CellPub Date : 2024-11-05DOI: 10.1016/j.cell.2024.10.014
Jinmin Liu, Amogh Kulkarni, Yong-Qi Gao, Daniel A. Urul, Romain Hamelin, Balázs Á. Novotny, Marcus J.C. Long, Yimon Aye
{"title":"Organ-specific electrophile responsivity mapping in live C. elegans","authors":"Jinmin Liu, Amogh Kulkarni, Yong-Qi Gao, Daniel A. Urul, Romain Hamelin, Balázs Á. Novotny, Marcus J.C. Long, Yimon Aye","doi":"10.1016/j.cell.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.014","url":null,"abstract":"Proximity labeling technologies are limited to indexing localized protein residents. Such data—although valuable—cannot inform on small-molecule responsivity of local residents. We here bridge this gap by demonstrating in live <em>C. elegans</em> how electrophile-sensing propensity in specific organs can be quantitatively mapped and ranked. Using this method, >70% of tissue-specific responders exhibit electrophile responsivity, <em>independent</em> of tissue-specific abundance. One responder, cyp-33e1—for which both human and worm orthologs are electrophile responsive—marshals stress-dependent gut functions, despite manifesting uniform abundance across all tissues studied. Cyp-33e1’s localized electrophile responsivity operates site specifically, triggering multifaceted responses: electrophile sensing through the catalytic-site cysteine results in partitioning between enzyme inhibition and localized production of a critical metabolite that governs global lipid availability, whereas rapid dual-cysteine site-specific sensing modulates gut homeostasis. Beyond pinpointing chemical actionability within local proteomes, organ-specific electrophile responsivity mapping illuminates otherwise intractable locale-specific metabolite signaling and stress response programs influencing organ-specific decision-making.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580516","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}
CellPub Date : 2024-11-05DOI: 10.1016/j.cell.2024.10.012
Shiyun Cao, Sheena Faye Garcia, Huigang Shi, Ellie I. James, Yuki Kito, Hui Shi, Haibin Mao, Sharon Kaisari, Gergely Rona, Sophia Deng, Hailey V. Goldberg, Jackeline Ponce, Beatrix Ueberheide, Luca Lignitto, Miklos Guttman, Michele Pagano, Ning Zheng
{"title":"Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress","authors":"Shiyun Cao, Sheena Faye Garcia, Huigang Shi, Ellie I. James, Yuki Kito, Hui Shi, Haibin Mao, Sharon Kaisari, Gergely Rona, Sophia Deng, Hailey V. Goldberg, Jackeline Ponce, Beatrix Ueberheide, Luca Lignitto, Miklos Guttman, Michele Pagano, Ning Zheng","doi":"10.1016/j.cell.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.012","url":null,"abstract":"Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 ligases to decode the targets’ degradation signals, i.e., degrons. Here, we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 proteins that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580517","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":"Regulatory mechanisms of strigolactone perception in rice","authors":"Qingliang Hu, Huihui Liu, Yajun He, Yanrong Hao, Jijun Yan, Simao Liu, Xiahe Huang, Zongyun Yan, Dahan Zhang, Xinwei Ban, Hao Zhang, Qianqian Li, Jingkun Zhang, Peiyong Xin, Yanhui Jing, Liquan Kou, Dajun Sang, Yonghong Wang, Yingchun Wang, Xiangbing Meng, Jiayang Li","doi":"10.1016/j.cell.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.009","url":null,"abstract":"Strigolactones (SLs) are hormones essential for plant development and environmental responses. SL perception requires the formation of the complex composed of an SL receptor DWARF14 (D14), F-box protein D3, and transcriptional repressor D53, triggering ubiquitination and degradation of D53 to activate signal transduction. However, mechanisms of SL perception and their influence on plant architecture and environmental responses remain elusive and controversial. Here, we report that key residues at interfaces of the AtD14-D3-ASK1 complex are essential for the activation of SL perception, discover that overexpression of the D3-CTH motif negatively regulates SL perception to enhance tillering, and reveal the importance of phosphorylation and N-terminal disordered (NTD) domain in mediating ubiquitination and degradation of D14. Importantly, low nitrogen promotes phosphorylation and stabilization of D14 to repress rice tillering. These findings reveal a panorama of the activation, termination, and regulation of SL perception, which determines the plasticity of plant architecture in complex environments.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574509","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}
CellPub Date : 2024-11-04DOI: 10.1016/j.cell.2024.10.010
Kautilya K. Jena, Julien Mambu, Daniel Boehmer, Benedetta Sposito, Virginie Millet, Joshua de Sousa Casal, Hayley I. Muendlein, Roberto Spreafico, Romain Fenouil, Lionel Spinelli, Sarah Wurbel, Chloé Riquier, Franck Galland, Philippe Naquet, Lionel Chasson, Megan Elkins, Vanessa Mitsialis, Natália Ketelut-Carneiro, Katlynn Bugda Gwilt, Jay R. Thiagarajah, Ivan Zanoni
{"title":"Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair","authors":"Kautilya K. Jena, Julien Mambu, Daniel Boehmer, Benedetta Sposito, Virginie Millet, Joshua de Sousa Casal, Hayley I. Muendlein, Roberto Spreafico, Romain Fenouil, Lionel Spinelli, Sarah Wurbel, Chloé Riquier, Franck Galland, Philippe Naquet, Lionel Chasson, Megan Elkins, Vanessa Mitsialis, Natália Ketelut-Carneiro, Katlynn Bugda Gwilt, Jay R. Thiagarajah, Ivan Zanoni","doi":"10.1016/j.cell.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.010","url":null,"abstract":"Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight into how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or type II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to caspase-8 activation and the cleavage of gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has implications for IBD patients or individuals exposed to radiation therapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"241 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574508","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}
CellPub Date : 2024-11-04DOI: 10.1016/j.cell.2024.10.019
Shuai Ma, Zhejun Ji, Bin Zhang, Lingling Geng, Yusheng Cai, Chao Nie, Jiaming Li, Yuesheng Zuo, Yuzhe Sun, Gang Xu, Beibei Liu, Jiaqi Ai, Feifei Liu, Liyun Zhao, Jiachen Zhang, Hui Zhang, Shuhui Sun, Haoyan Huang, Yiyuan Zhang, Yanxia Ye, Guang-Hui Liu
{"title":"Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging","authors":"Shuai Ma, Zhejun Ji, Bin Zhang, Lingling Geng, Yusheng Cai, Chao Nie, Jiaming Li, Yuesheng Zuo, Yuzhe Sun, Gang Xu, Beibei Liu, Jiaqi Ai, Feifei Liu, Liyun Zhao, Jiachen Zhang, Hui Zhang, Shuhui Sun, Haoyan Huang, Yiyuan Zhang, Yanxia Ye, Guang-Hui Liu","doi":"10.1016/j.cell.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.019","url":null,"abstract":"To systematically characterize the loss of tissue integrity and organ dysfunction resulting from aging, we produced an in-depth spatial transcriptomic profile of nine tissues in male mice during aging. We showed that senescence-sensitive spots (SSSs) colocalized with elevated entropy in organizational structure and that the aggregation of immunoglobulin-expressing cells is a characteristic feature of the microenvironment surrounding SSSs. Immunoglobulin G (IgG) accumulated across the aged tissues in both male and female mice, and a similar phenomenon was observed in human tissues, suggesting the potential of the abnormal elevation of immunoglobulins as an evolutionarily conserved feature in aging. Furthermore, we observed that IgG could induce a pro-senescent state in macrophages and microglia, thereby exacerbating tissue aging, and that targeted reduction of IgG mitigated aging across various tissues in male mice. This study provides a high-resolution spatial depiction of aging and indicates the pivotal role of immunoglobulin-associated senescence during the aging process.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"36 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574510","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":"Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders","authors":"Panrui Lu, Yalong Cheng, Lei Xue, Xintong Ren, Xilong Xu, Chenglong Chen, Longzhi Cao, Jiaojiao Li, Qingcui Wu, Shan Sun, Junjie Hou, Wei Jia, Wei Wang, Yan Ma, Zhaodi Jiang, Chao Li, Xiangbing Qi, Niu Huang, Ting Han","doi":"10.1016/j.cell.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.015","url":null,"abstract":"Targeted protein degradation (TPD) utilizes molecular glues or proteolysis-targeting chimeras (PROTACs) to eliminate disease-causing proteins by promoting their interaction with E3 ubiquitin ligases. Current TPD approaches are limited by reliance on a small number of constitutively active E3 ubiquitin ligases. Here, we report that (<em>S</em>)-ACE-OH, a metabolite of the antipsychotic drug acepromazine, acts as a molecular glue to induce an interaction between the E3 ubiquitin ligase TRIM21 and the nucleoporin NUP98, leading to the degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. Functionalization of acepromazine into PROTACs enabled selective degradation of multimeric proteins, such as those within biomolecular condensates, while sparing monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies cause diseases such as autoimmunity, neurodegeneration, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"33 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562157","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}
CellPub Date : 2024-10-31DOI: 10.1016/j.cell.2024.09.022
Shanghua Gao, Ada Fang, Yepeng Huang, Valentina Giunchiglia, Ayush Noori, Jonathan Richard Schwarz, Yasha Ektefaie, Jovana Kondic, Marinka Zitnik
{"title":"Empowering biomedical discovery with AI agents","authors":"Shanghua Gao, Ada Fang, Yepeng Huang, Valentina Giunchiglia, Ayush Noori, Jonathan Richard Schwarz, Yasha Ektefaie, Jovana Kondic, Marinka Zitnik","doi":"10.1016/j.cell.2024.09.022","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.022","url":null,"abstract":"We envision “AI scientists” as systems capable of skeptical learning and reasoning that empower biomedical research through collaborative agents that integrate AI models and biomedical tools with experimental platforms. Rather than taking humans out of the discovery process, biomedical AI agents combine human creativity and expertise with AI’s ability to analyze large datasets, navigate hypothesis spaces, and execute repetitive tasks. AI agents are poised to be proficient in various tasks, planning discovery workflows and performing self-assessment to identify and mitigate gaps in their knowledge. These agents use large language models and generative models to feature structured memory for continual learning and use machine learning tools to incorporate scientific knowledge, biological principles, and theories. AI agents can impact areas ranging from virtual cell simulation, programmable control of phenotypes, and the design of cellular circuits to developing new therapies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"239 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556317","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}
CellPub Date : 2024-10-30DOI: 10.1016/j.cell.2024.09.048
Lina Herhaus, Uxía Gestal-Mato, Vinay V. Eapen, Igor Mačinković, Henry J. Bailey, Cristian Prieto-Garcia, Mohit Misra, Anne-Claire Jacomin, Aparna Viswanathan Ammanath, Ivan Bagarić, Jolina Michaelis, Joshua Vollrath, Ramachandra M. Bhaskara, Georg Bündgen, Adriana Covarrubias-Pinto, Koraljka Husnjak, Jonathan Zöller, Ajami Gikandi, Sara Ribičić, Tobias Bopp, Ivan Dikic
{"title":"IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion","authors":"Lina Herhaus, Uxía Gestal-Mato, Vinay V. Eapen, Igor Mačinković, Henry J. Bailey, Cristian Prieto-Garcia, Mohit Misra, Anne-Claire Jacomin, Aparna Viswanathan Ammanath, Ivan Bagarić, Jolina Michaelis, Joshua Vollrath, Ramachandra M. Bhaskara, Georg Bündgen, Adriana Covarrubias-Pinto, Koraljka Husnjak, Jonathan Zöller, Ajami Gikandi, Sara Ribičić, Tobias Bopp, Ivan Dikic","doi":"10.1016/j.cell.2024.09.048","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.048","url":null,"abstract":"The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"5 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541555","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}
CellPub Date : 2024-10-30DOI: 10.1016/j.cell.2024.09.033
Ivan N. Zheludev, Robert C. Edgar, Maria Jose Lopez-Galiano, Marcos de la Peña, Artem Babaian, Ami S. Bhatt, Andrew Z. Fire
{"title":"Viroid-like colonists of human microbiomes","authors":"Ivan N. Zheludev, Robert C. Edgar, Maria Jose Lopez-Galiano, Marcos de la Peña, Artem Babaian, Ami S. Bhatt, Andrew Z. Fire","doi":"10.1016/j.cell.2024.09.033","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.033","url":null,"abstract":"Here, we describe “obelisks,” a class of heritable RNA elements sharing several properties: (1) apparently circular RNA ∼1 kb genome assemblies, (2) predicted rod-like genome-wide secondary structures, and (3) open reading frames encoding a novel “Oblin” protein superfamily. A subset of obelisks includes a variant hammerhead self-cleaving ribozyme. Obelisks form their own phylogenetic group without detectable similarity to known biological agents. Surveying globally, we identified 29,959 distinct obelisks (clustered at 90% sequence identity) from diverse ecological niches. Obelisks are prevalent in human microbiomes, with detection in ∼7% (29/440) and ∼50% (17/32) of queried stool and oral metatranscriptomes, respectively. We establish <em>Streptococcus sanguinis</em> as a cellular host of a specific obelisk and find that this obelisk’s maintenance is not essential for bacterial growth. Our observations identify obelisks as a class of diverse RNAs of yet-to-be-determined impact that have colonized and gone unnoticed in human and global microbiomes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"63 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541491","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}
CellPub Date : 2024-10-30DOI: 10.1016/j.cell.2024.10.006
Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T. Potak, Luisanna Pia, Angelo Amabile, Jaime Mateus-Tique, Noam Rabinovich, Matthew D. Park, Nelson M. LaMarche, Rachel Brody, Lindsay Browning, Jia-Ren Lin, Dmitriy Zamarin, Peter K. Sorger, Sandro Santagata, Miriam Merad, Alessia Baccarini, Brian D. Brown
{"title":"Ovarian cancer-derived IL-4 promotes immunotherapy resistance","authors":"Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T. Potak, Luisanna Pia, Angelo Amabile, Jaime Mateus-Tique, Noam Rabinovich, Matthew D. Park, Nelson M. LaMarche, Rachel Brody, Lindsay Browning, Jia-Ren Lin, Dmitriy Zamarin, Peter K. Sorger, Sandro Santagata, Miriam Merad, Alessia Baccarini, Brian D. Brown","doi":"10.1016/j.cell.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.006","url":null,"abstract":"Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"65 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541493","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}
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