Chronic interferon signaling at baseline is associated with acquired resistance to immunotherapy in metastatic melanoma.

Interferons can trigger robust anti-tumor responses following immune checkpoint blockade (ICB). However, chronic interferon signaling can also reshape tumor cell phenotypes, selecting for immune evasion mechanisms that drive resistance. In a cohort of 108 metastatic melanoma samples collected prior to first-line ICB, immune infiltration and bulk interferon gamma (IFNG) expression correlate with initial but not durable responses. Using a regression-based approach to deconvolve cancer cell signals from bulk tumors, we find that tumors from patients who initially respond but later acquire resistance exhibit heightened cancer cell-dependent IFN signaling at baseline, accompanied by MYC downregulation, dedifferentiation, and impaired major histocompatibility complex (MHC) class II induction. Genetically, acquired resistance also associates with reduced T cell interferon signaling, lower memory T cell activity, high tumor mutational burden, clonal diversification, and elevated subclonal neoantigen burden. These findings reveal baseline transcriptomic and genetic features distinguishing acquired resistance from durable ICB response, identifying candidate targets to prevent relapse and refine stratification.