Oxysterols in Cancer: From Biosynthesis and Pathophysiology to Targeted Therapeutics

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ABSTRACT Oxysterols are bioactive cholesterol oxidation products that link lipid metabolism, inflammation, immune regulation, and tumor progression. This review summarizes the generation, sensing, and cancer‐related functions of major oxysterols, with a particular emphasis on 25‐hydroxycholesterol and 27‐hydroxycholesterol. It begins by outlining both enzymatic and non‐enzymatic pathways for oxysterol production, as well as the key receptors and signaling pathways involved, including LXR, SREBP, ER, GPER, EBI2/GPR183, NF‐κB, and PI3K/AKT/mTOR. The review then compares the ways in which oxysterols regulate tumor cell proliferation, invasion, metastasis, stromal remodeling, immune suppression, and therapeutic resistance across various malignancies, revealing a context‐dependent duality of pro‐tumorigenic and tumor‐suppressive effects. Importantly, this review systematically evaluates pharmacological strategies that target oxysterol‐producing enzymes, sensing receptors, and downstream signaling nodes. Emerging advances are highlighted, including the first in vivo validation of selective CYP27A1 blockade using Dafadine‐A, Phase I clinical evaluations of LXR agonists demonstrating T cell expansion, GPR183‐engineered CAR‐T cells that exploit oxysterol gradients for enhanced tumor infiltration, and three preclinical combination frameworks that pair oxysterol pathway modulation with immune checkpoint blockade, targeted therapies, or metabolic multi‐node strategies. By integrating mechanistic, preclinical, and clinically relevant evidence, this review clarifies how oxysterol biology may inform biomarker discovery, patient stratification, and future precision cancer therapy.