biostudies-literatureMellone MRosetrees TrustCancer Research UKRosetreesWessex Medical Research4571-4585https://www.ebi.ac.uk/biostudies/studies/S-EPMC9755965biostudies-literatureUnknown82(24)Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species-producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblasCancer researchATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance.PMC9755965C11512/A20256C21825/A279C21825/A239S07M50624721Parsons JLLopez MAPiotrowska KDurant SWang CVenturi GKing EVJaquet VSavelyeva NJones GDDHanley CJValge-Archer VThomas GJJames LCox KLMellone MJames SEllis MJHughes GBeers SABzura ABuckingham JFSayan EfalseATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance.Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species-producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblas2022-01-01T00:00:00Z2022 Dec2026-05-28T03:49:56.66Z2025-04-06T14:10:57.185ZS-EPMC97559653635375210.1158/0008-5472.CAN-22-0435