TLR4 and cholangiocarcinoma: In causal mouse models that mimic clinical risk states (primary sclerosing cholangitis or colitis), increased gut permeability raised portal LPS, which activated hepatocyte TLR4, induced CXCL1, and recruited CXCR2+ polymorphonuclear MDSCs, thereby establishing an immunosuppressive niche that accelerates CCA [49, 163].