Of interest, rTHBS2 had no effect on the abovementioned cancer and stemness properties in cells cultured in 2D or in the presence of a RHO/ROCK pathway inhibitor (Y‐27632), suggesting that the ECM modification may represent an important process in THBS2‐mediated change in ability of HCC cells to migrate, invade, self‐renew, and resist 5‐FU treatment (Figure S5, Supporting Information). Here, THBS2 is linked to hepatocellular carcinoma.