Thinking small: Small molecules as potential synergistic adjuncts to checkpoint inhibition in melanoma

Abstract

Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to in-crease therapeutic responses, even in resistant melanoma. In this review, we will discuss the multi-tude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on estab-lished mechanisms of immunotherapy resistance.