ATM 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 fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intra-tumoral CD8 T-cell infiltration, and potentiated the response to anti-PD-1 blockade and antitumor vaccination. This work identi-fies a novel pathway regulating myoCAF differentiation and pro -vides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance.Significance: ATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combi-nation with checkpoint inhibition in myoCAF-rich, immune-cold tumors.

Automated summary

Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors have low T cell infiltration and poor response to immune-checkpoint blockade. This study identifies ATM as a central regulator of myoCAF differentiation, providing a potential therapeutic target for overcoming immunotherapy resistance in myoCAF-rich tumors.