Obesity and melanoma: unraveling the paradoxical survival benefit in immunotherapy

The incidence of melanoma has been steadily increasing worldwide, with metastatic disease accounting for a substantial proportion of melanoma-related deaths. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for advanced melanoma, yet patient responses remain highly variable. Interestingly, although obesity is a well-established risk factor for the development of melanoma, paradoxically, emerging clinical data reveal that obese patients may experience superior outcomes following ICI therapy—a phenomenon commonly referred to as the “obesity paradox”. The biological mechanisms underpinning this paradox remain incompletely elucidated. This review synthesizes current evidence through a critical examination of methodologies used to define obesity in oncology research, followed by an exploration of mechanistic links between obesity and melanomagenesis. We subsequently summarize clinical evidence supporting the obesity paradox in melanoma immunotherapy and discuss potential immune-mediated and metabolic mechanisms underlying this paradoxical association. The review concludes by addressing translational implications of these findings for patient stratification and novel therapeutic strategies.