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Increasing evidence suggests that intratumoral inflammation has an outsized influence on antitumor immunity. Here, we report that IL-17, a proinflammatory cytokine widely associated with poor prognosis in solid tumors, drives the therapeutic failure of anti–PD-L1. By timing the deletion of IL-17 signaling specifically in cancer-associated fibroblasts (CAFs) in late-stage tumors, we show that IL-17 signaling drives immune exclusion by activating a collagen deposition program in murine models of cutaneous squamous cell carcinoma (cSCC). Ablation of IL-17 signaling in CAFs increased the infiltration of cytotoxic T cells into the tumor mass and sensitized otherwise resistant cSCC to anti–PD-L1 treatment. Mechanistically, the collagen deposition program in CAFs was driven by IL-17–induced translation of HIF1α, which was mediated by direct binding of Act1, the adaptor protein of IL-17 receptor, to a stem-loop structure in the 3′ untranslated region (UTR) in Hif1α mRNA. Disruption of Act1’s binding to Hif1α mRNA abolished IL-17–induced collagen deposition and enhanced anti–PD-L1–mediated tumor regression.

IL-17–induced HIF1α drives resistance to anti–PD-L1 via fibroblast-mediated immune exclusion