Oxysterols at the crossroads of cholesterol metabolism and cancer

Oxysterols are enzymatically or non-enzymatically generated cholesterol derivatives that act as metabolic messengers at the interface of lipid homeostasis, nuclear receptor signaling, oxidative stress, and immunity. Their structural diversity endows them with highly selective biological activities: some function as ligands for LXRα/β, ERα, or GR; others regulate sterol trafficking, autophagy, redox equilibrium, and membrane organization. In cancer, this versatility translates into a dualistic influence on tumor biology. The oxysterol dendrogenin A activates differentiation programs, antioxidant defenses, and immunogenic pathways, whereas 27-hydroxycholesterol and oncosterone promote proliferation, endocrine resistance, and immune escape. The 5,6-epoxycholestanol pathway exemplifies this metabolic bifurcation: the same precursor may be routed toward dendrogenin A, supporting anticancer immunity, or toward OCDO, a glucocorticoid-like oncometabolite that suppresses cytotoxic lymphocytes and enhances tumor survival. A third axis, governed by CYP27A1, introduces additional complexity by hydroxylating the oncogenic oxysterol OCDO into an antiproliferative metabolite. These interlocking routes form a sterol-centered signaling network that integrates metabolic state with tumor progression and immune surveillance. Understanding how tumors rewire oxysterol metabolism, and how these lipid signals shape cellular plasticity and the tumor microenvironment, offers a promising framework for identifying metabolic vulnerabilities and designing sterol-based therapeutic strategies.