biostudies-literatureChen LJiangsu Provincial Medical Key DisciplineChangzhou Science and Technology Support Programthe Leading Talent of Changzhou“The 14th Five-Year Plan” High-Level Health Talents Training ProjectChangzhou Science and Technology Project (Applied Based Research)the National Natural Science Foundation of Chinathe Key R&D Project of Jiangsu ProvinceChangzhou Science and Technology Projectthe Leading Talent of Changzhou"The 14th Five-Year Plan" High-Level Health Talents Training ProjectChangzhou Medical Center of Nanjing Medical Universitythe Key R&amp;D Project of Jiangsu ProvinceChangzhou Clinical Medical CenterProspective Research Program of Changzhou Xitaihu Development Foundation For Frontier Cell-Therapeutic TechnologyProvincial-level Talent Program for National Center of Technology Innovation for Biopharmaceuticals25https://www.ebi.ac.uk/biostudies/studies/S-EPMC12801534biostudies-literatureUnknown24(1)<h4>Background</h4>Cancer-associated fibroblasts (CAFs) are key regulators in tumor microenvironment and tumor immunity, partly through MHC-II expression that modulates T-cell differentiation. However, the upstream cytokine signals controlling MHC-II expression in fibroblasts still remain poorly defined.<h4>Methods</h4>We examined MHC-II expression on fibroblasts under stimulation with interferon-γ (IFN-γ) and interleukin-1β (IL-1β) by using flow cytometry, transcriptomic analysis, and qRT-PCR. To dissect transcriptional regulation, we generated CIITA-overexpressing and CIITA-deficient fibroblast lines by lentiviral transduction and CRISPR/Cas9-mediated editing. Public scRNA-seq, ATAC-seq, and ChIP-seq datasets were further analyzed to validate molecular mechanisms.<h4>Results</h4>IFN-γ robustly up-regulated MHC-II expression on fibroblasts, while IL-1β selectively suppressed this induction without affecting PD-L1. Mechanistically, IL-1β attenuated IFN-γ-induced CIITA expression at the mRNA level but did not alter STAT1 abundance or phosphorylation. Functional assays confirmed that CIITA was indispensable for IFN-γ-driven MHC-II expression in fibroblasts. Integration of transcriptomic and epigenomic data demonstrated that CIITA directly bound MHC-II gene promoters and regulated chromatin accessibility.<h4>Conclusions</h4>Our study identifies an IFN-γ/STAT1/CIITA axis as the central regulator of MHC-II expression in fibroblasts and reveals IL-1β as a potent suppressor of this pathway. These findings highlight a novel cytokine-mediated regulatory mechanism underlying CAF-driven immunosuppression within the tumor microenvironment.Cell communication and signaling : CCSIL-1β-mediated suppression of CIITA attenuates IFN-γ-induced MHC-II expression on Fibroblasts.PMC128015342022P0108247326932270955BE2022719CJ20250116CE202350572024CZLJ009YXZDXK202236CZ20250020CZZX202201CZKYCMCC202301BE2022721NCTIB2024JS01012024P027Jiang JGeng RFang ZZheng XChen JChen LJiang HWu SMa HLang YTan BfalseIL-1β-mediated suppression of CIITA attenuates IFN-γ-induced MHC-II expression on Fibroblasts.<h4>Background</h4>Cancer-associated fibroblasts (CAFs) are key regulators in tumor microenvironment and tumor immunity, partly through MHC-II expression that modulates T-cell differentiation. However, the upstream cytokine signals controlling MHC-II expression in fibroblasts still remain poorly defined.<h4>Methods</h4>We examined MHC-II expression on fibroblasts under stimulation with interferon-γ (IFN-γ) and interleukin-1β (IL-1β) by using flow cytometry, transcriptomic analysis, and qRT-PCR. To dissect transcriptional regulation, we generated CIITA-overexpressing and CIITA-deficient fibroblast lines by lentiviral transduction and CRISPR/Cas9-mediated editing. Public scRNA-seq, ATAC-seq, and ChIP-seq datasets were further analyzed to validate molecular mechanisms.<h4>Results</h4>IFN-γ robustly up-regulated MHC-II expression on fibroblasts, while IL-1β selectively suppressed this induction without affecting PD-L1. Mechanistically, IL-1β attenuated IFN-γ-induced CIITA expression at the mRNA level but did not alter STAT1 abundance or phosphorylation. Functional assays confirmed that CIITA was indispensable for IFN-γ-driven MHC-II expression in fibroblasts. Integration of transcriptomic and epigenomic data demonstrated that CIITA directly bound MHC-II gene promoters and regulated chromatin accessibility.<h4>Conclusions</h4>Our study identifies an IFN-γ/STAT1/CIITA axis as the central regulator of MHC-II expression in fibroblasts and reveals IL-1β as a potent suppressor of this pathway. These findings highlight a novel cytokine-mediated regulatory mechanism underlying CAF-driven immunosuppression within the tumor microenvironment.2025-01-01T00:00:00Z2025 Dec2026-06-01T03:13:03.434Z2026-06-01T03:07:50.356ZS-EPMC128015344136642510.1186/s12964-025-02575-4