The Challenge of Treating Anti-PD-1-Resistant Advanced Melanoma

Immune checkpoint inhibitors, particularly antibodies targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4, have transformed the treatment landscape of metastatic melanoma. For a subset of patients, these therapies have led to durable responses and long-term survival. However, despite this progress, more than half of patients experience primary or acquired resistance to anti-PD-1 therapy, highlighting an urgent need for effective alternative treatments. As immune checkpoint inhibitors are increasingly used in neoadjuvant and adjuvant settings, a growing number of patients with newly diagnosed metastatic melanoma will have prior exposure to these agents-posing critical challenges for subsequent treatment strategies after anti-PD-1 failure.In this review, we outline mechanisms driving resistance to anti-PD-1 therapy, including both tumor-intrinsic and tumor-extrinsic factors, and discuss biomarkers relevant to clinical practice in melanoma. The current treatment landscape is reviewed, with an overview of key clinical trials that have shaped management across metastatic, adjuvant, and neoadjuvant settings. We discuss novel and promising investigational agents targeting immune and cellular pathways, such as cancer vaccines and recent advancements in T-cell therapy.A key focus is the critical need for predictive biomarkers to guide therapy selection and improve our understanding of long-term outcomes in patients previously treated with immune checkpoint inhibitors. Global efforts are underway to address anti-PD-1 resistance through diverse and innovative strategies, with the aim of developing therapies that maximize the clinical benefit while minimizing toxicity. As the treatment paradigm continues to evolve, overcoming resistance remains central to advancing the care of patients with melanoma.