Beyond the membrane: lipid rafts and oxysterols establish cholesterol as a dynamic signaling hub while underlying the cholesterol paradox in cancer.

Metabolic reprogramming of cholesterol extends beyond its canonical role in membrane biogenesis, serving as a dynamic signaling hub that facilitates tumor progression and therapy resistance. In cancer therapy, the limited clinical efficacy and variable outcomes of non-selective lipid-lowering interventions, such as statins, underscore an incomplete understanding of these underlying regulatory networks. This review addresses the paradoxical roles of cholesterol in oncology, in which cancer cells leverage oxysterols and membrane lipid rafts to promote metastasis, immunosuppression, and therapy resistance, while baseline cholesterol homeostasis remains essential for proper immune cell function. We review the initiation of cholesterol metabolic reprogramming and evaluate the resulting metabolic conflict. Furthermore, we examine how immune cells adapt metabolically to cholesterol competition within the tumor microenvironment (TME), the role of cholesterol in pre-metastatic niche formation and organotropism, and its involvement in drug resistance through efflux transporters and ferroptosis suppression. These mechanistic insights may inform the rationale for targeted metabolic therapeutic strategies.