Cell Research最新文献

{"title":"Correction: ZBP1 links infections to cancer immunotherapy","authors":"Lorenzo Galluzzi, Spencer Brackett, Neil Johnson","doi":"10.1038/s41422-025-01211-7","DOIUrl":"10.1038/s41422-025-01211-7","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 3","pages":"1-1"},"PeriodicalIF":25.9,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01211-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic and transcriptomic dynamics in the stepwise progression of lung adenocarcinoma","authors":"Fangqiu Fu, Jun Shang, Yueren Yan, He Jiang, Han Han, Hui Yuan, Zhendong Gao, Jingcheng Yang, Jian Gao, Jun Wang, Yunjian Pan, Yicong Lin, Ting Ye, Yiliang Zhang, Yawei Zhang, Jiaqing Xiang, Hong Hu, Zhiwei Cao, Yuanting Zheng, Yuan Li, Yang Zhang, Li Jin, Leming Shi, Haiquan Chen","doi":"10.1038/s41422-025-01200-w","DOIUrl":"10.1038/s41422-025-01200-w","url":null,"abstract":"Lung adenocarcinoma (LUAD) progresses from pre-invasive to invasive stages, as well as from ground-glass opacities (GGOs) to solid nodules. However, the dynamic genomic and transcriptomic changes underlying LUAD progression are incompletely understood. Here, we performed whole-genome and transcriptome sequencing on 1008 LUAD samples from 954 patients who underwent surgery at Fudan University Shanghai Cancer Center, with comprehensive follow-up data. There was one atypical adenomatous hyperplasia, 42 adenocarcinomas in situ, 116 minimally invasive adenocarcinomas, and 849 invasive adenocarcinomas spanning all pathological stages. EGFR was the most frequently mutated gene in the study cohort, followed by TP53, RBM10, KRAS, and KMT2D. Mutation frequencies of tumor suppressor genes, such as TP53, RB1, MGA, KEAP1, and STK11, increased as the disease progressed to higher stages. A higher level of genomic instability was seen in LUAD compared with AAH/AIS/MIA samples, characterized by a higher tumor mutation burden, increased somatic copy number alteration burden, and increased structural variation burden. Notably, MAP2K1 E102–I103 deletion was frequently observed in pre-invasive samples, which endowed alveolar type II cells with increased growth potential and initiated tumor formation, suggesting that it is a potential driver mutation of LUAD. In summary, our study highlights key molecular changes during the stepwise progression of LUAD, provides insights into the identification of novel therapeutic targets, and helps to define the curative time window for this disease.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1037-1055"},"PeriodicalIF":25.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01200-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing alternative splicing for off-the-shelf mRNA neoantigen vaccines in hepatocellular carcinoma","authors":"Haichao Zhao, Yifei Cheng, Tiancheng Zhang, Qianxi Wang, Yanan Xu, Ganggang Wang, Yuanli Song, Hang Chen, Yingcheng Wu, Mao Zhang, Youpei Lin, Changyou Zhan, Jia Fan, Qiang Gao","doi":"10.1038/s41422-025-01199-0","DOIUrl":"10.1038/s41422-025-01199-0","url":null,"abstract":"Hepatocellular carcinoma (HCC) remains a major therapeutic challenge. Although targeting tumor-specific antigens represents a cornerstone of cancer immunotherapy, current approaches focus predominantly on mutation-derived neoantigens, which offer limited population coverage. Through an integrative analysis of multi-omics data from 279 HCC patients, we demonstrate that aberrant splicing (AS) events occur at a > 59-fold higher frequency than somatic mutations and generate substantially more immunogenic peptides with broader patient applicability (50.94% vs 4.40% population coverage). Focusing on AS transcripts, our stringent selection pipeline identified 34 neoantigens, prioritizing strong immunogenicity for effective vaccine development. Proof-of-concept in vivo experiments demonstrated the efficacy of mRNA vaccines encoding these neoantigens, resulting in significant tumor regression and enhanced intra-tumor infiltration of neoantigen-reactive T cells. We also address the challenge of transporter-associated antigen processing (TAP) deficiency in HCC by proposing the use of TAP-independent AS-derived neoantigens to circumvent immune evasion. Our findings establish AS as a promising source of neoantigens for off-the-shelf mRNA vaccines in HCC and underscore the need to overcome antigen-presentation barriers for effective immunotherapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"970-986"},"PeriodicalIF":25.9,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the SPARDA defense system by filament assembly using a beta-relay signaling mechanism widespread in prokaryotic Argonautes","authors":"Edvinas Jurgelaitis, Evelina Zagorskaitė, Aurimas Kopūstas, Simonas Asmontas, Elena Manakova, Indrė Dalgėdienė, Ugnė Tylenytė, Arunas Silanskas, Paulius Toliusis, Algirdas Grybauskas, Marijonas Tutkus, Česlovas Venclovas, Mindaugas Zaremba","doi":"10.1038/s41422-025-01198-1","DOIUrl":"10.1038/s41422-025-01198-1","url":null,"abstract":"Present in all three domains of life, Argonaute proteins use short oligonucleotides as guides to recognize complementary nucleic acid targets. In eukaryotes, Argonautes are involved in RNA silencing, whereas in prokaryotes, they function in host defense against invading DNA. Here, we show that SPARDA (short prokaryotic Argonaute, DNase associated) systems from Xanthobacter autotrophicus (Xau) and Enhydrobacter aerosaccus (Eae) function in anti-plasmid defense. Upon activation, SPARDA nonspecifically degrades both invader and genomic DNA, causing host death, thereby preventing further spread of the invader in the population. X-ray structures of the apo Xau and EaeSPARDA complexes show that they are dimers, unlike other apo short pAgo systems, which are monomers. We show that dimerization in the apo state is essential for inhibition of XauSPARDA activity. We demonstrate by cryo-EM that activated XauSPARDA forms a filament. Upon activation, the recognition signal of the bound guide/target duplex is relayed to other functional XauSPARDA sites through a structural region that we termed the “beta-relay”. Owing to dramatic conformational changes associated with guide/target binding, XauSPARDA undergoes a “dimer–monomer–filament” transition as the apo dimer dissociates into the guide/target-loaded monomers that subsequently assemble into the filament. Within the activated filament, the DREN nuclease domains form tetramers that are poised to cleave dsDNA. We show that other SPARDAs also form filaments during activation. Furthermore, we identify the presence of the beta-relay in pAgo from all clades, providing new insights into the structural mechanisms of pAgo proteins. Taken together, these findings reveal the detailed structural mechanism of SPARDA and highlight the importance of the beta-relay mechanism in signal transduction in Argonautes.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1056-1078"},"PeriodicalIF":25.9,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages","authors":"Hui-Hui Hu, Xuefeng Wang, Bin Lan, Haili Cheng, Hong Wen, Fangfang Chen, Jianfeng Wu, Mengqi Li, Jiazhou Chen, Jinhui Zhang, Dongxu Chen, Shiyu Lin, Jieyu Lin, Mingyang Yang, Zhenhua Wu, Zhong-Zheng Zheng, Fuqing Chen, Jianyin Zhou, Gang Chen, Yu Chen, Xianming Deng, Chen-Song Zhang, Jingfeng Liu, Sheng-Cai Lin","doi":"10.1038/s41422-025-01195-4","DOIUrl":"10.1038/s41422-025-01195-4","url":null,"abstract":"Dysregulated metabolism in tumor tissues and para-tumor tissues alike can lead to immunosuppression, which may underlie cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib, which specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of hepatocellular carcinoma (HCC) in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity toward HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We also found that HCC tissues in aldometanib-treated mice were massively infiltrated with CD8+ T cells, which was not seen in mice with liver-specific knockout of AMPKα. Our findings thus suggest that the metabolic regulator AMPK rebalances the tumor microenvironment to allow cytotoxic immune cells inside the body to eliminate cancer cells and effectively contain the tumor tissues. The finding that metabolic intervention can make cancer a lifelong manageable disease may usher in a new era of cancer therapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"934-953"},"PeriodicalIF":25.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01195-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sanofi-Cell Research outstanding paper award of 2024","authors":"Cell Research Editorial Team","doi":"10.1038/s41422-025-01201-9","DOIUrl":"10.1038/s41422-025-01201-9","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"921-921"},"PeriodicalIF":25.9,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01201-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Branched-chain fatty acids fire up the peroxisome","authors":"Martina Wallace, Ramya S. Kuna, Christian M. Metallo","doi":"10.1038/s41422-025-01197-2","DOIUrl":"10.1038/s41422-025-01197-2","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 4","pages":"245-246"},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13013815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Destruction of VISTA by TRIM25 ablation in T cells potentiates cancer immunotherapy","authors":"Yishuang Sun, Zijian Zhang, Haiou Li, Xia Bu, Li Chen, Xiyong Wang, Lifang Fan, Baoxiang Chen, Lijun Kong, Panpan Dai, Wenjing Song, Xiangling Xiao, Jie Shi, Bolin Xiang, Chuan He, Yingmeng Yao, Wenjun Xiong, Haisheng Yu, Congqing Jiang, Qun Qian, Hudan Liu, Sufang Tian, Guoliang Qing, Zhiyong Yang, Wenyi Wei, Gordon J. Freeman, Haichuan Zhu, Jinfang Zhang","doi":"10.1038/s41422-025-01186-5","DOIUrl":"10.1038/s41422-025-01186-5","url":null,"abstract":"The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25–VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in mice with T cell-specific knockout of Trim25. Of note, genetic ablation of Trim25 in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25–VISTA as a potential strategy to enhance tumor immunotherapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1003-1020"},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZBP1 links infections to cancer immunotherapy","authors":"Lorenzo Galluzzi, Spencer Brackett, Neil Johnson","doi":"10.1038/s41422-025-01196-3","DOIUrl":"10.1038/s41422-025-01196-3","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 3","pages":"177-178"},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01196-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted destruction of VISTA boosts anti-tumor immunotherapy","authors":"Li Chen, Xia Bu, Yishuang Sun, Daoyuan Huang, Yong Chen, Tao Hou, Xiaoping Hu, Jingchao Wang, Peiqiang Yan, Yihang Qi, Weiwei Jiang, Yan Xiong, Jing Liu, Yang Gao, Mengxi Huan, Bin Wang, Qianjia Liu, Xiaoming Dai, Fabin Dang, John M. Asara, Masanori Fujimoto, Hiroyuki Inuzuka, Jian Jin, Jinfang Zhang, Gordon J. Freeman, Wenyi Wei","doi":"10.1038/s41422-025-01194-5","DOIUrl":"10.1038/s41422-025-01194-5","url":null,"abstract":"Immune checkpoints serve as regulatory pathways that are essential for regulating immune response and homeostasis. As such, many components along the pathway have emerged as pivotal targets in cancer therapy. To overcome the treatment resistance and limited efficacy encountered by current immune checkpoint therapies, there is an urgent need for new immunotherapeutic targets and strategies. V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint protein with a unique expression pattern and has emerged as a novel therapeutic target in anti-tumor immunotherapy; however, the precise role of VISTA and its regulatory mechanisms in tumor cells remain incompletely understood. Here, we identify a novel strategy targeting VISTA for cancer immunotherapy, enhancing therapeutic outcomes. Mechanistically, we show that VISTA undergoes anaphase-promoting complex/cyclosome (APC/C)/CDH1-mediated ubiquitination and subsequent proteasomal degradation, a process that can be reversed by the deubiquitinase USP2. Therapeutically, the USP2 inhibitor MS102 significantly reduces VISTA protein abundance in vitro and in vivo, enhances T cell responses, and synergizes with anti-PD-1 immunotherapy to improve survival in syngeneic mouse tumor models. Our findings reveal a regulatory network for VISTA stability control and support the combination of USP2 inhibitors with anti-PD-1 immunotherapy to enhance anti-tumor immune responses.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"987-1002"},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}