Glycolytic reprogramming of resident alveolar macrophages contributes to reduced SOCS3 secretion in non-small cell lung cancer

Jennifer M Speth¹Mikel D Haggadone^1,2Marc Peters-Golden^1*

• ¹University of Michigan, Ann Arbor, United States
• ²University of Pennsylvania, Philadelphia, United States

Alveolar macrophages (AMs), the resident immune cells of the lung, play a critical role in maintaining pulmonary homeostasis, in part through the secretion of suppressor of cytokine signaling 3 (SOCS3) – a recognized tumor suppressor – within extracellular vesicles (EVs). While we have previously observed that SOCS3 secretion by AMs is diminished in tumor-bearing lungs, the mechanisms underlying this impairment remain unclear. Here, we investigated whether increased glycolytic metabolism in AMs contributes to this defect within the tumor microenvironment. Analysis of published single-cell RNA sequencing datasets from an orthotopic Lewis lung cancer (LLC) model of adenocarcinoma and non-small cell lung cancer (NSCLC) patients revealed distinct AM clusters in tumor-bearing lungs enriched for glycolysis-associated genes. In a KrasG12D mutant mouse model of lung cancer, we found that AMs isolated from tumor-bearing lungs exhibited increased glucose uptake, which inversely correlated with SOCS3 secretion. Importantly, pharmacologic inhibition of glycolysis with 2-deoxy-D-glucose restored SOCS3 secretion in these AMs. Together, our findings demonstrate that lung tumor-associated AMs undergo a time-dependent metabolic shift toward glycolysis, resulting in impaired SOCS3 secretion – a phenotype that can be reversed by targeting glycolytic flux. These results highlight a potential therapeutic approach for modulating immune suppression in the tumor microenvironment.