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

Abstract 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.