Core Viewpoint - The study highlights the role of lactic acid in creating an immunosuppressive tumor microenvironment by activating the MondoA-TXNIP pathway, which inhibits CD8⁺ T cell responses and enhances T reg cell function, thereby promoting tumor growth and immune evasion [2][3][6]. Group 1 - Lactic acid accumulation in the tumor microenvironment damages CD8⁺ T cell cytotoxicity and promotes the immunosuppressive function of T reg cells, establishing a dual immune suppression barrier [2]. - The research team discovered that targeting the MondoA-TXNIP signaling axis can restore anti-tumor immunity in lactic acid-induced immunosuppressive environments and enhance the efficacy of anti-PD-1 therapy [3][7]. Group 2 - The study reveals that the transcription factor MondoA induces TXNIP, which is a common feature in the response of T reg and CD8⁺ T cells to lactic acid [6]. - MondoA deficiency in T reg cells reduces their immunosuppressive capacity, while its absence in lactic acid-induced environments enhances CD8⁺ T cell cytotoxicity by restoring glucose uptake and glycolysis [6]. Group 3 - Targeting the MondoA-TXNIP signaling axis can enhance anti-tumor immunity across various cancer types and synergize with anti-PD-1 therapies, particularly promoting effective T cell responses in colorectal cancer [7][10]. - The combination of MondoA inhibitor SBI-477 with anti-PD-1 monoclonal antibodies produces a synergistic anti-tumor effect, and SBI-477 alone is effective against microsatellite stable (MSS) tumors, which typically show poor T cell infiltration and resistance to immune checkpoint inhibitors [7][10].