Dietary Fish Oil Impairs Melanoma Growth and Promotes Anti–PD-1 Treatment Efficacy

INTRODUCTION: Anti–PD-1 immune checkpoint inhibition (αPD-1 ICI) treatment responses remain suboptimal in metastatic melanoma. We hypothesized that omega-3 fatty acids in dietary fish oil (FO) could ablate myeloid-induced T-cell suppression in the tumor microenvironment (TME) and improve ICI response in melanoma. METHODS: C57-BL/6J mice were injected with YUMM 1.7 melanoma in the flank. Mice were fed control chow (CTL) or omega-3 rich (FO) chow (30%kcal/kcal) starting day (D) 7. Intraperitoneal αPD1 or IgG2a vehicle were injected every 3 to 4 days starting D12. To assess the temporal flux of TME immune populations, tumors from mice in analogous experiments were assessed for growth and harvested on D12, D22, or D32. All listed results significant (p < 0.05) by 2-way ANOVA or t-test. RESULTS: In multiple models of solo and heterogeneous melanoma (metastatic model with a second melanoma cell line injected synchronously), FO decreased YUMM tumor growth vs CTL by D32 (>21% for all models). On D12, FO halved tumor-associated and M2 macrophage content, decreasing TME CD4 (CTLA-4+) and CD8 T cells. Conversely, by D22 FO increased M2 macrophages, CD4, and CD8 T cells, with PD-L1+ CD4s and PD1+ CD8s remaining increased at D32. At all three timepoints, FO increased TME monocytes and did not change NK cells. CONCLUSION: Fish oil impairs murine melanoma growth with and without αPD-1 ICI, delaying initial macrophage and CD4/ CD8 T-cell appearance in the TME while promoting cytotoxic T-cell persistence. Dietary FO may represent a cost-effective adjunct to αPD-1 immunotherapy in melanoma; further study in humans is warranted.