Fig. 2

The effects of TAMs on tumor progression. The protumor functions of TAMs include cancer initiation and promotion (blue), immune suppression (green), metastasis, establishment of a premalignant niche (orange), and promotion of angiogenesis (purple). (1) TAMs can produce cytokines such as IL-6/IL-17/IL-23 or mitogens to induce the initiation and progression of cancer via the NF-κB or STAT3 signaling pathway in tumor cells. (2) Suppression of CTL proliferation by TAMs is at least partly dependent on metabolism of l-arginine via iNOS or arginase I, which results in ROS production. TAMs inhibit CTL responses via PD1/PD-L1 signaling pathway. TAM-derived PGE2 and IL-10 promote the induction of Tregs, and TAM-derived CCL17/18/22 recruit Tregs, which results in CTL suppression. (3) Neoplastic cell invasion of ectopic tissue can be promoted through protease-dependent ECM remodeling that may directly affect neoplastic migration or the premalignant niche. TAM-derived CCL18 promotes tumor metastasis by triggering integrin clustering and enhancing their adherence to extracellular matrix (EM) in tumor cells. TAM-derived TGF-β plays important roles in initiation and progression of the EMT. TAMs-derived TNF-α, VEGF, and TGF-β can transport through the bloodstream to destination organs, where they induce macrophages to produce S100A8, which further recruits tumor cells to these organs and promotes the formation of metastatic foci. (4) Hypoxia induces HIF-1α expression in TAMs and further regulates the transcription of many genes associated with angiogenesis. Subsets of Tie2⁺ TAMs can interact with mural cells/pericytes to regulate vascular structure