Abstract
BACKGROUND: 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. METHODS: Functional studies were conducted in azoxymethane/dextran sodium sulfate and MC38 murine CRC models using CD300e systemic and myeloid-specific CD300e knockout mice, and adoptive transfer experiments assessed macrophage-intrinsic effects. Human studies included analysis of CD300e expression in matched tumor and normal tissue from patients with CRC and in vitro co-culture of patient-derived colon tumor organoids with monocytes to study CD300e induction and TAM polarization. RESULTS: In vivo, CD300e deficiency led to reduced tumor burden, enhanced major histocompatibility complex expression on TAMs, and improved T-cell responses. CD300e-deficient macrophages exhibited increased phagocytic activity, antigen presentation, and 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. In patients with CRC, CD300e is selectively upregulated in tumor-infiltrating monocytes and macrophages, driving a suppressive phenotype marked by impaired antigen presentation. Tumor-derived signals in vitro induce CD300e expression and promote a protumorigenic macrophage profile. CONCLUSIONS: 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.