A multimodal drug-diet-immunotherapy combination restrains melanoma progression and metastasis.

The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet. Despite its importance in oncogenesis, SCD underwent monoallelic co-deletion along with PTEN on chromosome 10q in about 47.5% of melanoma, and the other SCD allele was methylated, resulting in very low SCD expression. While this SCD deficient subset was refractory to SCD inhibitors, the subset of PTEN wildtype melanoma that retained SCD was sensitive. As dietary oleic acid could potentially blunt the effect of SCD inhibitors, a low-oleic acid custom diet was combined with SCD inhibitor. The combination reduced monounsaturated fatty acids and increased saturated fatty acids, inducing robust apoptosis and growth suppression and inhibiting lung metastasis with minimal toxicity in preclinical mouse models of PTEN wildtype melanoma. When combined with anti-PD1 immunotherapy, the SCD inhibitor improved T cell functionality and further constrained melanoma growth in mice. Collectively, these results suggest that optimizing SCD inhibitors with diets low in oleic acid may offer a viable and efficacious therapeutic approach for improving melanoma treatment.