In this study, we examined the effect of crosstalk between tumors and their microenvironment on chemoresistance and migration using HCC-MCTS models and found that the interaction between HCC cells and HSCs could facilitate the compactness of HCC spheroids via the accumulation of collagen 1A1 (COL1A1), thereby leading to chemoresistance in HCC. The gene discussed is COL1A1; the disease is hepatocellular carcinoma.