stephan ,&nbsp;Jing Wang ,&nbsp;Andrew G. Sikora ,&nbsp;Jawad Kazi ,&nbsp;Mitchell J. Frederick ,&nbsp;Faye M. Johnson","doi":"10.1016/j.canlet.2025.217814","DOIUrl":"10.1016/j.canlet.2025.217814","url":null,"abstract":"<div><div>PI3K inhibition causes apoptosis selectively in <em>NOTCH1</em>-mutant head and neck squamous cell carcinoma (HNSCC), but modest single-agent responses and acquired resistance (AR) limit the clinical efficacy of targeted agents. To address these limitations, we investigated novel combination therapies. We tested the efficacy of 5768 compounds as single agents and 139 in combination with PI3K inhibitors in sensitive and AR <em>NOTCH1</em>-mutant HNSCC cell lines. We generated synergy/efficacy classifications for the combinations using multiple metrics of statistical drug synergy and growth rate indices. The PLK1/PI3K combination's efficacy was validated using orthogonal <em>in vitro</em> methods and in two HNSCC xenograft models. Compound efficacy was enriched in 30 of 306 drug classes. Drugs from nine classes enhanced the cell killing of PI3K inhibition. We pursued experiments with PLK1 inhibitors based on clinical relevance and efficacy in parental and AR models. The combination of PLK1 and PI3K inhibition caused apoptosis, DNA damage, and immunogenic cell death <em>in vitro</em> and extended survival <em>in vivo</em>. PLK1 activity decreased following PI3K inhibition only in sensitive <em>NOTCH1</em>-mutant HNSCC cell lines and not in AR or resistant wild-type cells. The combination of PI3K and PLK1 inhibition causes robust killing of HNSCC and overcomes PI3K inhibitor resistance. Specific and well-tolerated PI3K and PLK1 inhibitors that do not have overlapping toxicity are in clinical development. We hypothesize that this combination may have a wide therapeutic window with significant efficacy but modest toxicity because it should spare normal cells that have wild-type <em>NOTCH1</em> and are not sensitive to PI3K inhibition.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"625 ","pages":"Article 217814"},"PeriodicalIF":9.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123857","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":"Multi-omics analysis unraveling stemness features associated with oncogenic dedifferentiation in 12 cancers","authors":"Jun Cheng ,&nbsp;Jiafan Cao ,&nbsp;Yalan Yang ,&nbsp;Ying Wang ,&nbsp;Xianzhe Hu ,&nbsp;Zhuoyuan Liu ,&nbsp;Qiuyin Huang ,&nbsp;Zhitao Ye ,&nbsp;Wei Xian ,&nbsp;Kexin Sun ,&nbsp;Mengyun Xie ,&nbsp;Jiayin Zheng ,&nbsp;Yijun Zhao ,&nbsp;Runhui Zheng ,&nbsp;Huo Tan ,&nbsp;Xiaoqi Wang ,&nbsp;Xi Zhang ,&nbsp;Chuanxin Wang ,&nbsp;Changzheng Li","doi":"10.1016/j.canlet.2025.217816","DOIUrl":"10.1016/j.canlet.2025.217816","url":null,"abstract":"<div><div>Tumorigenesis is typically accompanied by cellular dedifferentiation and the acquisition of stem cell-like attributes. However, few studies have comprehensively evaluated the putative relationships between these characteristics and various cancers. Here, we integrated gene expression and DNA methylation quantitative trait loci (<em>cis</em>-eQTL and <em>cis</em>-mQTL) data from the blood to perform multi-omics Mendelian randomization analysis. Our analyses revealed 967 stem cell-associated genes (P &lt; 0.05) and 11,262 methylation sites (P &lt; 0.01) significantly related to 12 cancers. <em>SMAD7</em> (cg14321542) in colon cancer, <em>IGF2</em> (cg13508136) in prostate cancer, and <em>FADS1</em> (cg07005513) in rectal cancer were prioritized as candidate causal genes and regulatory elements. Notably, using <em>cis</em>-eQTL data from the corresponding tissue sites, we detected 16 stem cell-associated genes dramatically causally associated with six cancers (FDR&lt;0.2). The gene <em>THBS3</em> was particularly common in both blood and stomach tissues and exhibited prognostic significance. Furthermore, it was markedly associated with one microbial metabolic pathway and four immunophenotypes. Functional validation using the ECC12 gastric cancer cell line revealed that the inhibition of its expression could accelerate oxidative phosphorylation and reactive oxygen species production, reduce clonal proliferation ability, and promote the apoptosis of stomach tumor cells. Additionally, based on spatial transcriptomic data from gastrointestinal cancers, the results demonstrated the clusters enriched with the most stem cell-associated genes exhibited significantly enhanced tumor-promoting potency, and the <em>THBS3</em>-expressing cells displayed suppressed oxidative phosphorylation. Overall, this study enhances our understanding of tumorigenic mechanisms and aids in the identification of therapeutic targets.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"625 ","pages":"Article 217816"},"PeriodicalIF":9.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123856","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":"Radiotherapy-induced TACC3 confers resistance of HCC to radiotherapy and enhances IL4-dependent immunosuppression to exacerbate hepatocarcinogenesis","authors":"Cheng-Rui Zhong ,&nbsp;Zong-Feng Wu ,&nbsp;Zi-Qi Zheng ,&nbsp;Zhu Lin ,&nbsp;Yong-Ling Liang ,&nbsp;Ze-Jin Lin ,&nbsp;Yun-Le Wan ,&nbsp;Guo-Lin Li","doi":"10.1016/j.canlet.2025.217819","DOIUrl":"10.1016/j.canlet.2025.217819","url":null,"abstract":"<div><div>Radiotherapy plays an increasingly crucial role in the treatment of hepatocellular carcinoma (HCC). However, resistance to radiotherapy remains a significant obstacle to achieving optimal treatment outcomes. Our objective is to elucidate the mechanisms underlying radiotherapy resistance. Through proteomic sequencing of radiotherapy-resistant cell lines and patient-derived xenograft tissues from HCC patients, we identified that Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) is upregulated in both radiotherapy-resistant cell lines and tissues. After radiotherapy treatment, DNAPK phosphorylates TACC3 at 315 threonine, leading to enhanced protein stability of TACC3. TACC3 facilitated the proliferative capacity and radiotherapy resistance of HCC cells by promoting the interaction between XRCC5 and XRCC6 through specific residues within its coiled-coil domain, namely ILE736, ASN742 and GLU773. This interaction facilitates DNA damage repair via the non-homologous end joining pathway in response to radiation, thereby contributing to the radiotherapy resistance in HCC cells. Furthermore, TACC3 increases the production of IL-4 and IL-10 within HCC cells, inducing the differentiation of M0 macrophages to M2 macrophages within the immune microenvironment, leading to the suppression of CD8⁺T cell cytotoxic functions and creating an immunosuppressive microenvironment in HCC. Targeting TACC3 with inhibitor KHS101 significantly inhibit the proliferation of HCC and improve the immune microenvironment of HCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"627 ","pages":"Article 217819"},"PeriodicalIF":9.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141536","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}