Lactate in Antitumor Immunity

Revealing the immune-protective role of lactate and developing acid-responsive nanoparticle therapies

Lactate, a key metabolite in glycolytic metabolism, plays a critical role in immune metabolism and is essential for designing immune adjuvants through metabolic regulation. However, lactate has often been confounded with lactic acid and has commonly been regarded as immunosuppressive.

Inspired by the discovery of severe acidity, I hypothesized that lactate’s physiological function is masked by the presence of protons. Using single-cell transcriptomics and epigenetic analyses, I revealed that sodium lactate has immune-protective effects by enhancing T cell stemness.

This discovery provides evidence of an unrecognized role for lactate in promoting anti-tumor immunity, apart from the pH-dependent effects of lactic acid. Building on this insight, we developed an acid-responsive negative feedback nanoparticle delivery system that specifically targets lactic acid export in the tumor microenvironment without systemic toxicity. This platform improved immunotherapy (e.g., anti-PD1) outcomes in head and neck cancer and melanoma models.

Lactate enhances CD8+ T cell stemness to promote anti-tumor immunity.

Selected Publications and Patent

  1. Feng, Q.; Liu, Z.; Yu, X.; Huang, T.; Chen, J.; Wang, J.; Wilhelm, J.; Li, S.; Song, J.; Li, W.; Sun, Z.; Sumer, B. D.; Li, B.; Fu, Y. X.; Gao, J. Lactate increases stemness of CD8+ T cells to augment anti-tumor immunity. Nat. Commun. 2022, 13, 4981. PMID: 36068198.

    This study discovered the immune-protective role of lactate, without the acidic counterpart, by enhancing the stemness of CD8+ T cells.

  2. Huang, T.; Feng, Q. (Co-first author); Wang, Z.; Li, W.; Sun, Z.; Wilhelm, J.; Huang, G.; Vo, T.; Sumer, B. D.; Gao, J. Tumor-Targeted Inhibition of Monocarboxylate Transporter 1 Improves T-Cell Immunotherapy of Solid Tumors. Adv. Healthcare Mater. 2021, 10, e2000549. PMID: 32431046.

    This work describes the tumor specific delivery of an inhibitor of lactic acid transporter to reverse tumor acidosis and related immunosuppression, improving antitumor efficacy at 50-fold reduced doses.

  3. pH Responsive Block Copolymer Compositions and Micelles that Inhibit MCT 1 and Related Protein, US20210338579A1.

    Patent related to tumor-targeted inhibition of monocarboxylate transporter.