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Immune signaling and metabolic regulation of macrophage fate decisions in tumor immunity 3668

Year: 2025
Type: article
Abstract: Description Macrophages play a critical role in maintaining tissue homeostasis and modulating immune responses. By integrating microenvironmental immune signals and available nutrients, macrophages orchestrate transcriptional networks and metallic reprogramming to dictate their phenotypical and functional heterogeneity. For instance, LPS/IFNγ and IL-4 induce classically (M1) and alternatively (M2) activated macrophages, respectively. Remodeling of cellular metabolism has been highlighted as a key process that regulates macrophage functional polarization. However, the precise mechanisms connecting metabolic reprogramming and functional polarization in macrophages remain incompletely understood. We report here that the kinase LKB1, a well-known negative regulator of the mTOR signaling pathway, serves as a metabolic checkpoint that controls macrophage mitochondrial metabolism during M2 polarization. Genetic depletion of LKB1 in macrophages facilitates the polarization towards M2-like macrophages, independently of the mTOR signaling pathway. LKB1-deficient macrophages rewire mitochondrial metabolism to support their M2 polarization, thereby promoting tumor immune evasion. Pharmacological blockade of mitochondrial oxidative phosphorylation reverses the heightened M2 polarization of LKB1-deficient macrophages. Our data demonstrate a previously unappreciated role for LKB1 in linking mitochondrial metabolism to the regulation of M2 macrophage polarization in regulating tumor immunity. Funding Sources Start up Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
DOI: 10.1093/jimmun/vkaf283.1440
Authors: Jing Yang, Joe Lechner, Kai Yang
Language: English
Subfield: Immunology
Open Access status: bronze
OpenAlex ID: W4416449868
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