HOXC6 promotes the metastasis of MSI-H CRC by interacting with M2 macrophages and inducing effector T cell exhaustion.

We previously discovered that HOXC6 was the most significantly upregulated gene in right-sided colon cancer compared to left-sided colon cancer according to our previous study; however, the role of HOXC6 in microsatellite instability-high (MSI-H) tumors remains poorly understood. Here, multiple public datasets, and in-house cohorts were used to analyze the differential expression and prognostic role of HOXC6 in colorectal cancer (CRC). Immunohistochemistry and immunofluorescence were performed to evaluate the correlation between HOXC6 expression and M2 macrophage infiltration. CCK8 and Transwell assays were used to evaluate the proliferation and migration of tumor cells in vitro. BALB/c nude mice were utilized to construct a humanized immune system model to evaluate the efficacy of ruxolitinib in vivo. We found that HOXC6 was overexpressed in MSI-H CRC and associated with a poor prognosis. Upregulation of CCL2 by HOXC6 increased M2 macrophage infiltration. IL6 secreted by M2 macrophages induced the epithelial-mesenchymal transition of tumor cells by upregulating HOXC6. M2 macrophages promoted effector T cell exhaustion by downregulating 4-1BB. Thus, inhibition of the IL6/JAK pathway in M2 macrophages restored 4-1BB expression and T-cell cytotoxicity offering a promising therapeutic target for the treatment of HOXC6-overexpressing MSI-H CRC.