MondoA-TXNIP axis maintains regulatory T cell identity and function in colorectal cancer microenvironment

Abstract Background & Aims The metabolic features and function of intratumoral Tregs are ambiguous in colorectal cancer. Tumor-infiltrating Tregs are reprogrammed to exhibit high glucose-depleting properties and adapt to the glucose-restricted microenvironment. The glucose-responsive transcription factor MondoA is highly expressed in Tregs. However, the role of MondoA in colorectal cancer-infiltrating Tregs in response to glucose limitation remains to be elucidated. Methods We performed studies using mice in which MondoA was conditionally deleted in Tregs and human colorectal cancer tissues. Seahorse and other metabolic assays were used to assess Treg metabolism. To study the role of Tregs in anti-tumor immunity, we used a subcutaneous MC38 colorectal cancer model and induced colitis-associated colorectal cancer in mice by azoxymethane (AOM) and dextran sodium sulfate (DSS). Results Here we analyzed single-cell RNA-seq data of colorectal cancer patients and revealed that intratumoral Tregs featured low activity of MondoA-TXNIP axis and increased glucose uptake. Although MondoA-deficient Tregs were less immune suppressive and selectively promoted Th1 responses in a subcutaneous MC38 tumor model, Treg-specific MondoA knockout mice were more susceptible to AOM-DSS-induced colorectal cancer. Mechanistically, suppression of MondoA-TXNIP axis promoted glucose uptake and glycolysis, induced hyper-glycolytic Th17-like Tregs, which facilitated Th17 inflammation, promoted IL-17A-induced of CD8+ T cell exhaustion and drove colorectal carcinogenesis. Blockade of IL-17A reduced tumor progression and minimized the susceptibility of MondoA-deficient mice to colorectal carcinogenesis. Conclusions The MondoA-TXNIP axis is a critical metabolic regulator of Treg identity and function in colorectal cancer microenvironment and a promising target for cancer therapy.