Our Science

UDT1: undisclosed target1

Our targeted metabolic pathways in the tumor microenvironment and their effect on antitumor immunity

Cancer immunotherapies involving the use of immune checkpoint inhibitors have demonstrated clinical efficacy in different types of cancer. However, many tumors show significant resistance to checkpoint blockade presumably due to insufficient reprogramming of the immunosuppressive tumor microenvironment (TME) and the limited reinvigoration of antitumor immunity.

Teon takes a unique twofold approach to reinvigorate anticancer immunity and enhance immunotherapies by targeting:

  1. Key pathways that are involved in metabolic reprogramming of the immunosuppressive TME.
  2. Specific G protein-coupled receptors (GPCRs) in the TME that are upregulated in cancer and immune cells and contribute to the creation of an immunosuppressive TME.

Teon’s goal is to develop combination treatments including metabolic checkpoint inhibitors (target 1) and GPCR immune checkpoint inhibitors (target 2) to unleash the full potential of immunotherapies by reinvigorating anticancer immunity.

The immunosuppressive state of the TME is regulated by the metabolic activity of cancer cells and plays an essential role in determining cancer progression. Rapid proliferation of tumor cells requires high levels of energy and therefore metabolic reprogramming has emerged as a key feature for cancer survival under hypoxia, stress and limited nutrients availability. Metabolic reprogramming not only supports cancer cell growth, but also generates metabolic products that alter the TME and adversely affect the survival and function of immune cells in the TME. The common feature of this metabolic reprogramming is that cancer cells switch their glucose metabolism toward “aerobic glycolysis” (Warburg effect), thus decreasing glucose availability and increasing lactic acid in the TME. The hypoxic, glucose-deprived and lactic acid-enriched TME impairs T cell function and thus antitumor immune response. Metabolic stress leads to the release of the danger signal molecule ATP into the TME. ATP is rapidly converted to adenosine, which activates adenosine A2A and A2B receptors on immune cells and consequently inhibits their function. Aberrant lipogenesis is another key feature of metabolic reprogramming in cancer cells. While lipids provide additional energy required by proliferating tumor cells, their metabolites, such as prostaglandin E2 (PGE2), can dampen the function of immune cells through activation of EP4 receptors.