Folate metabolism in tumor-associated macrophages drives immunosuppressive function to promote tumor growth

Tumor-associated macrophages (TAMs) have a role in promoting tumor growth and hindering the effectiveness of immune cells. Current therapies that target TAMs have not been successful in a clinical setting, and methods to change TAMs from an immunosuppressive state to a pro-inflammatory state have faced challenges due to systemic toxicity.

The study found that low folate levels in the tumor microenvironment, combined with TAMs' reliance on the high affinity folate receptor beta (FR{beta}) for folate uptake, creates a unique metabolic dependency in TAMs necessary for their immunosuppressive function. FR{beta}, encoded by Folr2, is found exclusively on myeloid cells and is upregulated on TAMs.

TAMs with FR{beta} display an immunosuppressive phenotype in melanoma, and their presence is associated with poorer clinical outcomes and resistance to immune checkpoint inhibitors (ICI) in melanoma patients. Researchers created a mouse model without Folr2 (Folr2-/-) to investigate why TAMs express a distinct folate receptor. They discovered that tumor growth slowed in the absence of Folr2, and the TAMs' polarization to a pro-inflammatory state in vivo increased the infiltration of cytotoxic T cells and natural killer cells into the tumors.

The study also showed that folate levels are low in the tumor microenvironment, confirmed by metabolomics analysis of melanoma tumors and normal tissue from human specimens. Increasing serum folate levels in Folr2-/- mice with a high folate diet led to an increase in tumor growth. Metabolomics and transcriptomic analysis revealed that Folr2-/- macrophages have reduced folate uptake and 1C metabolism-based conversion of oxidized glutathione in low folate conditions, leading to increased mitochondrial reactive oxygen species (ROS).

Elevated ROS results in the leakage of mitochondrial DNA into the cytoplasm, activating cGAS-STING signaling and promoting pro-inflammatory macrophage polarization through TBK1 and NF-kB. Overall, the findings suggest that the expression of FR{beta} by TAMs aids their immunosuppressive function by maintaining folate uptake in the low folate tumor microenvironment, indicating that FR{beta} could serve as a new metabolic checkpoint on TAMs.