Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses

Colorectal cancer (CRC) remains a leading cause of mortality, with most cases refractory to immunotherapy. Distinguishing tumor-induced from steady-state mucosal T cell responses represents a critical barrier to understanding CRC immunity. Using orthotopic transplantation of CRC organoids with and without metastatic potential, combined with T cell fate-mapping, we show that nonmetastatic tumors elicit early recruitment of CD8αβ+ and CD4+ T cells with cytotoxic and Th1-like programs, whereas pro-metastatic (pro-Met) tumors induce a naïve-like, hypoactivated state. Tumor-infiltrating CD4+ T cells underwent clonal expansion, including clones recognizing microbial and dietary antigens. T cells physically interacting with tumors, identified by universal LIPSTIC, were enriched for expanded and cytotoxic clones. Fate-mapped T cells from nonmetastatic tumors suppressed tumor growth in an IFN-γ–dependent manner. Mechanistically, pro-Met tumors downregulated MHCII, and Ciita targeting in nonmetastatic organoids reduced CD4+ clonal expansion and led to tumor progression. Together, these findings define divergent early T cell trajectories associated with CRC metastasis, indicating that ineffective local immune engagement precedes metastatic dissemination.