CAF-derived cardiotrophin-like cytokine factor 1 (CLCF1) increases chemokine (C-X-C motif) ligand 6 (CXCL6) and TGF-β secretion in HCC cells, which promotes HCC-cell stemness and TAN infiltration and polarizationHCC-derived CXCL6 and TGF-β activate ERK1/2 signaling of CAFs to produce more CXCF1 and promote HCC progressionSelective blocking of CLCF1 or ERK1/2 signaling could provide an effective therapeutic target for HCC patients. Here, CLCF1 is linked to hepatocellular carcinoma.