IDO1 inhibitor enhances the effectiveness of PD-1 blockade in microsatellite stable colorectal cancer by promoting macrophage pro-inflammatory phenotype polarization.

Abstract

Microsatellite stable (MSS) colorectal cancer (CRC) is a subtype of CRC that generally exhibits resistance to immunotherapy, particularly immune checkpoint inhibitors such as PD-1 blockade. This study investigates the effects and underlying mechanisms of combining PD-1 blockade with IDO1 inhibition in MSS CRC. Bioinformatics analyses of TCGA-COAD and TCGA-READ cohorts revealed significantly elevated IDO1 expression in CRC tumors, correlating with tumor mutation burden across TCGA datasets. In vivo experiments demonstrated that the combination of IDO1 inhibition and PD-1 blockade significantly reduced tumor growth and increased immune cell infiltration, particularly pro-inflammatory macrophages and CD8+ T cells. IDO1 knockdown in CRC cell lines impaired tolerance to interferon-γ and increased apoptosis in vitro, which were rescued by the application of kynurenine, the end product of IDO1. IDO1 knockdown in MSS CRC enhanced the effectiveness of PD-1 blockade therapy in vivo. IDO1 knockdown cancer cells promoted pro-inflammatory macrophage polarization and enhanced phagocytic activity in vitro, associated with the upregulation of JAK2-STAT3-IL6 signaling pathway. These findings highlight the role of IDO1 in modulating the tumor immune microenvironment in MSS CRC and suggest that combining PD-1 blockade with IDO1 inhibition could enhance therapeutic efficacy by promoting macrophage pro-inflammatory polarization and infiltration through the JAK2-STAT3-IL6 pathway.