The miR-146 Family at the Crossroads of Monocyte–Macrophage Biology and Gastrointestinal Cancer

The miR-146 family, comprising miR-146a and miR-146b, is one of the best-characterized negative regulators of innate immune signalling. Both members share an identical seed sequence and target IRAK1 and TRAF6, but differ in genomic organization, transcriptional regulation, and isomiR composition. This review follows the monocyte–macrophage lineage, from the transcriptional regulation of MIR146A and MIR146B to the reprogramming of tumor-associated myeloid cells in gastrointestinal cancers. miR-146a is induced rapidly through NF-κB, whereas miR-146b is induced later through IL-10- and TGF-β-dependent STAT3 signalling. In monocytes and macrophages, this system shapes inflammatory responses, endotoxin tolerance, differentiation, and polarization. Within the tumor microenvironment, both miRNAs are dysregulated in tumor-associated macrophages and myeloid-derived suppressor cells and can be exchanged between tumor and immune cells via extracellular vesicles. In tumor cells, they may also contribute to resistance to macrophage-mediated killing and angiogenesis. The effects of miR-146a and miR-146b differ in the regulation of tumor-associated inflammation and anti-tumor immunity. Notably, miR-146b deficiency can promote an immunoregulatory phenotype in tumor-associated macrophages while enhancing the response to anti-PD-1 therapy. Therapeutic modulation must therefore account for the specific family member, cell type, and disease stage.