Closed-loop of Catalyzed Lactate Oxidization Synergistically Sensitizes Apoptosis and Ferroptosis for Cancer Therapy

Lactate accumulated in Tumor is a key oncometabolite and associated with various oncogenic processes, including proliferation, invasion, angiogenesis, metastasis, immunosuppression and therapeutic resistance. Particularly, lactate contributes to the apoptosis and ferroptosis resistance in cancer cells. Consequently, blockade of lactate provides a promising opportunity for cancer therapy. However, due to abnormal tumor microenvironment (TME) and intracellular glutathione (GSH) mediated ferroptosis resistance, the current approaches for regulating lactate to sensitize cells to apoptosis and ferroptosis are still challenging. Herein, we developed a catalytic lactate oxidizing liposomes (Lip-LM) incorporated with lactate oxidase (LOX)-loaded MnO2 nanoparticles. O2 regenerated from H2O2 constitute closed-loop of lactate oxidation catalyzed by LOX, enhancing the lactate-consuming efficacy in TME. Besides, glutathione is consumed by MnO2 to amplify the ferroptosis susceptibility of cancer cells. The results showed that Lip-LM achieved synergistical apoptosis and ferroptosis to enhance the anti-tumor efficacy of amplified oxidative stress in cancer cells through the strategy of self-sufficient O2 supplying and GSH consumption. The results of transcriptomics and proteomics analyses also support the synergistical anti-tumor mechanisms of Lip-LM. Hence, it is a promising catalytic nanoplatform combined lactate regulation and oxidative stress amplification and have great potential to further enhance therapeutic outcomes based on synergistical apoptosis and ferroptosis.

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