Serum starvation-induced cholesterol reduction increases melanoma cell susceptibility to cytotoxic T lymphocyte killing.

While calorie restriction has been suggested to reduce tumor incidence and slow tumor progression through promoting anti-tumor immune response, evidence disclosing how absence of specific nutrient component and alterations of its related metabolic pathways contribute to the process of anti-tumor immune response is still vague. Using human HLA-A*02:01 restricted New York esophageal squamous cell carcinoma-1 (NY-ESO-1) T cell receptor-engineered T (TCR-T) cells as a tool to investigate the impact from nutrient factors on tumor cells for targeted cytotoxicity, we serum-starved both human and murine melanoma cells and monitored their responses to TCR-T cell killing. Serum starvation sensitizes melanoma cells predominantly by reducing cholesterol availability without causing unwanted off-target effect, as supplementation of cholesterol compromises the sensitization toward TCR-T cell killing. In response to serum starvation, tumor cells upregulate cholesterol biogenesis pathways as a compensatory mechanism. Our study reveals the critical role of cholesterol reduction in mediating serum starvation-induced enhancement of anti-tumor immune response, highlighting the importance of plasma membrane composition in determining tumor cell response to TCR-T cell killing.