Synchronous Interference of Dual Metabolic Pathways Mediated by H2S Gas/GOx for Augmenting Tumor Microwave Thermal Therapy

Sublethal tumor cells have an urgent need for energy, making it common for them to switch metabolic phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) for compensatory energy supply; thus, the synchronous interference of dual metabolic pathways for limiting energy level is essential in inhibiting sublethal tumor growth. Herein, a multifunctional nanoplatform of Co-MOF-loaded anethole trithione (ADT) and myristyl alcohol (MA), modified with GOx and hyaluronic acid (HA) was developed, namely, CAMGH. It could synchronously interfere with dual metabolic pathways including glycolysis and OXPHOS to restrict the adenosine triphosphate (ATP) supply, achieving the inhibition to sublethal tumors after microwave (MW) thermal therapy. Under low-power MW irradiation, CAMGH induced certain tumor thermal damage while ensuring the safety of the surrounding normal tissues. The loaded GOx consumed glucose in tumors, undoubtedly blocking the main energy supply pathway, the glycolytic pathway. Then, H₂O₂ generated from GOx reacted with Co²⁺ to produce cytotoxic ·OH, combining with the released H₂S from ADT to co-obstruct OXPHOS and then synergy with the above glycolysis blocking for a more effective ATP inhibition. The powerful depletion of ATP caused significant suppression of damage resistance protein upregulated after thermal stimulation, i.e., HSP90, and then the activation of caspase-3, achieving the simultaneous reversal of heat resistance and apoptosis resistance. Altogether, the CAMGH-based synchronous interference of dual metabolic pathways shows the potential to break down tumor self-repair, presenting an alternative strategy to enhance the therapeutic effect of tumor MW thermal therapy.