Authors
Jinhong Du, Shu Han, Rui Song, Jianze Wang, Linyu Zhang, Yueyang Xu, Haoyi Zhou, Feng Wang, Sen Qin, Da Xu, Yameng Hao, Kui Li, Xin Zhou, Jiadong Wang, Luyang Sun, Zhi Yang, Zhaofei Liu
Published in
Nature nanotechnology. Jun 15, 2026. Epub Jun 15, 2026.
Abstract
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.
PMID:
42298103
Bibliographic data and abstract were imported from PubMed on 16 Jun 2026.
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