CXCR3 signaling promotes Delta One T cell recruitment and antitumor efficacy in colorectal cancer.

Immunotherapy has transformed cancer treatment, yet its efficacy in solid tumors, and particularly in colorectal cancer (CRC), remains limited by insufficient infiltration of endogenous or adoptively transferred immune cells. Our group developed Delta One T (DOT) cells, an allogeneic Vδ1-enriched γδ T-cell product with demonstrated efficacy in CRC models, but the critical mechanisms guiding their tumor homing are unclear. Here we show that DOT cells acquire a specific chemokine receptor profile during expansion to support tumor infiltration, characterized by prominent CXCR3 expression. Importantly, CXCR3 ligands (CXCL9-11) are expressed by CRC cell lines and primary tumors, and correlate with Vδ1 T cell infiltration and DOT-cell recruitment. CXCR3 signaling is critical for DOT-cell migration in vitro and in vivo, as pharmacologic blockade reduced tumor homing, whereas enhancing CXCR3 ligand expression increased DOT-cell infiltration and improved tumor control. These findings establish CXCR3 signaling as a key regulator of DOT-cell trafficking and a prime target to boost γδ T cell-based immunotherapies for CRC.