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

Dysregulated cancer metabolism, driven in part by excessive lactate export through monocarboxylate transporters 1 (MCT1) and 4 (MCT4), generates an acidic tumour microenvironment that suppresses antitumour immunity and diminishes therapeutic efficacy. Although small-molecule inhibitors targeting MCT1 and/or MCT4 have been explored, their clinical translation is limited by systemic toxicity. Here we developed polymer-based lysosome-targeting chimeras that selectively degrade CD147, a chaperone protein co-expressed with MCT1 and MCT4, in liver cancer cells, reducing lactate efflux and reprogramming lactate metabolism within the tumour microenvironment. We further engineered polymer-based acid-responsive CD147-targeting lysosome-targeting chimeras to achieve controlled intra-tumoural release under acidic conditions. Systemic administration of polymer-based acid-responsive CD147-targeting lysosome-targeting chimeras significantly suppressed tumour progression in several orthotopic liver cancer models. Moreover, these CD147-targeting lysosome-targeting chimeras potentiated the efficacy of multi-kinase inhibition, immunotherapy and radiotherapy, maintaining a favourable safety profile. Collectively, our nano-enabled spatially selective strategy modulates lactate metabolism in vivo, augmenting antitumour immunity and improving the efficacy of standard-of-care cancer therapies.