Cholesterol metabolism reprogramming: shaping tumor immunity and immunotherapy

Abstract

Cholesterol, a vital biomolecule with essential physiological functions, undergoes frequent reprogramming of its metabolic pathways during tumorigenesis and progression. This reprogramming enables it to participate in immune regulation through multiple mechanisms. Accumulating evidence reveals the aberrant activation of cholesterol metabolic pathways across various malignancies. This dysregulation is characterized by enhanced synthesis, increased uptake, reduced efflux, and the accumulation of derivatives, such as cholesteryl esters and oxysterols. These alterations suggest that targeting cholesterol metabolism represents a promising strategy to enhance the efficacy of tumor immunotherapy. In cancer cells, reprogrammed cholesterol metabolism supports proliferation, stemness, and resistance to cell death, including ferroptosis and autophagy. Conversely, in immune cells, it modulates effector functions, polarization states, and the expression of immune checkpoints like PD-L1. Collectively, these effects shape an immunosuppressive tumor microenvironment that facilitates immune evasion. Furthermore, cholesterol metabolism intersects with critical oncogenic signaling pathways and is fine-tuned by non-coding RNAs, thereby further driving tumor progression and therapy resistance. This review systematically delineates the regulatory landscape of cholesterol homeostasis in both malignant and immune cells, highlighting its multifaceted impact on tumor immunity and therapeutic responses. A deeper understanding of cholesterol and its metabolite dynamics within the tumor microenvironment, as well as their crosstalk with other signaling networks, will not only aid in optimizing current immunotherapeutic approaches but also provide a crucial conceptual foundation for developing novel combination strategies.