Pan-cancer analysis of cholesterol metabolism reveals the uptake as a modulator of tumor immune features and of the KRAS pathway.

Cholesterol dysregulation plays a central role in tumor progression and has emerged as a potential therapeutic target. Its dysregulation within the tumor microenvironment is increasingly considered a strong modifier of multiple cancer traits. Targeting cholesterol, particularly its biosynthetic pathway, has been explored to enhance therapy, yet outcomes remain inconsistent, likely reflecting a tumor-specific reprogramming of cholesterol metabolism. TCGA and GTEx transcriptomic data from 11,735 samples was analyzed to conduct an integrative assessment of key cholesterol-related processes-biosynthesis, uptake, storage, efflux, and catabolism-across 26 cancer types. Cholesterol metabolism dysregulation was highly heterogeneous among tumors, affecting different metabolic pathways, the magnitude of those differences and the direction relative to normal tissue. Notably, we identified cholesterol uptake as the most consistently altered pathway across tumors, positively correlated with tumor aggressiveness and poorer patient survival. Uptake correlated positively with inflammatory pathways (e.g., Complement System and IL-6-JAK-STAT3 Signaling) and with immune microenvironment features, including Tregs, cytotoxic and CD4+ T cells, eosinophils, endothelial cells, as well as elevated expression of immune checkpoints. Cholesterol uptake also correlated with enhanced KRAS signaling. Particularly, KRAS mutations were more frequent in tumors with high uptake scores, and those patients had the worst overall survival. Nonetheless, high uptake tumors lacking KRAS mutations had higher KRAS signaling scores than KRAS-mutant tumors with low uptake, highlighting a central role of cholesterol uptake on the regulation of KRAS signaling. In summary, cholesterol uptake emerges as a conserved driver of tumor aggressiveness and a promising therapeutic target to synergize with immunotherapy and KRAS inhibition.