Immunosuppressive Tumor Microenvironment in Colorectal Cancer and the Rationale for Combination Immunotherapy

Dr. Saeed and Dr. Ahn discuss the biologic features that make non-MSI-high colorectal cancer resistant to immune checkpoint inhibition and the scientific rationale for combining multi-kinase inhibitors with immunotherapy. Dr. Saeed describes colorectal cancer as an immunologically cold tumor characterized by an immunosuppressive microenvironment driven in part by active angiogenesis through VEGF and MET pathways, as well as the TAM family of kinases. These pathways contribute to upregulation of myeloid-derived suppressor cells and regulatory T cells, facilitating immune evasion. Dr. Ahn reinforces that clinical data confirm the near-zero response rate to checkpoint inhibitor monotherapy in MSS disease, underscoring why targeting these immunosuppressive pathways in combination with checkpoint blockade represents a scientifically grounded strategy. The discussants frame this mechanistic foundation as the basis for the clinical investigations reviewed throughout the program.