通过抑制糖酵解调控代谢竞争以实现安全有效的肿瘤免疫治疗

Metabolic competition between tumors and T cells is fierce in the tumor microenvironment (TME). Tumors usually exhaust glucose and accumulate lactic acid in TME. Nutrient deprivation and lactic acid accumulation in TME blunt T cell functions and antitumor immune responses.

Here, we reported that glycolysis-related genes were upregulated in melanoma patients with weak immune responses and T cell poorly infiltrated tumors of BRCA and COAD patients. Dimethyl fumarate (DMF), a GAPDH inhibitor, which is FDA proved to treat autoimmune diseases was identified to promote oxidative pentose phosphate pathway through glucose-6-phosphate dehydrogenase (G6PD) but to suppress aerobic glycolysis and oxidative phosphorylation in tumor cells.

Additionally, DMF normalized metabolic competition between tumors and T cells, thus potentiate antitumor responses of tumor infiltrating CD8 + T lymphocytes (TILs).

Moreover, DMF optimized the efficiency of immune checkpoint therapy and interleukin-2 (IL-2) therapy while eliminating severe toxicity induced by IL-2 therapy.

This study indicates a novel clinically feasible therapy strategy aiming shared metabolic pathway of tumors and T cells for effective and less toxic tumor immunotherapy.