CD300e is a driver of the immunosuppressive tumor microenvironment and colorectal cancer progression via macrophage reprogramming

Abstract Colorectal cancer (CRC) progression is shaped by the tumor microenvironment, particularly tumor-associated macrophages (TAMs), which often adopt immunosuppressive functions. CD300e, a myeloid receptor involved in immune regulation, has an uncharacterized role in CRC. Here, we show that CD300e is selectively upregulated in tumor-infiltrating monocytes and macrophages, driving a suppressive phenotype marked by impaired antigen presentation. In vitro cocultures of patient-derived tumor organoids and human monocytes revealed that tumor-derived signals induce CD300e expression and promote a protumorigenic macrophage profile. Using CD300e knockout mice in AOM/DSS and MC38 CRC models, we found that CD300e loss reduced tumor burden, enhanced MHC expression on TAMs, and improved T-cell responses. Transcriptomic and functional analyses demonstrated that CD300e-deficient macrophages exhibit increased phagocytosis, upregulated antigen presentation, and greater support for T-cell proliferation and cytotoxicity. Adoptive transfer confirmed that macrophage-intrinsic CD300e expression is sufficient to suppress T-cell function and promote tumor growth. Our findings identify CD300e as a critical regulator of macrophage-mediated immune suppression in CRC and a potential target for reprogramming TAMs to enhance immunotherapy.