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July 1st, 2025
Version: 2
University of Padova
cancer biology
biorxiv

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

Barizza, A.Open in Google Scholar•Vassallo, S.Open in Google Scholar•Masatti, L.Open in Google Scholar•Laffranchi, M.Open in Google Scholar•Giacometti, S.Open in Google Scholar•Lonardi, S.Open in Google Scholar•Bugatti, M.Open in Google Scholar•Coletta, S.Open in Google Scholar•Pizzini, S.Open in Google Scholar•Vermi, W.Open in Google Scholaret al.

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.

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