Advances in Cutaneous Melanoma Therapy: The Emerging Role of CDK4/6 Inhibitors

Cutaneous melanoma is a highly aggressive malignancy; however, recent advancements in targeted and immunologic therapies have significantly improved patient outcomes. MAPK-directed therapies and immune checkpoint inhibitors such as anti-PD-1 and CTLA-4 have increased overall survival for patients with advanced melanoma. Unfortunately, resistance to MAPK-directed therapies and a lack of response to immunotherapy in a subset of patients remain major challenges, underscoring the need for novel therapeutic strategies. The CDK4/6 pathway, which regulates cell cycle progression through the p16-cyclin D-CDK4/6-RB axis, is frequently dysregulated in melanoma, presenting a viable target for therapeutic intervention. CDK4/6 inhibitors (CDK4/6i), which have already demonstrated efficacy in hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer, show promise in melanoma by inducing tumor senescence, modulating the tumor microenvironment, and enhancing patient immune responses. Preclinical and translational studies suggest that CDK4/6i could be particularly effective when combined with existing therapies, including MAPK inhibitors, immune checkpoint inhibitors, and senolytic agents. Ongoing clinical trials and emerging data on combination strategies underscore the promise of CDK4/6i as a critical component of future melanoma therapy. This review summarizes the current melanoma treatment landscape and explores the potential of CDK4/6i in advancing melanoma treatment, highlighting their ability to overcome therapy resistance, improve therapeutic efficacy, and offer new strategies for patients with advanced cutaneous melanoma.