Reprogramming T cell-myeloid crosstalk overcomes immune resistance in colorectal cancer.

Colorectal cancer (CRC) accounts for 10% of cancer cases and is the second leading cause of cancer-related deaths. Although anti-PD-1 therapy improves outcomes, 50% of advanced mismatch repair-deficient (MMRd) and most mismatch repair-proficient (MMRp) CRC cases fail to respond. Using orthotopic and patient-derived CRC models with single-cell and spatial analyses, we show that tumor control during anti-PD-1 treatment associates with colocalization of MHC+ C1Q+ CXCL9+ macrophages and TCF+ PRF1+ T cells. Resistance correlates with increased TIM3, LAG3, TIGIT, and PD-1 expression on T cells and enrichment of TREM2+ macrophages in T cell-excluded regions. A combinatorial blockade targeting TREM2, LAG3, CTLA4, and PD-1 induces up to 100% tumor clearance in MMRd and >70% in MMRp models. This strategy promotes immune memory mediated by interactions among MHC+ macrophages and CD4+/CD8+/TCF+ T cells, while reducing immunosuppressive myeloid infiltration and T cell exhaustion, identifying key cellular programs that overcome immune escape in CRC.