PD-1 blockade treatment in melanoma: Mechanism of response and tumor-intrinsic resistance

Malignant melanoma is characterized by high immunogenicity, genetic heterogeneity, and diverse pathological manifestations, affecting both skin and mucosa over the body. Pembrolizumab and nivolumab, both anti-PD-1 monoclonal antibodies, were approved by the US FDA for unresectable or metastatic melanoma in 2011 and 2014, respectively, with enduring and transformative outcomes. Despite marked clinical achievements, only a subset of patients manifested a complete response. Approximately 55% of melanoma patients exhibited primary resistance to PD-1 antibodies, with nearly 25% developing secondary resistance within 2 years of treatment. Thus, there is a critical need to comprehensively elucidate the mechanisms underlying the efficacy and resistance to PD-1 blockade. This review discusses the fundamental mechanisms of PD-1 blockade, encompassing insights from T cells and B cells, and presents resistance to anti-PD-1 with a particular focus on tumoral-intrinsic mechanisms in melanoma.