PPARα at the crossroad of metabolic–immune regulation in cancer

Rewiring metabolism to sustain cell growth, division, and survival is the most prominent feature of cancer cells. In particular, dysregulated lipid metabolism in cancer has received accumulating interest, since lipid molecules serve as cell membrane structure components, secondary signaling messengers, and energy sources. Given the critical role of immune cells in host defense against cancer, recent studies have revealed that immune cells compete for nutrients with cancer cells in the tumor microenvironment and accordingly develop adaptive metabolic strategies for survival at the expense of compromised immune functions. Among these strategies, lipid metabolism reprogramming toward fatty acid oxidation is closely related to the immunosuppressive phenotype of tumor-infiltrated immune cells, including macrophages and dendritic cells. Therefore, it is important to understand the lipid-mediated crosstalk between cancer cells and immune cells in the tumor microenvironment. Peroxisome proliferator-activated receptors (PPARs) consist of a nuclear receptor family for lipid sensing, and one of the family members PPARα is responsible for fatty acid oxidation, energy homeostasis, and regulation of immune cell functions. In this review, we discuss the emerging role of PPARα-associated metabolic–immune regulation in tumor-infiltrated immune cells, and key metabolic events and pathways involved, as well as their influences on antitumor immunity.