Loss of proton-sensing TDAG8 increases tumor progression in mouse models of colon cancer

T-cell death-associated gene 8 (TDAG8) is a proton-sensing G-protein-coupled receptor that is activated by neutral to acidic extracellular pH. TDAG8 is primarily expressed in leukocytes and leukocyte-rich tissues, including the spleen, lymph nodes, and thymus. Genome-wide association studies have identified TDAG8 as a risk gene for inflammatory bowel disease (IBD). Patients with IBD have an increased risk of developing colorectal cancer (CRC), and TDAG8 has been implicated in regulating anti-tumor immunity. We used the MC38 and azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models of CRC to evaluate the effect of TDAG8 deficiency on tumor growth. Tumor development was assessed by measuring size and weight, and tumor tissue was analyzed by immunohistochemistry (IHC), real-time quantitative polymerase chain reaction (qPCR), flow cytometry, and apurinic/apyrimidinic (AP) site quantification. In the MC38 model, Tdag8-deficient mice presented a significantly increased tumor burden together with significantly increased numbers of neutrophils and monocytes in tumor tissue compared with wild-type (WT) mice. In the AOM/DSS model of CRC, Tdag8-deficient mice exhibited significantly increased tumor size, weight, and number of AP sites compared with WT mice. Additionally, Tdag8-deficient mice showed a significantly increased number of macrophages in tumor tissue and an elevated CD4⁺/CD8⁺ ratio, as confirmed by IHC and flow cytometry. In conclusion, loss of Tdag8 significantly worsened colon cancer progression in mice and correlated with increased infiltration of tumor-associated phagocytes. These findings suggest that positive allosteric TDAG8 modulators could represent a promising therapeutic strategy for CRC treatment.