DHA-enriched omega-3 supplementation remodels adipose endocrine function and potentiates brown adipose secretome-mediated killing of melanoma cells

Abstract Background Omega-3 polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), have well-established anti-inflammatory properties and have been increasingly investigated for their potential role in modulating tumor progression. However, the contribution of adipose tissue to these effects remains poorly understood. Here, we investigated whether dietary supplementation with DHA-enriched omega-3 modulates systemic inflammation, adipose tissue phenotype, and adipose tissue–tumor crosstalk, with particular emphasis on the biological activity of brown (BAT) and subcutaneous white adipose tissue (sWAT)-derived secretomes against melanoma cells. Methods Female C57BL/6 mice received DHA-enriched omega-3 supplementation (DHA: EPA ratio 5:1; 1 g/kg body weight/day) for 35 days. Systemic inflammation and cellular redox-associated responses were assessed by serum cytokine profiling and flow cytometric analysis of total peritoneal lavage cells. Adipose tissue depots were evaluated by histological and molecular analyses. Conditioned media (CM) derived from BAT and sWAT of control and supplemented mice were characterized for metabolic and inflammatory mediators and tested for their effects on B16-F10 melanoma cells and NIH/3T3 non-tumoral fibroblasts. Results DHA-enriched omega-3 supplementation significantly attenuated systemic inflammatory markers and reduced oxidant-sensitive fluorescence in total peritoneal lavage cells without affecting body weight. Supplemented mice exhibited reduced adipose tissue mass, decreased adipocyte size in gonadal white adipose tissue, and lower TGF-β expression in BAT, whereas classical thermogenic and lipolytic markers remained largely unchanged. Adipose tissue–derived CM from supplemented animals displayed depot-specific metabolic and inflammatory changes. Functionally, BAT-derived CM from DHA-enriched omega-3-supplemented mice markedly reduced B16-F10 melanoma cell viability, while preserving NIH/3T3 fibroblast viability. In addition, CM from supplemented animals attenuated melanoma-associated inflammatory signaling, including reduced IL-6 production and normalization of TGF-β levels. Conclusions These findings demonstrate that DHA-enriched omega-3 supplementation remodels adipose tissue phenotype and secretory function, generating a BAT-derived secretome with selective cytotoxic activity against melanoma cells. Our results identify adipose tissue, particularly BAT, as an active mediator of the systemic and antitumor effects of DHA and highlight adipose tissue–tumor crosstalk as a potential mechanism linking dietary lipids to cancer biology.