1. Academic Validation
  2. Lactate released by lung adenocarcinoma (LUAD) cells promotes M2 macrophage polarization via the GPR132/cAMP/PKA pathway

Lactate released by lung adenocarcinoma (LUAD) cells promotes M2 macrophage polarization via the GPR132/cAMP/PKA pathway

  • Genes Genomics. 2025 Mar 7. doi: 10.1007/s13258-025-01622-1.
Xiao Chen 1 Zhongzheng Zhang 2 Kangwu Wang 3
Affiliations

Affiliations

  • 1 Department of Geriatrics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
  • 2 Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical University, 287 Chang Huai Road, Bengbu, 233000, Anhui, China.
  • 3 Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical University, 287 Chang Huai Road, Bengbu, 233000, Anhui, China. wangkangwu0552@163.com.
Abstract

Background: Increasing evidence suggests that lactate is an essential compound in the tumor microenvironment, and especially for macrophage cells. However, the mechanism by which lactate affects macrophages remains unclear.

Objective: This study investigated whether and how lactate affects macrophage polarization in lung adenocarcinoma (LUAD).

Methods: Clinical samples of LUAD and paracancerous tissue were obtained for evaluation of Lactate Dehydrogenase A (LDHA) expression. LUAD cell lines and THP-1 induced macrophages were used in this study. Quantitative Real-Time PCR (QPCR), western blotting, and immunohistochemical (IHC) staining were performed to detect gene expression. Flow cytometry and ELISA assays were used to detect the levels of M1 macrophage and M2 macrophage biomarkers.

Results: LDHA was highly expressed in the LUAD tissues. Culture medium supernatants derived from LUAD cells (CM) promoted macrophage M2 polarization, and lactate levels were elevated in the CM. Inhibition of LDHA in LUAD cells decreased lactate levels and suppressed M2 macrophage polarization. Moreover, overexpression of GPR132 in macrophages promoted, while GPR132 knockdown in macrophages suppressed M2 macrophage polarization and cAMP (Cyclic Adenosine 3',5'-Monophosphate)/PKA (Protein Kinase) pathway activation induced by lactate. The effect of GPR132 overexpression was reversed by a PKA Inhibitor (H-89).

Conclusion: Collectively, our results confirmed that lactate released by LUAD cells promoted M2 macrophage polarization via the GPR132/cAMP/PKA pathway.

Keywords

GPR132; LDHA; Lactate; Lung adenocarcinoma (LUAD); Macrophage polarization.

Figures
Products