ACOX2 at the crossroads of peroxisomal metabolism, DNA damage sensing, and anticancer immunity

Peroxisomal metabolism was long regarded as a housekeeping pathway with minimal involvement in cancer. Nonetheless, accumulating data demonstrate that peroxisomal lipid oxidation critically modulates genome stability and antitumor immunity. The acyl-CoA oxidase (ACOX) family-including ACOX1, ACOX2 and ACOX3-catalyzes the initial oxidative step of peroxisomal fatty acid β-oxidation, and governs lipid metabolism, redox homeostasis, as well as acyl-CoA-related post-translational modifications such as lysine crotonylation. Notably, ACOX2 has gained growing attention for its connections with DNA damage sensing, cGAS-STING activation and anticancer immunity. Dysregulated ACOX2 expression correlates with tumor progression, therapeutic response and clinical prognosis across various cancers, though direct functional evidence varies by tumor type. Mechanistically, ACOX2-related lipid metabolism maintains intracellular redox balance and stress adaptation, with its pathway-specific signaling still poorly defined. In clear cell renal cell carcinoma, ACOX2 binds MRE11 to destabilize the MRN complex, inducing cytosolic DNA buildup and cGAS-STING-mediated type I interferon signaling, while its universal role in other malignancies awaits validation. ACOX2 acts in a context-dependent fashion: it exerts tumor-suppressive effects in liver, prostate and lung cancers, yet facilitates metabolic adaptation and chemoresistance under therapeutic stress. This review summarizes ACOX2 as a key integrator of metabolism, immunity and genome integrity, and highlights its translational potential as a cancer biomarker and therapeutic target.