Synchronous intervention of TCA cycle and lactic acid metabolism through self-enhanced cuproptosis and acidosis for tumor metabolic symbiosis destruction

Abnormal metabolic symbiosis is one of the most typical features of tumors that distinguishes them from normal tissues. Disrupting tumor metabolic symbiosis has been recognized a promising tumor therapeutic approach. However, a single pathway intervention strategy greatly impedes its treatment efficiency. Herein, α-cyano-4-hydroxycinnamic acid (CHCA) and elesclomol (ES) co-loaded Cu 7 S 4 nanoplatform (named as CCE) is developed to synchronously intervene tricarboxylic acid (TCA) cycle and lactic acid metabolism through self-enhanced cuproptosis and acidosis for tumor metabolic symbiosis destruction. CCE could be triggered by up-regulated glutathione (GSH) in cancer cells to release ES, CHCA, Cu ions, and S 2− ions. On the one hand, ES significantly improves the influx efficiency of Cu ions to mitochondria where cuproptosis is initiated and TCA cycle is attacked. Meanwhile, the H 2 S produced by the binding of S 2− to H + in acidic tumor cells could induce mitochondrial damage and inhibit Cu ions efflux by depriving energy supply. Moreover, the GSH consumption reduces its chelation with Cu ions. Collectively, the increased intracellular Cu ions level significantly boosts cuproptosis mediated proteotoxicity of TCA cycle, thus aggravating TCA cycle injury. On the other hand, CHCA down-regulates the expression of monocarboxylate transporters 4 (MCT4) and inhibits lactic acid transport between tumor cells, causing the tumor cytoplasm acidification. Interestingly, H 2 S accelerates lactate production by promoting the glucose uptake to further potent the lactate metabolic disorder. In vitro and in vivo experiments confirm anti-tumor efficacy and biosafety of CCE. This study further enriches tumor therapeutic strategy.