{"title":"Bile acid-FXR signaling facilitates the long-term maintenance of hepatic characteristics in human iPSC-derived organoids.","authors":"Taro Shimizu, Masato Miyoshi, Sei Kakinuma, Jun Tsuchiya, Daisuke Yamane, Keiya Watakabe, Tomohiro Mochida, Kento Inada, Kaho Yamada, Kotomi Shinozaki, Ayako Sato, Shun Kaneko, Fukiko Kawai-Kitahata, Miyako Murakawa, Sayuri Nitta, Mina Nakagawa, Mamoru Watanabe, Yasuhiro Asahina, Ryuichi Okamoto","doi":"10.1016/j.celrep.2025.115675","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115675","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (iPSCs) can be differentiated into hepatocyte-like cells (iPS-Heps); however, maintaining the long-term proliferation and hepatic characteristics of iPS-Heps remains a challenge. In this study, we aimed to develop a human iPSC-derived hepatic organoid (iHO) culture system that effectively retains hepatic characteristics long term. Our original culture strategy, using bile acids and their receptor (farnesoid X receptor [FXR]) agonists, yielded human iHOs capable of long-term culture with a distinctive \"grape-like\" structure. Comprehensive analysis showed that these iHOs maintained hepatocyte-like phenotypes, even after multiple passages, whose gene expression profiles were consistent with those of fetal hepatocytes. In addition, the overexpression of small heterodimer partner (SHP), a downstream gene of FXR, in iHOs negatively regulated genes related to the intestine and cholangiocytes. Our data demonstrated that bile acid-FXR signaling promotes both the hepatic characteristics and proliferative potential of iHOs, offering promising potential for future applications in regenerative medicine and as a disease model.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":" ","pages":"115675"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076172","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}
Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115560
Chengcheng Hu, Qing Hu, Tongtong Yang, Panpan Xu, Fangyuan Xiong, Xinyang Wang, Chao Wang, Kai Jiang, Donald L Hill, Lin Xue, Changlu Tao, Chuanhai Fu, Liang Zhang, Dan Liu, Shengqi Xiang, Jianye Zang, Zhikai Wang, Xuebiao Yao, Xing Liu
{"title":"Condensation-dependent multivalent interactions of EB1 and CENP-R regulate chromosome oscillations in mitosis.","authors":"Chengcheng Hu, Qing Hu, Tongtong Yang, Panpan Xu, Fangyuan Xiong, Xinyang Wang, Chao Wang, Kai Jiang, Donald L Hill, Lin Xue, Changlu Tao, Chuanhai Fu, Liang Zhang, Dan Liu, Shengqi Xiang, Jianye Zang, Zhikai Wang, Xuebiao Yao, Xing Liu","doi":"10.1016/j.celrep.2025.115560","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115560","url":null,"abstract":"<p><p>Mitotic chromosomes oscillate between the spindle poles upon the establishment of bi-orientation, which is essential for chromosome alignment and subsequent synchronous segregation. However, the molecular mechanisms underlying the oscillatory movement remain unclear. Recent studies revealed that phase separation of the end-binding protein 1 (EB1) is essential for eukaryotic cell division. Here, we show that EB1 interacts with CENP-R and that the phase separation-defective EB1 mutant fails to power the chromosome oscillations. Biochemical analyses reveal a co-condensation of EB1 and CENP-R, a subunit of the constitutive centromere-associated network. Nuclear magnetic resonance assays reveal that the interaction and co-condensation are largely mediated by the structured end-binding homology domain of EB1 and the non-structured N-terminal intrinsic disorder region of CENP-R. Chromosome oscillation is perturbed in cells expressing the EB1-binding-defective CENP-R mutant. Thus, phase-separated EB1 binding to CENP-R forms a physical link between inner kinetochore and dynamic spindle microtubule plus-ends to guide accurate chromosome oscillations.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115560"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967568","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}
Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115680
Lindsey N Guerin, Timothy J Scott, Jacqueline A Yap, Annelie Johansson, Fabio Puddu, Tom Charlesworth, Yilin Yang, Alan J Simmons, Ken S Lau, Rebecca A Ihrie, Emily Hodges
{"title":"Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification.","authors":"Lindsey N Guerin, Timothy J Scott, Jacqueline A Yap, Annelie Johansson, Fabio Puddu, Tom Charlesworth, Yilin Yang, Alan J Simmons, Ken S Lau, Rebecca A Ihrie, Emily Hodges","doi":"10.1016/j.celrep.2025.115680","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115680","url":null,"abstract":"<p><p>Chromatin and DNA modifications mediate the transcriptional activity of lineage-specifying enhancers, but recent work challenges the dogma that joint chromatin accessibility and DNA demethylation are prerequisites for transcription. To understand this paradox, we established a highly resolved timeline of their dynamics during neural progenitor cell differentiation. We discovered that, while complete demethylation appears delayed relative to shorter-lived chromatin changes for thousands of enhancers, DNA demethylation actually initiates with 5-hydroxymethylation before appreciable accessibility and transcription factor occupancy is observed. The extended timeline of DNA demethylation creates temporal discordance appearing as heterogeneity in enhancer regulatory states. Few regions ever gain methylation, and resulting enhancer hypomethylation persists long after chromatin activities have dissipated. We demonstrate that the temporal methylation status of CpGs (mC/hmC/C) predicts past, present, and future chromatin accessibility using machine learning models. Thus, chromatin and DNA methylation collaborate on different timescales to shape short- and long-term enhancer regulation during cell fate specification.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115680"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965893","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}
Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115693
Louise Duncalf, Xinru Wang, Abdulrahman A Aljabri, Amy E Campbell, Rawan Q Alharbi, Ian Donaldson, Andrew Hayes, Wolfgang Peti, Rebecca Page, Daimark Bennett
{"title":"PNUTS:PP1 recruitment to Tox4 regulates chromosomal dispersal in Drosophila germline development.","authors":"Louise Duncalf, Xinru Wang, Abdulrahman A Aljabri, Amy E Campbell, Rawan Q Alharbi, Ian Donaldson, Andrew Hayes, Wolfgang Peti, Rebecca Page, Daimark Bennett","doi":"10.1016/j.celrep.2025.115693","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115693","url":null,"abstract":"<p><p>Ser/Thr protein phosphatase 1 (PP1) forms a large nuclear holoenzyme (with PNUTS, WDR82, and Tox4) whose emerging role is to regulate transcription. However, the role of Tox4, and its interplay with the other phosphatase subunits in this complex, is poorly understood. Here, we combine biochemical, structural, cellular, and in vivo experiments to show that, while tox4 is dispensable for viability, it is essential for fertility, having both PNUTS-dependent and -independent roles in Drosophila germline development. We also show that Tox4 requires zinc for PNUTS TFIIS N-terminal domain (TND) binding, and that it binds the TND on a surface distinct from that used by established TND-interacting transcriptional regulators. We also show that selective disruption of the PNUTS-Tox4 and the PNUTS-PP1 interaction is critical for normal gene expression and chromosomal dispersal during oogenesis. Together, these data demonstrate how interactions within the PNUTS-Tox4-PP1 phosphatase combine to tune transcriptional outputs driving developmental transitions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115693"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967225","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}
Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115685
Alexandra G Bardon, Jesus J Ballesteros, Scott L Brincat, Jefferson E Roy, Meredith K Mahnke, Yumiko Ishizawa, Emery N Brown, Earl K Miller
{"title":"Convergent effects of different anesthetics on changes in phase alignment of cortical oscillations.","authors":"Alexandra G Bardon, Jesus J Ballesteros, Scott L Brincat, Jefferson E Roy, Meredith K Mahnke, Yumiko Ishizawa, Emery N Brown, Earl K Miller","doi":"10.1016/j.celrep.2025.115685","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115685","url":null,"abstract":"<p><p>Many anesthetics cause loss of consciousness despite having diverse underlying molecular and circuit actions. To explore the convergent effects of these drugs, we examine how anesthetic doses of ketamine and dexmedetomidine affect bilateral oscillations in the prefrontal cortex of nonhuman primates. Both anesthetics increase phase locking in the ventrolateral and dorsolateral prefrontal cortex, within and across hemispheres. However, the nature of the phase locking varies. Neighboring prefrontal subregions within a hemisphere show decreased phase alignment with both drugs. Local analyses within a region suggest that this finding could be explained by broad cortical distance-based effects, such as large traveling waves. In contrast, homologous areas across hemispheres become more aligned in phase. Our results suggest that both anesthetics induce strong patterns of cortical phase alignment that are markedly different from those during waking and that these patterns may be a common feature driving loss of responsiveness from different anesthetic drugs.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115685"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984447","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}
Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115677
Leyao Yu, Patricia Dugan, Werner Doyle, Orrin Devinsky, Daniel Friedman, Adeen Flinker
{"title":"A left-lateralized dorsolateral prefrontal network for naming.","authors":"Leyao Yu, Patricia Dugan, Werner Doyle, Orrin Devinsky, Daniel Friedman, Adeen Flinker","doi":"10.1016/j.celrep.2025.115677","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115677","url":null,"abstract":"<p><p>The ability to connect the form and meaning of a concept, known as word retrieval, is fundamental to human communication. While various input modalities could lead to identical word retrieval, the exact neural dynamics supporting this process relevant to daily auditory discourse remain poorly understood. Here, we recorded neurosurgical electrocorticography (ECoG) data from 48 patients and dissociated two key language networks that highly overlap in time and space, critical for word retrieval. Using unsupervised temporal clustering techniques, we found a semantic processing network located in the middle and inferior frontal gyri. This network was distinct from an articulatory planning network in the inferior frontal and precentral gyri, which was invariant to input modalities. Functionally, we confirmed that the semantic processing network encodes word surprisal during sentence perception. These findings elucidate neurophysiological mechanisms underlying the processing of semantic auditory inputs ranging from passive language comprehension to conversational speech.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115677"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954109","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}
Cell reportsPub Date : 2025-05-09DOI: 10.1016/j.celrep.2025.115647
Saar Krell, Amit Hamburg, Ofer Gover, Kfir Molakandov, Gil Leibowitz, Kfir Sharabi, Michael D Walker, Aharon Helman
{"title":"Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling.","authors":"Saar Krell, Amit Hamburg, Ofer Gover, Kfir Molakandov, Gil Leibowitz, Kfir Sharabi, Michael D Walker, Aharon Helman","doi":"10.1016/j.celrep.2025.115647","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115647","url":null,"abstract":"<p><p>Precise regulation of insulin secretion by pancreatic β cells is essential to prevent excessive insulin release. Here, we show that the nutrient sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) is rapidly activated by glucose in β cells via the insulin secretion machinery, positioning mTORC1 as a sensor of β cell activity. Acute pharmacological inhibition of mTORC1 during glucose stimulation enhances insulin release, suggesting that mTORC1 acts as an intrinsic feedback regulator that restrains insulin secretion. Phosphoproteomic profiling reveals that mTORC1 modulates the phosphorylation of proteins involved in actin remodeling and vesicle trafficking, with a prominent role in the RhoA-GTPase pathway. Mechanistically, mTORC1 promotes RhoA activation and F-actin polymerization, limiting vesicle movement and dampening the second phase of insulin secretion. These findings identify a glucose-mTORC1-RhoA signaling axis that forms an autonomous feedback loop to constrain insulin exocytosis, providing insight into how β cells prevent excessive insulin release and maintain metabolic balance.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115647"},"PeriodicalIF":7.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978255","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}
Cell reportsPub Date : 2025-05-08DOI: 10.1016/j.celrep.2025.115512
Jamal Fahoum, Maria Billan, Julia K Varga, Dan Padawer, Yelena Britan-Rosich, Maya Elgrably-Weiss, Pallabi Basu, Miri Stolovich-Rain, Leah Baraz, Einav Cohen-Kfir, Sujata Kumari, Esther Oiknine-Djian, Manoj Kumar, Orly Zelig, Guy Mayer, Michail N Isupov, Dana G Wolf, Shoshy Altuvia, Reuven Wiener, Ora Schueler-Furman, Alexander Rouvinski
{"title":"Transfer of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition.","authors":"Jamal Fahoum, Maria Billan, Julia K Varga, Dan Padawer, Yelena Britan-Rosich, Maya Elgrably-Weiss, Pallabi Basu, Miri Stolovich-Rain, Leah Baraz, Einav Cohen-Kfir, Sujata Kumari, Esther Oiknine-Djian, Manoj Kumar, Orly Zelig, Guy Mayer, Michail N Isupov, Dana G Wolf, Shoshy Altuvia, Reuven Wiener, Ora Schueler-Furman, Alexander Rouvinski","doi":"10.1016/j.celrep.2025.115512","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115512","url":null,"abstract":"<p><p>SARS-CoV-2 infection triggers a strong antibody response toward nucleocapsid protein (NP), suggesting its extracellular presence beyond intravirion RNA binding. Our co-culture experiments show NP decorates infected and proximal uninfected cell surfaces. We propose a mechanism whereby extracellular NP on uninfected cells contributes to COVID-19 pathogenicity. We show that NP binds to cell-surface sulfated glycosaminoglycans using its RNA-binding sites, facilitated by the flexible, positively charged linker. Coating uninfected lung-derived cells with NP attracted anti-NP IgG from lung fluids and sera of COVID-19 patients. Immune recognition was significantly higher in moderate versus mild COVID-19. Binding of anti-NP IgG in sera generated clusters, triggering C3b deposition via the classical complement pathway on SARS-CoV-2 non-susceptible cells co-cultured with infected cells. The heparin analog enoxaparin outcompeted NP binding, rescuing cells from anti-NP IgG-mediated complement deposition. Our findings reveal how extracellular NP may exacerbate COVID-19 damage and suggest preventative therapy avenues.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115512"},"PeriodicalIF":7.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987380","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}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115679
Zhuo Wang, Wendong Guo, Xiaowen Zhang, Yufei Wei, Wanying Zhang, Ning Du, Chunlu Li, Xuan Wu, Fei Yi, Tingting Zhou, Xiang Dong, Qiqiang Guo, Hongde Xu, Erli Wang, Na Li, Rong Cheng, Ziwei Li, Xiaoyu Song, Yingxian Sun, Xun Sun, Liu Cao
{"title":"Tumor microenvironment-associated oxidative stress impairs SIRT1 secretion to suppress anti-tumor immune response.","authors":"Zhuo Wang, Wendong Guo, Xiaowen Zhang, Yufei Wei, Wanying Zhang, Ning Du, Chunlu Li, Xuan Wu, Fei Yi, Tingting Zhou, Xiang Dong, Qiqiang Guo, Hongde Xu, Erli Wang, Na Li, Rong Cheng, Ziwei Li, Xiaoyu Song, Yingxian Sun, Xun Sun, Liu Cao","doi":"10.1016/j.celrep.2025.115679","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115679","url":null,"abstract":"<p><p>Sirtuin-1 (SIRT1) is a classical histone deacetylase well known for its roles in intracellular pathways such as energy metabolism, DNA damage response, and genome stability maintenance. We report that SIRT1 can be secreted into the tumor microenvironment (TME) through an unconventional protein secretion pathway, effectively inhibiting tumor growth. However, under the stressful conditions of the TME, SIRT1 undergoes increased methylation, which impedes its secretion. Consequently, tumor-infiltrating M2 macrophages are unable to acquire sufficient SIRT1 from the TME, resulting in a significant decrease in SIRT1 levels within these cells. This SIRT1 decline leads to elevated expression of programmed cell death ligand 1 (PD-L1) on M2 macrophages, which in turn contributes to CD8<sup>+</sup> T cell exhaustion through the programmed cell death protein 1/PD-L1 interaction pathway. These findings unveil the multifaceted roles and regulatory mechanisms of SIRT1 within the complex TME, providing deeper insights that significantly enhance our understanding of tumor immune-evasion strategies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115679"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975303","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}
Cell reportsPub Date : 2025-05-07DOI: 10.1016/j.celrep.2025.115698
Daniel A Skelly, John P Graham, Mingshan Cheng, Mayuko Furuta, Andrew Walter, Thomas A Stoklasek, Hongyuan Yang, Timothy M Stearns, Olivier Poirion, Ji-Gang Zhang, Jessica D S Grassmann, Diane Luo, William F Flynn, Elise T Courtois, Chih-Hao Chang, David V Serreze, Francesca Menghi, Laura G Reinholdt, Edison T Liu
{"title":"Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response.","authors":"Daniel A Skelly, John P Graham, Mingshan Cheng, Mayuko Furuta, Andrew Walter, Thomas A Stoklasek, Hongyuan Yang, Timothy M Stearns, Olivier Poirion, Ji-Gang Zhang, Jessica D S Grassmann, Diane Luo, William F Flynn, Elise T Courtois, Chih-Hao Chang, David V Serreze, Francesca Menghi, Laura G Reinholdt, Edison T Liu","doi":"10.1016/j.celrep.2025.115698","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115698","url":null,"abstract":"<p><p>Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy is experimentally challenging. Our approach, utilizing the Collaborative Cross mouse genetic resource, fixes the tumor genomic configuration while varying host genetics. We find that response to anti-PD-1 (aPD1) immunotherapy is significantly heritable in four distinct murine tumor models (H<sup>2</sup>: 0.18-0.40). For the MC38 colorectal carcinoma system, we map four significant ICI response quantitative trait loci (QTLs) with significant epistatic interactions. The differentially expressed genes within these QTLs that define responder genetics are highly enriched for processes involving antigen processing and presentation, allograft rejection, and graft vs. host disease (all p < 1 × 10<sup>-10</sup>). Functional blockade of two top candidate immune targets, GM-CSF and IL-2RB, completely abrogates the MC38 transcriptional response to aPD1 therapy. Thus, our in vivo experimental platform is a powerful approach for discovery of host genetic factors that establish the tumor immune microenvironment propitious for ICI response.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115698"},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981582","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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