Tumors often generate acidic microenvironments that are hostile to immune cells and impede anti-tumor immune responses. In Nature Metabolism, Xu et al. identify the transcription factor MondoA (also known as MLXIP) as a response element to the buildup of lactic acid in T cells. MondoA promotes a pro-tumor response in CD4+ regulatory T cells, as well as handicapping cytotoxic CD8+ T cells, to generate an immunosuppressive microenvironment. Mechanistically, the authors show that in the presence of lactic acid, the SUMO-specific protease SENP1 liberates cytoplasmic MondoA to translocate to the nucleus to induce expression of TXNIP, which encodes a protein known to impair the function of effector T cells by altering their cellular metabolism. Blocking the activity of MondoA with a small-molecule inhibitor, SBI-477, suppressed expression of TXNIP and relieved the lactic acid-induced inhibition of CD8+ T cells by increasing their glycolytic flux and simultaneously impairing the suppressive activity of regulatory T cells. MondoA inhibition or deletion potentiated checkpoint blockade immunotherapy mediated by an anti-PD-1 antibody in multiple mouse tumor models. These findings provide a potential means to enhance anti-tumor responses that promote effector T cell fitness in acidic tumor microenvironments.

Original reference: Nat. Metab. https://doi.org/10.1038/s42255-025-01347-1 (2025)