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Updated: Jun 17, 2026
Site-Specific Lysine Lactylation via Genetic Code Expansion in E. coli and Mammalian Cells
Published on: February 24, 2026
Nano-enabled spatially selective protein degradation modulates lactate metabolism to potentiate antitumor immunity in
Jinhong Du1, Shu Han1, Rui Song1
1Department of Radiation Medicine, School of Basic Medical Sciences, Peking University and Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China.
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.
Insights
New polymer-based therapies degrade CD147, a protein linked to cancer metabolism. This approach reduces lactate export, reprogramming the tumor microenvironment to enhance anti-tumor immunity and improve cancer treatment efficacy.
Area of Science:
- Oncology
- Biotechnology
- Cancer Metabolism
Background:
- Dysregulated cancer metabolism, particularly excessive lactate export via monocarboxylate transporters 1 (MCT1) and 4 (MCT4), creates an acidic tumor microenvironment.
- This acidic environment suppresses anti-tumor immunity and reduces the effectiveness of cancer therapies.
- Existing small-molecule inhibitors for MCT1/MCT4 face challenges in clinical translation due to systemic toxicity.
Purpose of the Study:
- To develop novel polymer-based therapeutics targeting CD147, a chaperone protein co-expressed with MCT1 and MCT4.
- To investigate the efficacy of these therapeutics in reducing lactate efflux and reprogramming tumor lactate metabolism.
- To engineer acid-responsive drug release for controlled intra-tumoral delivery.
Main Methods:
- Development of polymer-based lysosome-targeting chimeras designed to selectively degrade CD147 in liver cancer cells.
- Engineering of acid-responsive chimeras for controlled release in the acidic tumor microenvironment.
- Evaluation of systemic administration in orthotopic liver cancer models, assessing tumor progression and combination therapy efficacy.
Main Results:
- Systemic administration of acid-responsive CD147-targeting chimeras significantly suppressed tumor progression in preclinical liver cancer models.
- The developed chimeras effectively reduced lactate efflux and reprogrammed lactate metabolism within the tumor microenvironment.
- Combination therapy with multi-kinase inhibitors, immunotherapy, and radiotherapy showed potentiated efficacy with a favorable safety profile.
Conclusions:
- Nano-enabled, spatially selective degradation of CD147 offers a promising strategy to modulate tumor lactate metabolism in vivo.
- This approach enhances anti-tumor immunity and improves the efficacy of standard cancer therapies.
- The developed acid-responsive chimeras represent a potential advancement in liver cancer treatment with improved safety and efficacy.
