Targeting cholesterol metabolism: a core regulator of tumor-associated macrophage plasticity and immunotherapy response.

Tumor-associated macrophages (TAMs) are one of the main immunosuppressive components in the tumor microenvironment (TME). Growing evidence indicates that their functional state is closely related to metabolic signaling, with cholesterol metabolism dysregulation receiving increasing attention. Abnormal cholesterol metabolism alters membrane lipid composition and signaling pathways, resulting in impaired antigen presentation, upregulation of immune checkpoint molecules, and persistent immunosuppression, thereby facilitating tumor immune evasion and metastasis. The imbalance in cholesterol uptake, esterification, and efflux within TAMs has emerged as a 'metabolic checkpoint' that influences their plasticity between pro-tumoral and anti-tumoral states. In this review, we systematically summarize current research progress on the mechanisms of these processes and discuss how cholesterol metabolism dysregulation reshapes the phenotype of TAMs. We further highlight current therapeutic strategies targeting cholesterol metabolism and the challenges that impede their clinical translation. Finally, we outline emerging advancements in nanomedicine, spatial multi-omics, and artificial intelligence, which may facilitate more precise metabolic reprogramming of TAMs in future immunotherapy.