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

Nonmetastatic colorectal cancer organoids trigger early recruitment of cytotoxic CD8αβ+ and Th1-like CD4+ T cells, while pro-metastatic (pro-Met) organoids induce a naïve-like, hypoactivated T cell state.

• Why it matters: CRC often resists immunotherapy, and it remains unclear how tumor-driven mucosal T cell responses differ from steady-state immunity during early disease.
• What they did: Orthotopic transplantation of CRC organoids with and without metastatic potential, combined with T cell fate-mapping and universal LIPSTIC labeling, tracked early recruitment, clonal expansion, and tumor-interacting T cells.
• The result: Fate-mapped T cells from nonmetastatic tumors suppressed tumor growth in an IFN-γ–dependent manner, whereas pro-Met tumors downregulated MHCII and Ciita targeting reduced CD4+ clonal expansion and enabled progression.