Mount Sinai Study: Quad-Target Immunotherapy Combo Overcomes Resistance in Treatment-Refractory Colorectal Cancer

Researchers at the Icahn School of Medicine at Mount Sinai (Tisch Cancer Institute) published findings in Cell Reports Medicine identifying a new combinatorial immunotherapy approach that overcomes checkpoint inhibitor resistance in colorectal cancer — a critical unmet need since the vast majority of colorectal cancers are immunologically 'cold' and fail to respond to standard PD-1 blockade. The team identified a dual immune evasion mechanism: exhausted T cells co-existing with TREM2-positive tumor-associated suppressive macrophages that create a deeply immunosuppressive tumor microenvironment. Simultaneous targeting of four checkpoints — PD-1, CTLA-4, LAG-3, and TREM2 — achieved complete tumor clearance in mismatch repair-deficient (MMR-d) colorectal models and over 70% tumor eradication in mismatch repair-proficient (MMR-p) models that are typically refractory to all checkpoint inhibitors. Immune memory responses were observed, suggesting protection against recurrence. MMR-p colorectal cancer — the majority of cases — has remained one of the most checkpoint-resistant tumor types. This preclinical study opens a translational path toward clinical trials combining anti-TREM2 agents (in early clinical development) with established checkpoint inhibitors. Colorectal cancer is the second-leading cause of cancer death in the US.