Putative Role of Tie2-Expressing Monocytes/Macrophages in Colorectal Cancer Progression Through Enhancement of Angiogenesis and Metastasis

Colorectal cancer (CRC) is a major global health burden and a leading cause of cancer-related mortality, with metastasis representing the primary cause of death. Angiogenesis plays a critical role in this process, and macrophages within the tumor microenvironment (TME) are its key regulators. Among these, Tie2-expressing macrophages (TEMs) constitute a distinct pro-angiogenic subset that localizes to perivascular regions and responds to angiopoietin2 (Ang2) signaling. Moreover, TEMs contribute to vessel destabilization and the formation of permissive niches for cancer cell intravasation, linking them to both angiogenic and non-angiogenic modes of malignant tumor progression. The significance of TEMs in CRC remains controversial. This controversy, as we noticed, stems from a confluence of methodological challenges, lack of standardized markers, small-scale studies, inconsistent findings across studies, and the inherent complexity of both CRC biology and macrophage biology. Evidence from preclinical models and patient samples highlights the correlation between Ang2/Tie2 activity, TEM infiltration, and poor prognosis in CRC. This review summarizes current knowledge on the role of TEMs and the Ang/Tie2 axis in CRC angiogenesis, metastasis, and resistance to anti-angiogenic therapies. Advancing our understanding of TEMs may enable novel macrophage-focused strategies to inhibit CRC progression and improve patient outcomes.