Targeting Lipid Metabolism in Tumor-associated Macrophages

Tumor-associated macrophages (TAMs) are heterogenous myeloid populations that dictate the inflammatory tone of the tumor microenvironment (TME). Although TAMs pervade various types of solid tumors, immunotherapies targeting the recruitment or repolarization of TAMs have yielded little success in clinical trials, urging the discovery of novel mechanisms that control the immunosuppressive states of TAMs. As the metabolic landscape of the TME can restrict effector functions of immune cells, in this thesis research, we aimed to understand how specific metabolites, such as lipids, dictate the function of TAMs in cancer. First, we characterized the metabolic heterogeneity within TAM populations using bioinformatics and experimental approaches. Next, we established lipid accumulation as a hallmark of TAM dysfunction in solid tumors. Moreover, we dissected the role of scavenger receptor CD36 in dampening TAM’s anti-tumoral functions through binding to oxidized lipids in the TME. Lastly, we discussed some preliminary data on targeting cholesterol metabolic pathways in TAMs using genetic knockout models. In summary, our findings suggested that lipid metabolic pathways are critical regulators of TAM functions in cancer, providing rationale for therapeutically targeting lipid receptors or selected lipid metabolic processes to rejuvenate anti-tumor innate immunity.