Fig. 2.

The mechanism of STAT3-related immune cells at in breast cancer TME. Three primer immune cells can be targeted when STAT3 influences the TME of breast cancer. The immune cells population, phenotypes and related gene expression were shaped in tumor milieu. a Node A: MDSCs conditioned by STAT3 cascade in TME induced paralysis of T lymphocytes, activity of CSCs, and carcinogenic factors generation. Meanwhile, the release of ROS might enhance the immunosuppression in various routes. b Node B: Intracellular STAT3 cascade in the macrophages affects the PGE2 and PD-L1 secretion, and induces the Sox2-positive CSCs in TME. Moreover, the HA and A-FABPs induced STAT3 activation is directly associated with TAMs formation and enables the interaction between tumor cells and macrophages, such as promoting TGF-β1 and HIF-1α generation. c Node C: STAT3 cascade suppressed DCs differentiation and deprived the DCs ability to stimulate T cells. Through inhibiting CD86 expression, STAT3 indirectly inhibited the CTLA-4 and promoted IFN-γ expression in TME. Moreover, FLT3L-induced DCs accumulated in immunization site and significantly increased the anti-tumor T cells response and remarkably delayed the tumor growth. The FL3TL/STAT3/Pu.1 cascade promote the differentiation and maturation of DCs, while FL3TL/STAT3 interacts with E2-2/Tcf4 pathway to enhance pDCs-related immune response. d Node D: STAT3 cascade in tumor cells inhibits the MDSCs in TME, which was directly mediated by intercellular G-CSF/IRF-8 function. The co-culture between tumor cells and DCs stimulated STAT3-related HER-2/neu, TGF-β1 and HIF-1α generation. Moreover, the macrophages related PEG2 in TME might stimulate PI3K/Akt pathway via the tumor surface EP4 receptor recognition, which was closely connected to breast cancer cells metastasis