Inflammaging in melanoma: Precision control for optimizing immune checkpoint inhibition

Aging is a major risk factor for melanoma and is accompanied by a chronic, low-grade inflammatory state termed "inflammaging". Although inflammation is essential for host defense and antitumor immunity, not all inflammatory states are beneficial. Instead, inflammaging can drive immune dysfunction and impair responses to immune checkpoint inhibitors (ICIs). ICIs have revolutionized the treatment of advanced melanoma; however, durable clinical benefit is limited to a subset of patients, and immune-related adverse events remain a major challenge. These limitations highlight the need to better understand how inflammaging intersects with anti-tumor immunity and immunotherapy outcomes. In this review, we focus on key inflammaging-associated cytokines-interleukin-6 (IL-6), interleukin-1 (IL-1), and tumor necrosis factor-α (TNF-α)-and discuss their roles in shaping melanoma progression and responses to ICIs. IL-6 has emerged as a key mediator linking tumor-promoting inflammation to immune suppression and immunotherapy-related toxicity, with growing preclinical and clinical evidence supporting its selective blockade as a strategy to enhance ICI tolerability and efficacy. IL-1 signaling contributes to tumor-promoting inflammation and immune dysregulation in melanoma, although clinical evidence supporting IL-1-targeted strategies remains limited. TNF-α exhibits context-dependent effects, acting as both a mediator of anti-tumor immunity and resistance to ICIs when chronically sustained. Together, these findings support a model in which selective modulation of pathological inflammaging, rather than broad suppression of inflammation, may improve the therapeutic index of ICIs. Targeting specific cytokine pathways offers a translationally relevant strategy to optimize immunotherapy outcomes in melanoma, particularly in inflammaging-associated contexts.