Dietary ω-3 polyunsaturated fatty acids (PUFAs) reduce cholesterol-driven non-small cell lung cancer (NSCLC) progression in mouse models of disease.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality, and most patients fail to respond to immune checkpoint inhibitors (ICIs). Nutritional factors, particularly dietary lipids, influence cancer progression and immunity. Cholesterol can promote tumor growth and immune evasion, whereas ω-3 polyunsaturated fatty acids (PUFAs) may exert anti-inflammatory and immunostimulatory effects. We aimed to determine how dietary lipids influence NSCLC progression and whether ω-3 PUFA supplementation can enhance the efficacy of PD-1 blockade. METHODS: Serum lipid profiles from 152 NSCLC patients were analyzed for associations with prognosis. Female murine NSCLC models were fed diets enriched in cholesterol, saturated fats, or ω-3 PUFAs, with or without anti-PD-1 therapy. Tumor growth, immune infiltration, cytokine production, and epithelial-mesenchymal transition (EMT) markers were assessed by flow cytometry, ELISA, and gene expression analysis. RESULTS: In patients, elevated serum triglycerides correlate with poor outcomes, and tumor cholesterol metabolism links to EMT marker expression. In female mice, cholesterol-rich diets accelerate tumor growth, increase EMT-associated genes (SNAIL, Vimentin), and elevate pro-tumoral cytokines (IL-6, IL-10, IL-17A). ω-3 PUFA diets reduce tumor burden, lower immunosuppressive cytokines, decrease regulatory T cells, and enhance cytotoxic T cell activity. Combining ω-3 PUFAs with anti-PD-1 therapy synergistically suppresses tumor growth and improves antitumor immune responses. CONCLUSIONS: Dietary lipids modulate NSCLC progression via metabolic, inflammatory, and immune pathways. ω-3 PUFA supplementation counteracts cholesterol-driven tumor promotion and augments PD-1 blockade efficacy, supporting dietary modulation as a complementary strategy to improve immunotherapy outcomes in NSCLC.