Figure 3.
The TAMs regulate tumors and polarize M1/M2 cells. The tumor stage, tissue, microenvironment, and paracrine signals affect them. Macrophages recruit the support of T and NK cells to fight against cancers. Cancer and tissue repair are two macrophage populations that produce antigen-presenting cells (APCs) like M1. Malignant M2 macrophages cause tumors to develop. Macrophages in the hypoxic TME use immunosuppressive mediators to fuel tumor development, angiogenesis, invasion, and metastasis. The same holds for inflammation, cancer stem cell (CTC) self-renewal, tissue remodeling, and EMT. Moreover, to coordinate CD8+ T cell responses, TAMs activate immunological checkpoints, downregulate antigen presentation, and release regulatory factors. Additionally, TAMs inhibit dendritic cell antigen presentation and invasion. TAMs release TGF-β and CSF-1, which boost myeloid-derived suppressor cell (MDSC) proliferation. TAMs attract immune-suppressive Treg cells and impair NKT cell activity, suppressing it. Furthermore, PD-L1 on TAMs and tumor cells interacts with PD-1 on cytotoxic T lymphocytes (CTLs) to reduce anti-tumor immunity. CD47-SIRPa interaction between TAMs and cancer cells helps tumors avoid phagocytosis. Moreover, chemokines, such as CCL1, CCL17, CCL18, CCL22, and CCL24, are abundantly expressed by M2-like macrophages, along with CD163, CD206, CD200R, CD209, and CD301. Various anti-inflammatory factors, such as TGF-β, IL-4, IL-13, IL-10, and IL-1RA, are released through macrophages. Furthermore, M2-like TAMs have reduced the amounts of the inflammatory cytokines IL-6, IL-12, IL-23, and TNF-α. In addition to MMPs, M2-like macrophages secrete autocrine extracellular matrix components, including fibronectin, beating-h3 (BIG-H3), enzymes that cross-link ECM, transglutaminase, and proteins that bridge gaps in bone [150]. M2-like macrophages increase Arg-1 and VEGF expression, aiding proline and polyamine production. Proline promotes ECM formation, and polyamines enhance cell growth. PDGF and IGF, which enhance cell proliferation, are also released by M2-like macrophages and implicated in angiogenesis [151,152]. Created in BioRender. Saeed, A. (2025) https://BioRender.com/kim50ti.