The XCL1–XCR1 axis supports intestinal tissue residency and antitumor immunity

Tissue-resident memory T cells (T_RM) provide frontline protection against pathogens and emerging malignancies. Tumor-infiltrating lymphocytes (TIL) with T_RM features are associated with improved clinical outcomes. However, the cellular interactions that program T_RM differentiation and function are not well understood. Using murine genetic models and targeted spatial transcriptomics, we found that the CD8⁺ T cell–derived chemokine XCL1 is critical for T_RM formation and conventional DC1 (cDC1) supported the positioning of intestinal CD8⁺ T cells during acute viral infection. In tumors, enforced Xcl1 expression by antigen-specific CD8⁺ T cells promoted intratumoral cDC1 accumulation and T cell persistence, leading to improved overall survival. Notably, analysis of human TIL and T_RM revealed conserved expression of XCL1 and XCL2. Thus, we have shown that the XCL1–XCR1 axis plays a non-cell autonomous role in guiding intestinal CD8⁺ T_RM spatial differentiation and tumor control.