Combining lactate oxidase and metformin in cancer cell membrane-biomimetic liposomes for synergistic ferroptosis induction and hypoxia-alleviated cancer therapy.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxide accumulation, offers a promising strategy to circumvent tumor drug resistance. However, solid tumors exhibit intrinsic resistance to ferroptosis due to elevated antioxidant systems and hypoxic microenvironments, limiting H₂O₂-mediated lipid peroxidation. Herein, we developed a tumor-homing liposomal platform (ML-MLip) for co-delivery of lactate oxidase (LOX) and metformin (MET) to leverage the tumor microenvironment for enhanced ferroptosis induction. LOX catalyzes intratumoral abundant lactate (due to the Warburg effect) to generate H₂O₂, while MET alleviates tumor hypoxia by inhibiting mitochondrial complex I, ensuring sufficient oxygen for LOX activity. Concurrently, MET suppresses SLC7A11-mediated GSH synthesis and disabling GPX4-mediated lipid peroxide detoxification. Soybean phosphatidylcholine (SPC) within ML-MLip provides polyunsaturated lipids as substrates for peroxidation, overcoming endogenous lipid shortages. In vitro and in vivo studies demonstrated that ML-MLip preferentially accumulated at tumor sites, triggering iron-dependent lipid peroxidation (LPO) and ferroptosis. Additionally, lactate depletion and ferroptosis reversed the tumor immunosuppressive microenvironment, promoting the release of tumor antigens and damage-associated molecular patterns (DAMPs) to augment systemic immune responses. This strategy converts tumor-specific metabolites (lactate) and ions (iron) into therapeutic effectors, offering a microenvironment-responsive approach for synergistic ferroptosis-immunotherapy against malignant tumors.