Targeting cholesterol-driven immunometabolism in cancer: from molecular circuits to clinical translation.

Cholesterol integrates membrane organization, oncogenic signaling, and tumor immune regulation. Consistent with this central role, cholesterol homeostasis is frequently rewired in cancer, and dysregulated cholesterol metabolism is increasingly recognized as a key contributor to tumor initiation and progression. Accumulating evidence indicates a mutually reinforcing interplay between oncogenic pathways and cholesterol metabolism: malignant transformation upregulates cholesterol biosynthesis and related homeostatic programs, and the ensuing metabolic reprogramming supports tumor growth, metastatic competence, and immune evasion. Beyond serving as structural components of cellular membranes in proliferating cells, cholesterol and its derivatives can act as signaling mediators that reshape membrane microdomains, reprogram oncogenic circuitry, and modulate stress-adaptation pathways in a context-dependent manner. Importantly, cholesterol metabolism is also remodeled in immune cells within the tumor microenvironment, where alterations in sterol flux and oxysterol signaling can influence antigen presentation, T-cell activation versus dysfunction, and myeloid polarization, thereby shaping responses to immunotherapy. Although cholesterol metabolism represents a promising therapeutic target, clinical translation of cholesterol-modulating agents remains limited. Key obstacles include the poor tumor specificity of current drugs (e.g., statins and cholesterol absorption inhibitors), cancer cell metabolic plasticity, and context-dependent tumor-immune interactions. Emerging next-generation strategies encompass enzymatic inhibitors, targeted delivery platforms, and gene-editing systems. While these approaches show promising preclinical results, their clinical translation demands systematic optimization, pharmacodynamic biomarker development, and patient stratification aligned with precision oncology principles. This review synthesizes mechanistic links between cholesterol-driven metabolic rewiring and cancer and critically appraises preclinical and clinical advances, including representative clinical trials combining cholesterol-lowering interventions with systemic anti-cancer therapies.