Cancer Communications最新文献

{"title":"Intranuclear paraspeckle-circular RNA TACC3 assembly forms RNA-DNA hybrids to facilitate MASH-related hepatocellular carcinoma growth in an m⁶A-dependent manner.","authors":"Jingbo Fu, Yanping Wei, Yun Yang, Xinwei Yang, Tao Ouyang, Xianming Wang, Shuzhen Chen, Zenglin Liu, Yu Su, Jing Fu, Miao Yu, Haihua Qian, Hao Song, Shuo Xu, Ru Zhao, Xue Jiang, Yunfei Huo, Man Zhang, Pinhua Yang, Zhao Yang, Kui Wang, Liang Li, Hongyang Wang","doi":"10.1002/cac2.70061","DOIUrl":"https://doi.org/10.1002/cac2.70061","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is anticipated to become the leading cause of hepatocellular carcinoma (HCC). Accumulating evidence indicates that N6-methyladenosine (m⁶A)-modified circular RNAs (circRNAs) play key roles in tumor malignant progression. However, the precise molecular mechanisms by which circRNAs and their m⁶A modification regulatory networks respond to metabolic reprogramming, such as lipid overload stress, to drive malignant tumor progression in the context of MASH-related HCC remain unclear. This study aimed to investigate the role and regulatory network of m⁶A-modified circRNAs in MASH-related HCC.</p><p><strong>Methods: </strong>Epitranscriptomic microarray and in situ hybridization assays were used to validate circTACC3 expression in MASH-related HCC specimens. Palmitic acid (PA) and oleic acid (OA) was applied to NAC-organ assembled three-dimensional-organoid and HCC cell lines to imitate pathological lipid overload. The circTACC3-paraspeckle interaction was studied utilizing fluorescence lifetime imaging microscopy-Forster resonance energy transfer. An integrative analysis combining DNA-RNA immunoprecipitation combined with chromatin isolation by RNA purification (DRIP-ChIRP), γH2AX cleavage under target and tagmentation, and high-throughput/resolution chromosome conformation capture sequencing were used to study chromatin remodeling induced by circTACC3-formed RNA-DNA hybrids (R loops) at DNA double-strand break (DSB) loci during lipid overload.</p><p><strong>Results: </strong>The most prevalent m⁶A-modified circRNA in MASH-related HCC, circTACC3, had a substantial impact on the intracellular lipid accumulation, growth, and environmental adaptive survival of tumor cells. Under lipid overload conditions, circTACC3 interacted directly with non-POU domain-containing octamer-binding protein (NONO/p54^nrb) to assemble intranuclear paraspeckle. This process was dependent on the m⁶A-modification sites of circTACC3 and facilitated its nuclear retention. Using DRIP-ChIRP-sequencing, we demonstrated that circTACC3-containing paraspeckles were recruited to DSB foci to form R loops (DSB-circTACC3-R loops). We discovered 4 highly enriched motifs of DSB-circTACC3-R loops. DSB-circTACC3-R loops further facilitated the contact and fusion of topologically associated domains (TADs) and selectively activated genes related to the malignant phenotype of MASH-related HCC. Interestingly, circTACC3-R loops exerted positive feedback control over the assembly of circTACC3 paraspeckle and clustering of TADs.</p><p><strong>Conclusions: </strong>The m⁶A modification-dependent circTACC3-paraspeckle assembly results in the formation of R loops at DSB foci, leading to chromatin remodeling and the activation of genes involved in MASH-related HCC malignant progression. This process identifies potential therapeutic targets.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306893","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":"RNA m¹A methyltransferase TRMT61A promotes colorectal tumorigenesis by enhancing ONECUT2 mRNA stability and is a potential therapeutic target.","authors":"Xiaoting Zhang, Na Qin, Fenfen Ji, Hao Su, Haiyun Shang, Hongyan Chen, Dan Huang, Qing Li, Jing Ren, Weixin Liu, Yifei Wang, Wei Kang, Jiabin Wu, Chi-Chun Wong, Zongwei Cai, Matthew Tak Vai Chan, William Ka Kei Wu, Jun Yu, Huarong Chen","doi":"10.1002/cac2.70070","DOIUrl":"https://doi.org/10.1002/cac2.70070","url":null,"abstract":"<p><strong>Background: </strong>The role of N1-methyladenosine (m¹A) in cancer is poorly understood. Here we explored the function of RNA methyltransferase TRNA methyltransferase 61A (TRMT61A) in colorectal cancer (CRC) and its potential as a therapeutic target.</p><p><strong>Methods: </strong>RNA m¹A levels were assessed through liquid chromatography-mass spectrometry. The expression and clinical significance of TRMT61A were investigated across five human CRC cohorts. The function of TRMT61A was elucidated using CRC cell lines, patient-derived organoids, xenografts, and transgenic mouse models. Integrated analyses of m¹A-sequencing and RNA-sequencing revealed the underlying mechanisms of TRMT61A. A nanoparticle-based small interfering RNA (siRNA) delivery system and a specific inhibitor were developed to target TRMT61A. The efficacy and safety of targeting TRMT61A were assessed.</p><p><strong>Results: </strong>Our research revealed a consistent increase in TRMT61A expression and total RNA m¹A levels within primary CRCs. High TRMT61A expression was associated with poor prognosis of CRC patients. Through CRISPR/Cas9 screenings, we identified TRMT61A as the most essential gene among m¹A regulators. Furthermore, we established that TRMT61A promoted CRC tumorigenesis and progression by enhancing the mRNA stability of critical targets in an m¹A-dependent manner. In particular, TRMT61A boosted the mRNA stability of one cut homeobox 2 (ONECUT2), which in turn triggered son of sevenless homolog 1 (SOS1) transcription, leading to the induction of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling in CRC. Notably, our study underscored the safety and substantial anti-CRC effects achievable by inhibiting TRMT61A using nanoparticle-encapsulated siTRMT61A or our newly discovered small molecule compound, pentagalloylglucose.</p><p><strong>Conclusions: </strong>Our study unveiled the tumor-promoting role of TRMT61A in CRC via the m¹A-ONECUT2-SOS1-MAPK/ERK pathway. Targeting TRMT61A showed promise as a therapeutic strategy for treating CRC.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306923","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":"Tumor-infiltrating lymphocyte therapy and the mucosal melanoma treatment landscape.","authors":"Jennifer Thomas, Max Julve, James Larkin, Andrew Furness","doi":"10.1002/cac2.70069","DOIUrl":"https://doi.org/10.1002/cac2.70069","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291240","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":"CD24 is a promising immunotherapeutic target for enhancing efficacy of third-generation EGFR-TKIs on EGFR-mutated lung cancer.","authors":"Jiaqi Liang, Guoshu Bi, Xiaolong Huang, Zhijie Xu, Yiwei Huang, Yunyi Bian, Guangyao Shan, Wei Guo, Yuanliang Yan, Qihai Sui, Xiaodong Yang, Zhencong Chen, Tao Lu, Huan Zhang, Qun Wang, Wei Jiang, Cheng Zhan","doi":"10.1002/cac2.70068","DOIUrl":"https://doi.org/10.1002/cac2.70068","url":null,"abstract":"<p><strong>Background: </strong>Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show initial efficacy in EGFR-mutated lung cancer, but residual disease persists. This study aimed to investigate cluster of differentiation 24 (CD24) as a translational immunotherapeutic target for enhancing third-generation EGFR-TKI efficacy.</p><p><strong>Methods: </strong>We conducted RNA-sequencing (RNA-seq) on drug-responsive, drug-tolerant persister, and drug-resistant cells to identify therapeutic targets to pair with EGFR-TKIs. For validation, we integrated single-cell RNA-seq data from 29 lung cancer specimens and used single-nucleus RNA-seq and immunohistochemistry on clinical residual tumor samples following TKI therapy (TKI-residual). With CRISPR/Cas9, we studied the effect of CD24 on proliferation and phagocytic clearance during EGFR-TKI treatment. We tested CD24 knockout or ATG-031 (a first-in-class CD24 antibody) with EGFR-TKIs in vitro, xenografts, and spontaneous lung cancer models. To explore mechanisms, we used DNA affinity precipitation, chromatin immunoprecipitation sequencing, and luciferase assays to identify transcription factors regulating CD24. Co-immunoprecipitation combined with mass spectrometry and phosphoproteomics were used to study YIN-YANG-1 (YY1) S247 phosphorylation's expression and function, while kinase inhibitors assessed upstream phosphorylation of YY1 S247 and its regulation of CD24.</p><p><strong>Results: </strong>CD24 expression rose in drug-responsive, -resistant, and -tolerant lung cancer cells and post-EGFR-TKI treatment clinical specimens. This elevation promoted cell proliferation and shielded tumor cells from macrophage-mediated phagocytosis. Genetic depletion of CD24 or treatment with ATG-031 significantly enhanced phagocytosis and tumor eradication in vitro, in xenografts, and in mice harboring EGFRL858R·T790M-driven spontaneous lung tumors. Furthermore, we revealed that YY1 S247 phosphorylation was responsible for the upregulation of CD24 upon EGFR-TKI treatment, facilitating YY1 dimerization and the formation of promoter-enhancer loops that regulate CD24 expression.</p><p><strong>Conclusions: </strong>CD24 is a promising target in EGFR-mutated lung cancers, potentially enhancing efficacy of third-generation EGFR-TKIs.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285759","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":"Breaking barriers: the cGAS-STING pathway as a novel frontier in cancer immunotherapy.","authors":"Yuheng Yan, Ximin Tan, Bin Song, Ming Yi, Qian Chu, Kongming Wu","doi":"10.1002/cac2.70067","DOIUrl":"https://doi.org/10.1002/cac2.70067","url":null,"abstract":"<p><p>Since its discovery, the cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon gene (STING) signaling pathway has been considered a pivotal component of innate immunity and a promising target for cancer immunotherapy. Beyond its canonical role in pathogen defense, accumulating evidence has demonstrated that the cGAS-STING pathway critically regulates diverse cellular processes, including cellular senescence, autophagy, cell death, and tumor immunosurveillance; therefore, dysregulation of this pathway correlates with the pathogenesis and progression of various human diseases, ranging from autoimmune and inflammatory disorders to cancer. Herein, we reviewed the regulatory mechanisms and cellular functions of the cGAS-STING pathway, highlighting its essential role in maintaining immune homeostasis. We systematically discussed the dual roles of the cGAS-STING pathway in cancer immunity, in which it triggers both antitumor and immunosuppressive effects. Finally, we summarized the recent advances and challenges in therapeutic strategies targeting the cGAS-STING pathway and discussed the next generation of therapies, including nanomaterials, antibody-drug conjugates, engineered bacteria, alternative strategies, optogenetic approaches, and combination strategies. We hope that our efforts will advance the understanding of the fundamental principles of innate immune recognition and response, and provide novel directions for improving the clinical outcomes of cGAS-STING-targeted therapies.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278981","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":"Efficacy and safety of glecirasib in solid tumors with KRAS G12C mutation: A pooled analysis of two phase I/II trials.","authors":"Jian Li, Ting Deng, Yanhong Gu, Antonio Calles Blanco, Zhihua Li, Chunmei Bai, Lin Wu, Jing Huang, Xingya Li, Yu Yao, Zhengbo Song, Yongsheng Li, Lian Liu, Ligang Xing, Wenming Wu, Julia Martínez-Pérez, Ayala Hubert, Jon Zugazagoitia, Jian Zhang, Yongsheng Wang, Yanqiu Zhao, Guilan Wen, Guohao Xia, Diansheng Zhong, Xueqin Chen, Kuirong Jiang, Andrea Wang-Gillam, Yuli Ding, Sumei Liu, Zhiyue Rao, Xinghu Liu, Lin Shen","doi":"10.1002/cac2.70056","DOIUrl":"10.1002/cac2.70056","url":null,"abstract":"<p><strong>Background: </strong>Glecirasib, an inhibitor of Kirsten rat sarcoma viral oncogene homolog glycine-to-cysteine substitution at codon 12 (KRAS G12C), has exhibited clinical activity in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). Here, we investigated the efficacy and safety of glecirasib in patients with pancreatic ductal adenocarcinoma (PDAC) and other solid tumors (excluding NSCLC and CRC) that rarely harbor the KRAS G12C mutation but for which effective treatment options remain limited.</p><p><strong>Methods: </strong>We conducted and analyzed two open-label, phase I/II trials in adult patients with KRAS G12C mutant solid tumors, in which glecirasib was administered orally. The two trials had similar eligibility criteria and endpoints but differed in the regions of patient recruitment. We performed a pooled analysis of all patients, excluding NSCLC and CRC, from both trials. The primary endpoint in the pooled population was objective response rate (ORR). Efficacy and safety were assessed in patients who received at least one dose of glecirasib.</p><p><strong>Results: </strong>As of June 30, 2024, the pooled analysis included 54 patients who were treated with glecirasib: 32 PDACs, 8 biliary tract cancers (BTCs), 4 small intestinal cancers, 3 gastric cancers, 2 appendiceal cancers, and 5 other tumors. At baseline, 24 received ≥ two prior lines of systemic therapy. Of the 53 efficacy-evaluable patients, the confirmed ORR was 50.9% (95% confidence interval [CI], 36.8%-64.9%), with an ORR of 46.9% (95% CI, 29.1%-65.3%) in PDAC patients. Among other solid tumors, ORR was 71.4% (5/7) in BTC, 100% (4/4) in small intestinal cancer, and 66.7% (2/3) in gastric cancer. Median progression-free survival and median overall survival were 6.9 and 10.8 months, respectively, in the overall population, and 5.5 and 10.8 months, respectively, in patients with PDAC. Treatment-related adverse events (TRAEs) of any grade occurred in 94.4% patients, with grade ≥ 3 TRAEs in 27.8%. No fatal TRAEs or TRAEs leading to treatment discontinuation occurred.</p><p><strong>Conclusions: </strong>Glecirasib showed promising efficacy and was well tolerated in patients with PDAC and other advanced solid tumors (beyond NSCLC and CRC), warranting further expedited clinical development in this patient population.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT05009329 and NCT05002270.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211883","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":"Diagnostic performance of a circulating tumor DNA-based blood test compared to fecal immunochemical test in colorectal cancer screening.","authors":"Hermann Brenner, Teresa Seum, Megha Bhardwaj, Michael Hoffmeister","doi":"10.1002/cac2.70066","DOIUrl":"https://doi.org/10.1002/cac2.70066","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198651","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":"Cover Image, Volume 45, Issue 9","authors":"Seonghye Kim,&nbsp;Bongseong Kim,&nbsp;Kyu-won Jung,&nbsp;Ga Eun Nam,&nbsp;Wonyoung Jung,&nbsp;Junhee Park,&nbsp;Kyung-Do Han,&nbsp;Dong Wook Shin","doi":"10.1002/cac2.70065","DOIUrl":"https://doi.org/10.1002/cac2.70065","url":null,"abstract":"<p>The cover image is based on the article <i>Associations of body mass index and waist circumference with incidence of overall and of 27 site-specific cancers: a population-based retrospective cohort study</i> by Dong Wook Shin et al., https://doi.org/10.1002/cac2.70039.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 9","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Circulating tumor cells share RNA modules with early embryo trophectoderm and with metastatic cancer\".","authors":"","doi":"10.1002/cac2.70062","DOIUrl":"https://doi.org/10.1002/cac2.70062","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147816","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":"Mechanism and role of regulated cell death in tumor immunity and immunotherapy.","authors":"Jingwen Hu, Yan Li, Bingjie Lian, Yitao Mao, Luqing Zhao","doi":"10.1002/cac2.70064","DOIUrl":"https://doi.org/10.1002/cac2.70064","url":null,"abstract":"<p><p>Cancer immune checkpoint inhibitors (ICIs) have brought breakthroughs, but only about one-third of cancer patients benefit from ICIs. In recent years, targeting non-apoptotic regulated cell death (RCD) subtypes, such as ferroptosis, necroptosis, autophagy, cuproptosis, and pyroptosis, has emerged as a novel strategy in cancer therapy due to their ability to release damage-associated molecular patterns (DAMPs), enhance antigen presentation, and remodel the tumor immune microenvironment, thereby activating anti-tumor immune responses. A number of studies have shown that precise induction of these pathways by small molecules or nanoparticles can reverse the resistance to chemoradiotherapy and ICIs, promote the transformation of \"cold tumors\" to \"hot tumors,\" and ultimately establish durable immune memory. This article systematically reviewed the key mechanisms and immunomodulatory functions of five types of non-apoptotic RCD (ferroptosis, necroptosis, autophagy, cuproptosis, and pyroptosis), discussed the related treatment strategies, and prospects for the future application in combination with existing immunotherapy.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147769","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}