mTORC2 inhibition reduces tumor burden via STAT1 activation and enhanced response to anti-PD-L1 therapy.

Although melanoma treatment has progressed considerably in recent years, increasing patient response rates remains a significant challenge. The interferon pathway is known to promote immune recognition, but its sustained activation can contribute to adaptive immune exhaustion. In this study, we demonstrate that myeloid-specific deletion of Rictor in a mouse melanoma model enhances STAT1 signaling while reducing PD-L1 expression. Furthermore, IFN-γ-activated macrophages inhibited melanoma growth in a human skin organoid model. Notably, in vivo inhibition of AKT, in conjunction with anti-PD-L1 therapy, suppressed tumor progression. Mechanistically, we identified IFN-γ-mediated downregulation of IGF-1 as a key event during inflammation, and showed that supplementation with recombinant IGF-1 dampens STAT1 activation. Our findings reveal that targeting the Rictor-AKT axis induces a dual effect - boosting pro-inflammatory signaling while downregulating immunosuppressive factors such as PD-L1 and IGF-1. These results support the potential of AKT inhibitors to enhance the efficacy of immune checkpoint therapies in melanoma patients.