Fig. 2

STAT3 induces the immunosuppression in the TME. STAT3 activity in tumor cells supports multiple hallmarks of cancer, including increased secretion of immunosuppressive factors such as IL-6, IL-10 and EGFR, which can activate STAT3 in the innate and adaptive immune cell subsets as well as CAFs in the TME. Likewise, immune cells and CAFs within the TME can release certain factors including IL-6, which subsequently enhance STAT3 signaling in tumor cells. Elevated STAT3 in the TME has dual effects. On the one hand, STAT3 favors the accumulation and enrichment of immunosuppressive Treg cells and B cells, as well as the polarization of M2-like macrophages, which instigate immune evasion. Particularly, STAT3 is a major driver for increased expression of immune checkpoint molecules (such as PD-L1, PD-L2 and CTLA-4) in these cells. On the other hand, STAT3 in CD8⁺ T cells, NK cells and neutrophils evokes restrained anti-tumor cytolytic activities. STAT3 can also inhibit the anti-tumor ability of DCs through dampening their maturation, activation and antigen presentation. Besides, STAT3 in CAFs can promote their proliferation, survival and migration, and drive the remodeling of tumor stroma for tumor progression. Collectively, STAT3 induces the immunosuppression in the TME, thereby promoting tumor progression with diminishing the anti-tumor immunity.