Abstract
Hedgehog (Hh) signaling is a highly conserved pathway that plays a pivotal role during embryonic development. Mounting evidence has implicated Hh signaling in various types of cancer. Accordingly, inhibition of aberrant Hh signaling continues to be pursed across multiple cancer types -with some success in certain malignancies. In addition, with the renaissance of antitumor immunotherapy, an in-depth understanding of the molecular mechanisms underlying how the multifaceted functions of Hh signaling shape immunologically suppressive tumor microenvironment might be the key to unlocking a new era of oncological treatments associated with a reduced propensity for the development of drug resistance. Here, we focus on the latest advances regarding the immunological effects of misregulation of Hh signaling on tumor immunity. We also review the current status of clinically approved Hh inhibitors and dissect the mechanisms of drug resistance. Finally, we discuss the potential clinical applications that harness the immunomodulatory effects of Hh signaling not only to circumvent drug resistance, but also to achieve durable efficacy following immunotherapies, thus ultimately resulting in improved patient outcomes.