Primary Mtb infection exploits STAT3-dependent signals in phagocytes for bacterial survival benefits. (a) Mtb antigens ESAT-6 and α-crystalline 1 (Acr1) activate the STAT3 signal pathway to induce the production of IL-6 and IL-10 and inhibit the translocation of NF-κB, Akt and mTOR in phagocytes in primary Mtb infection. This also represses the expression/synthesis of iNOS and NO, favoring Mtb survival. (b) Mtb-induced IL-27 induces STAT3 phosphorylation and inhibits the production of TNF-α and IL-12 in activated macrophages. (c) IL-10 exerts its effects in a partly STAT3-dependent manner, inhibiting the production of C/EBP-beta, with potential enhancement of HIV-1 replication, as observed in THP-1 cells. (d) Mtb infection facilitates STAT3 expression and phosphorylation by decreasing the repression of miR-17. ESAT-6, early secreted antigenic target of 6 kDa; IL, interleukin; iNOS, inducible nitric oxide synthase; NO, nitric oxide; Mtb, Mycobacterium tuberculosis; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; STAT3, signal transducer and activator of transcription 3; TB, tuberculosis; TNF-α, tumor necrosis factor-α.