Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment

Abstract

In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (T_reg) immunosuppressive function and restraining CD8⁺ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both T_reg and CD8⁺ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient T_reg cells, loss of MondoA enhanced CD8⁺ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA-TXNIP axis, which impaired TCR/CD28-signal-induced CD8⁺ T cell activation. Importantly, targeting the MondoA-TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA-TXNIP axis is a promising therapeutic target for improving cancer immunotherapy.