IGSF9 promotes immunotherapy resistance in colon cancer by orchestrating an immunosuppressive tumor microenvironment and enables combinatorial targeting strategies.

Colon cancer (CC), a significant global health burden with high incidence and mortality, is often accompanied by an immunosuppressive tumor microenvironment (TME) that limits the efficacy of immunotherapy. Immunoglobulin superfamily member 9 (IGSF9), a cell surface protein involved in cell adhesion and signaling, has been shown to promote tumor progression and regulate TME in other cancers, but its role in CC remains poorly understood. This study integrated multi-omics analyses, single-cell sequencing, and preclinical models to explore IGSF9's function in CC and its correlation with immunotherapy resistance. The results showed that IGSF9 was significantly upregulated in CC tumors, positively correlated with advanced tumor stages and poor prognosis such as reduced overall survival in colon adenocarcinoma (COAD). High IGSF9 expression was correlated with an immunosuppressive TME characterized by increased infiltration of regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and reduced immune cell infiltration; it was also linked to lower tumor mutational burden (TMB) and microsatellite instability (MSI), predicting poor response to anti-PD-1 immunotherapy in clinical datasets. Single-cell and spatial transcriptomics revealed that IGSF9 was predominantly expressed in malignant epithelial cells, correlated with epithelial-mesenchymal transition (EMT) pathways. Drug sensitivity analysis identified Doramapimod, a MAPK inhibitor, which combined with anti-PD-1 therapy significantly enhanced tumor regression in mouse models by reducing Treg infiltration. In conclusion, this study establishes IGSF9 as a prognostic and predictive biomarker for immunotherapy resistance in CC and suggests that targeting IGSF9-associated KRAS/MAPK pathways with Doramapimod may offer a novel combination strategy to overcome TME-mediated resistance, warranting further clinical investigation for personalized CC treatment.