Noncanonical Hedgehog signaling through Smoothened controls cytotoxic T cell migration in the tumor microenvironment

The Hedgehog (Hh) signaling pathway is aberrantly regulated in cancer. Hh inhibitors are successful in treating basal cell carcinoma (BCC) and Sonic Hedgehog–driven medulloblastoma but have largely failed in clinical trials of other solid cancers. We show that Hh inhibitor treatment specifically diminishes CD8 T cell migration into the tumor microenvironment, both in murine cancer models and resected BCCs from patients treated with the Smoothened (Smo) inhibitor vismodegib. Using small-molecule antagonists and genetic knockout models of key Hh signaling components, we demonstrate that the migration defect is mediated exclusively by the signal transducer Smo and not Hh ligands or Gli transcription factors. Smo acts noncanonically as a G protein–coupled receptor to regulate the migration of murine and human CD8 T cells via RhoA. Our data establish a link between Hh inhibition in vivo and the antitumor immune response and provide the basis for improved Hh targeting approaches for patients with cancer.