Cholesterol metabolism in tumor immunity: Mechanisms and therapeutic opportunities for cancer

Cholesterol is an essential component of the cell membrane which plays a critical role in the survival of immune and tumor cells. Reprogramming of cholesterol metabolism in both tumor cells and immune cells can impact tumor progression and anti-tumor immune responses. Strategies aimed at modulating cholesterol metabolism have been demonstrated to be effective in hindering tumor growth and boosting anti-tumor immune functions. This review provides a thorough analysis of intracellular cholesterol homeostasis regulation in cells, focusing on key genes and signaling pathways. It particularly emphasizes the regulatory mechanisms and importance of the cholesterol presence state (esterified/free), levels of cholesterol, and its metabolites in immune and tumor cells. Additionally, the review thoroughly explores how cholesterol metabolism and sources (endogenous/exogenous) in the tumor microenvironment (TME) contribute to the interplay among tumor cells, immune suppressor cells, and immune effector cells, promoting cancer progression and immune evasion. It also delves into current insights on the influence of cholesterol metabolites and related drugs in regulating tumor development or immunotherapy. Finally, it presents an overview of recent advancements in clinical and preclinical trials investigating the efficacy of targeted cholesterol metabolism treatments and combination therapies in cancer management, while proposing potential future research directions in tumor immunity. This review is poised to offer fresh perspectives and avenues for examining the potential of cancer immunotherapy centered on cholesterol metabolism regulation.