Taken together, our RNA-seq, phosphoproteomic analysis, bioinformatic analysis, as well as pharmacological and genetic modulations of the mTOR pathway establish that malfunction of IFN-γ signaling engages the mTOR-JAK1/2 axis in melanoma cells, which may represent an attractive target for therapeutic interventions to bypassing ICB resistance in melanomas lacking functional IFN-γ signaling. This evidence concerns the gene IFNG and melanoma.