The role of interferons in melanoma resistance to immune checkpoint blockade: mechanisms of escape and therapeutic implications

Immune checkpoint blockade (ICB) therapy has achieved unprecedented success in the treatment of metastatic melanoma, though its efficacy is often limited by innate and acquired mechanisms of resistance. Type I and type II interferons (IFNs) act as key determinants of checkpoint blockade therapeutic outcome, and tumour-intrinsic and -extrinsic factors that disrupt IFN activity confer resistance to various checkpoint inhibitors. This review highlights our current understanding of the mechanisms by which tumours disrupt IFN function in the context of ICB, and it discusses therapeutic strategies to overcome these mechanisms of resistance and improve the clinical reach of ICB therapy in patients with melanoma.