Fibroblast-specific ablation of MHC-I antigen presentation via the IGF2 axis cripples CD8+ T cell surveillance in lung cancer.

How cancer-associated fibroblasts (CAFs) dictate CD8+ T cell dysfunction during lung cancer remains unclear. Through single-cell analysis of 84 human NSCLC samples, we identified insulin-like growth factor 2 (IGF2) as a key immunosuppressive factor in a specific CAF subset. IGF2+ CAF infiltration correlated with CD8+ T cell dysfunction. Fibroblast-specific IGF2 knockout enhanced antigen presentation cell-autonomously via major histocompatibility complex class I (MHC-I), boosting CD8+ T cell effector function, tumor suppression, survival, and PD-1 blockade synergy. Mechanistically, IGF2 sustained MYC signaling to up-regulate DNA methyltransferase 1 (DNMT1), which methylated the STAT1 promoter, epigenetically silencing STAT1. This impaired MHC-I presentation and CD8+ T cell activation. Clinically, high IGF2 levels associated with reduced CD8+ T cell cytotoxicity and poor outcomes. An IGF2+ fibroblast signature predicted worse response to immunotherapy in multiple cohorts. Our findings establish IGF2 as a central regulator of CAF-mediated immunosuppression and a stromal target for enhancing immunotherapy in lung cancer.