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

  • Nat Nanotechnol. 2026 Jun 15. doi: 10.1038/s41565-026-02196-z.
Jinhong Du  1 ,  Shu Han  1 ,  Rui Song  1 ,  Jianze Wang  1 ,  Linyu Zhang  1 ,  Yueyang Xu  1 ,  Haoyi Zhou  1 ,  Feng Wang  1  2 ,  Sen Qin  3 ,  Da Xu  4 ,  Yameng Hao  5 ,  Kui Li  1 ,  Xin Zhou  1  2 ,  Jiadong Wang  1 ,  Luyang Sun  3 ,  Zhi Yang  1  2 ,  Zhaofei Liu  6  7  8
Affiliations
  • 1. Department of Radiation Medicine, School of Basic Medical Sciences, Peking University and Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China.
  • 2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital and Institute, Beijing, China.
  • 3. Department of Biochemistry, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 4. Department of Hepatopancreatobiliary Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
  • 5. State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Nuclear Medicine, Peking University Third Hospital, Beijing, China.
  • 6. Department of Radiation Medicine, School of Basic Medical Sciences, Peking University and Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China. [email protected].
  • 7. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital and Institute, Beijing, China. [email protected].
  • 8. State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Nuclear Medicine, Peking University Third Hospital, Beijing, China. [email protected].
PMID: 42298103 DOI: 10.1038/s41565-026-02196-z
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.

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