Search

CN-122005525-A - Use of glutaconic acid to enhance T cell antitumor effect by metabolic reprogramming

CN122005525ACN 122005525 ACN122005525 ACN 122005525ACN-122005525-A

Abstract

The invention provides application of glutaconic acid (GC) in enhancing anti-tumor effect of T cells through metabolic reprogramming, and belongs to the technical field of biological medicines. The invention discovers that GC is exogenously supplemented in the tumor progress process, can rapidly inhibit the growth of tumors, and the anti-tumor effect depends on TME regulation and control mechanism. The TME immune landscape can be remarkably remodeled through GC treatment, the GC treatment can enhance the effector function of CD8 + T cells and delay the depletion process of the CD8 + T cells, and the infiltration of CD8 + T cells in tumors of a GC treatment group is remarkably increased. In particular, after the anti-CD 8 antibody was used to clear mouse CD8 + T cells, the anti-tumor effect of GC completely disappeared, confirming that its tumor-inhibiting effect was dependent on CD8 + T cells. Thus, the present invention demonstrates that lysine catabolite GC, as an immunostimulatory metabolite, can shape an immune-activated TME by reactivating the function of tumor-infiltrating CD8 + T cells.

Inventors

  • WANG DI
  • YU WEIWEI

Assignees

  • 浙江大学

Dates

Publication Date
20260512
Application Date
20260324

Claims (10)

  1. 1. Application of glutaconic acid in preparing immunomodulator for regulating tumor microenvironment is provided.
  2. 2. The use of claim 1, wherein the modulation comprises shaping the tumor microenvironment to an immunocompetent tumor microenvironment.
  3. 3. The use of claim 2, wherein the immunocompetent tumor microenvironment comprises at least one of a significant expansion of an anti-tumor T cell subpopulation, a significant reduction of immunosuppressive or depleting T cells, a transition of T cells to an activated state, and an enhancement of effector function of CD8 + T cells.
  4. 4. The use according to claim 3, wherein the anti-tumour T cell subpopulation comprises the CD8 effector T cell subpopulation cd8t_ Gzmk.
  5. 5. Use of glutaconic acid in the preparation of an activator for activating anti-tumor CD8 + T cells.
  6. 6. Application of glutaconic acid in preparing antineoplastic medicine is disclosed.
  7. 7. The use according to claim 6, wherein the therapeutic profile of the antitumor drug comprises intestinal cancer, renal cancer, lung cancer, head and neck squamous carcinoma, basal cell carcinoma, melanoma and liver cancer.
  8. 8. Application of glutaconic acid in preparing synergist of tumor immunotherapy medicine is provided.
  9. 9. An antitumor drug is characterized by comprising glutaconic acid and pharmaceutically acceptable auxiliary materials.
  10. 10. An antitumor drug is characterized by comprising glutaconic acid, a tumor immunotherapy drug and pharmaceutically acceptable auxiliary materials.

Description

Use of glutaconic acid to enhance T cell antitumor effect by metabolic reprogramming Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of glutaconic acid in enhancing anti-tumor effect of T cells through metabolic reprogramming. Background Tumor cells model microenvironments (tumor microenvironment, TME) that facilitate tumor growth and immune escape by reconstructing metabolic networks. As the tumor progresses, the metabolic landscape in TME continues to evolve dynamically, which is simultaneously doubly regulated by tumor cells and their interactions with the microenvironment components. As the principal force of anti-tumor, immune cells in TMEs continue to face challenges of nutrient availability, metabolic preference, and metabolic applicability, ultimately leading to immune dysfunction and impaired immunotherapeutic effects. The current research mainly focuses on tumor cells to suppress immune cells through nutritional competition and secretion of immunosuppressive metabolites, but the specific mechanism of how to optimize metabolic synergy to achieve rapid proliferation and immune escape co-evolution for tumors is still unclear. While greedy uptake of nutrients by tumor cells supports anabolism, and amino acid catabolism is generally thought to enhance inhibition of T cell immunity, current cognition is still very limited as to whether it actively limits the utilization of specific nutrients and metabolic pathways to promote tumor progression. Amino acids are essential nutrients for the rapid proliferation of tumor cells, and lack of availability severely impairs T cell activation and function. Prior studies have shown that TMEs exhibit deprivation of nonessential amino acids (e.g., glutamine, arginine, asparagine) and essential amino acids (e.g., methionine, tryptophan). In contrast, although lysine as an essential amino acid plays a key role in biosynthesis, energy supply and antioxidant activity, its dynamic change characteristics in TME and its specific effects on tumor progression and immune escape are still unclear, for example, lysine catabolic pathways are not yet completely resolved, and the relationship of key catalytic enzymes to the corresponding metabolites is still unclear, which hinders the cognition of lysine metabolism in tumors and the development of related accurate therapies. A few previous studies suggest that the lysine catabolic enzyme glutaryl coa dehydrogenase (glutaryl-CoA dehydrogenase, GCDH) may promote survival and chromatin stability of specific tumor cells such as melanoma and glioblastoma stem cells. However, how tumor cells and tumor infiltrating immune cells (especially cytotoxic CD8 + T cells) dynamically utilize lysine and its catabolites to affect tumor progression is still rarely studied. Disclosure of Invention The invention provides application of glutaconic acid (GC) in enhancing anti-tumor effect of T cells through metabolic reprogramming, the GC can shape immune activated TME, and through metabolic reprogramming Cheng Zengjiang CD8 + T cell function, the GC is closely related to anti-tumor immune response of cancer patients and can remarkably enhance curative effect of immunotherapy. The invention provides application of glutaconic acid in preparing an immunomodulator for regulating and controlling tumor microenvironment. In one embodiment of the invention, the modulation comprises shaping the tumor microenvironment to an immunocompetent tumor microenvironment. In one embodiment of the invention, the immune-activated tumor microenvironment comprises at least one of the following that the anti-tumor T cell subset is obviously amplified, the immunosuppressive or depletion T cells are obviously reduced, the T cells are promoted to be converted into an activated state, and the effector function of the CD8 + T cells is enhanced. In one embodiment of the invention, the anti-tumor T cell subpopulation includes the CD8 effector T cell subpopulation cd8t_ Gzmk. The invention also provides application of the glutaconic acid in preparing an activator for activating the anti-tumor CD8 + T cells. The invention also provides application of the glutaconic acid in preparing antitumor drugs. In one specific embodiment of the invention, the therapeutic spectrum of the antitumor drug comprises intestinal cancer, renal cancer, lung cancer, head and neck squamous cell carcinoma, basal cell carcinoma, melanoma and liver cancer. The invention also provides application of the glutaconic acid in preparing a synergist of a tumor immunotherapy medicament. The invention also provides an antitumor drug comprising glutaconic acid and pharmaceutically acceptable auxiliary materials. The invention also provides an anti-tumor drug, which comprises glutaconic acid and tumor immunotherapy drug, and also comprises pharmaceutically acceptable auxiliary materials. Advantageous effects based on the general feature that mos