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

Qi Shu; Huijuan Ma; Tingqian Wang; Peiyao Wang; Huan Xu

doi:10.1016/j.toxlet.2023.11.002

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

Toxicol Lett. 2023 Dec 1:390:5-14. doi: 10.1016/j.toxlet.2023.11.002. Epub 2023 Nov 7.

Authors

Qi Shu¹, Huijuan Ma¹, Tingqian Wang¹, Peiyao Wang¹, Huan Xu²

Affiliations

¹ Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: xuhuan@ecust.edu.cn.

PMID: 37944650
DOI: 10.1016/j.toxlet.2023.11.002

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.

Keywords: Formaldehyde; Glycolytic metabolism; HIF-1α; T cell suppression; Tumor cell proliferation; Tumor-associated macrophage.

MeSH terms

Animals
Carcinogenesis
Glycolysis
Mice
Mice, Nude
Neoplasms* / chemically induced
Tumor Microenvironment
Tumor-Associated Macrophages*