Nano-enabled spatially selective protein degradation modulates lactate metabolism to potentiate antitumor immunity in liver cancer

While direct MCT1 and/or MCT4 inhibitors show promise, clinical translation remains limited by systemic toxicity. In this study, we developed polymer-based lysosome-targeting chimeras (LYTACs) that selectively degrade CD147, the MCT1/4 chaperone, in liver cancer cells, reducing lactate efflux in cancer cells while sparing healthy cells, thereby reprogramming lactate metabolism within the TME.

We further engineered polymer-based acid-responsive CD147-targeting LYTACs (PARTACs) to achieve controlled intratumoral release under acidic conditions. Systemic administration of PARTACs significantly suppressed tumor progression in several orthotopic liver cancer models. Moreover, PARTACs sensitized tumors to chemo-, immuno-, and radiotherapy with a favorable safety profile.