Figure 1. Graphical depiction of the proposed TGFβ‐IL‐6 paracrine signaling axis in PDAC TME pathogenesis.

TGFβ acts through its cognate receptor, TGFβR2, on cancer‐associated fibroblasts (CAF) to induce IL‐6 secretion. Both TGFβ and IL‐6 independently act on elements of the innate immune system such as natural killer (NK) cells to promote an immunosuppressive milieu. On the PDAC cancer cell, TGFβ acts through canonical signaling pathways to inhibit proliferation, while this signaling is blocked with TGFBR2 mutation. IL‐6 acts through its receptor, IL6R, to activate JAK/STAT signaling enhancing cell growth. Monoclonal antibody against TGFβR2, 2G8, disrupts this paracrine signaling network.