Squalene epoxidase in cancer: Mechanistic insights, therapeutic potential, and future perspectives

Metabolic reprogramming is a hallmark of malignancy. SQLE, a key regulated enzyme catalyzing the first oxygen-dependent step of cholesterol biosynthesis downstream of canonical HMG-CoA reductase, is aberrantly upregulated across multiple human malignancies and drives tumor progression and therapeutic resistance. This review examines the emerging role of SQLE as a potential metabolic-immune checkpoint, systematically integrating cutting-edge epitranscriptomic regulatory mechanisms published from 2024 to 2026, dissecting the full spectrum of SQLE-mediated immunosuppressive pathways, and conducting critical comparative analysis between repurposed antifungal SQLE agents and novel mammalian-selective inhibitors to advance combinatorial immunotherapy strategies. Beyond summarizing canonical transcriptional, post-transcriptional and post-translational cascades governing SQLE cholesterol homeostasis, we elaborate how SQLE reshapes membrane lipid signaling, sustains cancer stem cell stemness, facilitates epithelial-mesenchymal transition, and triggers redox and epigenetic remodeling to fuel malignant phenotypes. We further thoroughly unpack three interconnected immunosuppressive axes orchestrated by SQLE: oxysterol-driven myeloid-derived suppressor cell recruitment, stabilized PD-L1 palmitoylation mediating T cell exhaustion, and squalene depletion-triggered persistent NF-κB inflammatory signaling, which collectively lock tumors into an immune-excluded "cold" state in selected preclinical models. We objectively dissect the pharmacokinetic bottlenecks limiting terbinafine's single-agent anti-tumor efficacy and discuss the developmental advantages and toxic challenges of human-specific SQLE inhibitors. Finally, we highlight unresolved research gaps, prioritize translational directions including SQLE expression as a potential biomarker for immunotherapy responsiveness requiring independent cohort validation, the development of low-toxicity selective SQLE degraders, and synergistic regimens combining SQLE blockade with immune checkpoint inhibitors or ferroptosis inducers, offering a comprehensive and critical update for lipid metabolism and tumor immunology researchers.