MECHANISMS DRIVING IMMUNOTHERAPY RESISTANCE IN COLORECTAL CANCER LIVER METASTASES

Abstract

Colorectal cancer liver metastases (CRLM) represent one of the most immunologically hostile environments encountered in clinical oncology which prevents most patients from benefiting from immune checkpoint inhibitors (ICIs). While microsatellite instability-high (MSI-H) tumors respond favorably to anti-PD-1 therapy the predominant microsatellite stable (MSS) subtype which accounts for 80-85% of cases shows almost complete resistance to immunotherapy in liver metastatic cases. The review presents the existing research evidence about ICI resistance mechanisms in CRLM which include hepatic immune tolerance mechanisms and tumor-specific molecular changes and immune cell dysfunction and stromal changes and metabolic changes and systemic immune system loss. The main resistance factors stem from the immunosuppressive activities of Kupffer cells and hepatic stellate cells and liver sinusoidal endothelial cells which create a barrier that prevents T-cells from entering the tumor through WNT/β-catenin pathways and TGF-β which inhibits cytotoxic immune responses and the tumor environment which leads to higher regulatory T cell and myeloid-derived suppressor cell expansion and the metastatic site which causes PD-L1 to be incorrectly increased. The article examines how current approaches which target these mechanisms through LAG-3 inhibition and VEGF/VEGFR co-blockade and TGF-β pathway antagonism and locoregional liver-directed therapies will be implemented in clinical practice. The design of effective combination treatment plans for transforming immunologically cold liver metastases into treatable lesions requires an understanding of resistance mechanisms.