Introduction Melanoma is a highly aggressive malignancy characterized by a strong metastatic potential, underscoring the need to elucidate the mechanisms driving its progression in order to improve clinical outcomes. Increasing evidence points to a tumor-promoting interaction between melanoma cells and subcutaneous adipose tissue; however, the contribution of extracellular vesicles (EVs) to this intercellular crosstalk remains largely undefined.

Methods We investigated the impact of melanoma-derived EVs on adipocyte phenotype and lipid metabolism, as well as the functional consequences on melanoma cells. Activation of the cAMP/PKA/HSL signaling pathway, induction of lipolysis, and release of free fatty acids (FFAs) were analyzed in adipocytes exposed to melanoma EVs. FFA uptake and tumor-associated behaviors in melanoma cells were assessed, together with the role of the fatty acid transporter CD36 using pharmacological inhibitors, including sulfo-N-succinimidyl oleate (SSO) and SMS121.

Results Melanoma-derived EVs reprogram adipocytes toward a cancer-associated state by activating the cAMP/PKA/HSL signaling pathway, resulting in enhanced lipolysis and increased FFA release. These FFAs are subsequently taken up by melanoma cells, where they promote a stem-like phenotype characterized by increased proliferation, clonogenic capacity, survival, migration, invasion, and resistance to anoikis. Importantly, CD36 was identified as a critical mediator of this metabolic crosstalk, as pharmacological inhibition of CD36 effectively abolished the pro-tumorigenic effects induced by adipocyte-derived FFAs.

Conclusions Collectively, our findings support a model in which melanoma-derived EVs establish a metabolic feedback loop with adipocytes that enhances tumor aggressiveness. Targeting CD36 may therefore represent a promising therapeutic strategy to disrupt this pathogenic intercellular communication.