Fig. 3

TAMs coordinate with other cellular components in the TME to mediate immunosuppression and therapeutic resistance. TAMs can maintain CSC stemness and endow tumor cells with therapeutic resistance through direct interplays, such as the secretion of MIF, GDF15, TGF-β, IL-1β, IL-6, IL-33, IL-34, CCL5, CCL7, CCL8, CXCL7, FN1, GPNMB, CHI3L1, miR-21, miR-223, miR-222-3p, miRNA-21-5p and the expression of cell surface protein like CD44, BTN3A3, Ephrin44, NOTCH and CD36. TAMs also interplay with other cells to orchestrate an immunosuppressive TME through the following pathways: (i) Promoting the trans-differentiation or polarization of other cells such as TAMs, TANs, CAFs, and T lymphocytes into certain pro-tumorigenic cell subsets; (ii) Recruiting and activating immunosuppressive functions including M2-type TAMs, TANs, Treg and MDSCs; (iii) Restraining the cytotoxic activity and cytokines production of effector immune cells including NK cells and CTLs. Collectively, these interactions reshape an immunosuppressive TME and are responsible for therapeutic tolerance