Formaldehyde promotes tumor-associated macrophage polarizations and functions through induction of HIF-1α-mediated glycolysis

Abstract

Formaldehyde (FA) exposure has been positively correlated with many diseases including various types of cancers. However, the mechanisms of FA-related carcinogenesis are still unclear. Tumor-associated macrophages (TAMs) are the most abundant immune cells in tumor microenvironment, which is a heterogeneous population consist of both pro-inflammatory (M1) and immunosuppressive (M2) cells. TAMs are deeply involved in tumor development and progression. Our previous studies demonstrated that FA enhanced M1 polarization of macrophages through induction of HIF-1α-mediated glycolysis. To examine if TAM polarizations are also potentiated by FA, BALB/c nude mice were inoculated with A549 cells to develop subcutaneous tumors and exposed to 2.0 mg/m3 FA for 14 days. Significant increases of both M1 and M2 polarizations of TAMs were observed in tumor tissues of FA-exposed mice. After confirmation of the potentiation effects in RAW264.7 and THP-1-derived in vitro TAM models, FA at 25 and 50 μM was found to enhance TAM immunosuppressive functions and glycolytic metabolism. In addition, FA-induced glycolysis in TAMs was reversed by a specific HIF-1α inhibitor PX-478 at 5 μM, and suppression of glycolytic metabolism with a glucose analog 2-DG at 1 mM also alleviated FA-potentiated TAM functions, which indicated that FA induced TAM polarizations through the upregulation of HIF-1α-mediated glycolysis. These results illustrated a potential carcinogenic mechanism of FA through metabolic disturbance of tumor immunity, which could be utilized to develop preventative or therapeutic agents for FA-induced carcinogenesis and immune disorders.