An exciting development in the recent anticancer therapy field is the unprecedented success of immunotherapies that invigorate the body’s immune system in eradicating cancer cells. As cancers progress, they develop microenvironments that suppress tumor-targeting cytotoxic effector T cells. Direct nutritional competition of effector T cells against metabolically active and voracious cancer cells restrict the metabolic activities required for effector T cell proliferation and function. Tumors also enhance the recruitment and activity of immune suppressor cells (Treg cells, MDSCs and M2 type macrophages) that depend on different metabolic pathways for their functions. Recently, it has been shown that small molecules manipulating metabolic pathways of cancer cells, T cells or immune suppressor cells can enhance anti-cancer immunities and suppress tumor growth. For instance, metformin enhances development of memory T cell by switching cellular metabolism from glycolysis to mitochondrial respiration. Moreover, suppression of MDSCs by an inhibitor of fatty acid oxidation was also shown to inhibit tumor growth, raising an exciting possibility of reinvigorating anti-cancer immunity by small molecules targeting cellular metabolic pathways.
IM188, in late stage lead optimization, is a novel biguanides specifically selected to increase T effector cells by decreasing myeloid derived suppressor cells (MDSC) and Treg cells in tumor microenvironment. Immune suppressive cells in tumor microenvironment are a potential significant factor that limits anti-check point blockers and its activity on T effector cells. Tumors attract Immune suppressive cells and recruited immune suppressive cells adapt unique cellular metabolism in tumor microenvironment, IM188 inhibits the unique metabolism of immune suppressive cells and promote subtype switching to non-suppressive cells.
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