Figure 3.

A disorganized liver ECM impacts immune surveillance machinery

A low ECM complexity state within the matrix triggers tumor necrosis factor (TNF) and interferon γ (IFN-γ) to facilitate Kupffer cell and natural killer (NK) cell migration and recruitment within tumors for efficient phagocytosis and killing of cancer cells. Moreover, Kupffer cells stimulate regulatory T cells (Tregs) to recruit cytotoxic CD8⁺ T cells that are induced by increased TNF and IFN harbored within a compliant ECM. CD8⁺ T cells release perforin and granzyme to mediate tumor killing. With increased ECM disorganization, high collagen and elastin fiber deposition create a stiff matrix for trapping NK cells. Increased pro-angiogenic growth factors (VEGF, IL-8, and PDGFβ) and matrix metalloproteinases MMP9 and MMP14 generate abnormal vasculature and an EMT that favors tumor growth via TAM recruitment. Highly contractile CAFs also stimulate an EMT under the guidance of TGF-β and IL-6. Independently, a stiff ECM also induces PD-L1 via dendritic cells (DCs), TGF-β, and cyclooxygenase-2 (COX2), all of which suppress CD8⁺ T cell activity to generate a pro-tumorigenic immune response.