Mahmoudian_2025_Int.J.Mol.Sci_26_

Tumor-associated macrophages (TAMs) are one of the most abundant cell types in the colorectal cancer (CRC) tumor microenvironment (TME). CRC cell-derived exosomes support macrophage polarization toward an M2-like phenotype, which leads to tumor growth and metastasis. Neuroligin 1 (NLG1) is a transmembrane protein critical in synaptic function. We reported that NLG1 via an autocrine manner promotes CRC progression by modulating the APC/beta-catenin pathway. This study aimed to answer whether NLG1 is involved in the exosome-mediated intercellular cross-talk between CRC and TAMs. Our results showed that exosomes of NLG1-expressing CRC cells induce M2-like (CD206(high) CD80(low)) polarization in macrophages. On the other hand, we found that the exosomes of the NLG1 knocked-down CRC cells reinforce the expression of CD80 and pro-inflammatory genes, including IL8, IL1beta, and TNFalpha, in the macrophages, indicating an M1-like phenotype polarization. In conclusion, NLG1, as a cell-membrane-integrated protein, could be a therapeutic target on the surface of the CRC cells for developing clinical treatments to inhibit exosome-induced anti-inflammatory immune responses in TME.