Type I interferons are a family of pleiotropic cytokines that exert anti-tumor actions directly on tumor cells and indirectly on the tumor immune microenvironment (TIME). Hitherto, therapeutic strategies aiming to garner the efficacies of interferon responses are still limited. Here we show a novel strategy that elicits an interferon signature response while targeting both tumor cells using antineoplastic mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) inhibitor and the TIME using

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... ll-like receptor 7 (TLR7)-based immune adjuvant. The combination of MEK1/2 inhibitor and TLR7 agonist unlocked an interferon signature response unexpectedly in macrophages, which was otherwise tightly constrained by TLR7 agonist alone. Deficiency of interferon regulatory factor 1 (Irf1) completely abrogated the responses and prevented the reprogramming of activated macrophages, subduing them in an immunosuppressive state. In a murine melanoma model, combination therapy with TLR7 agonist and MEK1/2 inhibitor synergistically extended survival in wild-type but not Irf1-deficient mice. Specifically, we identified interferon response genes as favorable prognosis markers for cutaneous melanoma patients. Our findings demonstrate a novel strategy for combination therapy that targets both tumor cells and the immunosuppressive TIME through additive effects of monotherapies and synergistic interferon responses.