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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.

Interferons (IFNs) are potent pleiotropic cytokines that broadly alter cellular functions in response to viral and other infections. These alterations include changes in protein synthesis, proliferation, membrane composition, and the nutritional microenvironment. Recent evidence suggests that antiviral responses are supported by an IFN-induced rewiring of the cellular metabolism. In this review, we discuss the roles of type I and type II IFNs in regulating the cellular metabolism and biosynthetic reactions. Furthermore, we give an overview of how viruses themselves affect these metabolic activities to promote their replication. In addition, we focus on the lipid as well as amino acid metabolisms, through which IFNs exert potent antiviral and immunomodulatory activities. Conversely, the expression of IFNs is controlled by the nutrient sensor mammalian target of rapamycin or by direct reprograming of lipid metabolic pathways. These findings establish a mutual relationship between IFN production and metabolic core processes.