Synergistic Anticancer Strategy Targeting ECM Stiffness: Integration of Matrix Softening and Mechanical Signal Transduction Blockade in Primary Liver Cancers

Abstract The development of primary liver cancer (hepatocellular carcinoma [HCC] and intrahepatic cholangiocarcinoma [ICC]) is linked to its physical microenvironment, particularly extracellular matrix (ECM) stiffness. Potential anticancer strategies targeting ECM stiffness include prevention/reversal of the stiffening process and disruption of the response of cancer cells to mechanical signals from ECM. However, each strategy has limitations. Therefore, the authors propose integrating them to maximize their strengths. Compared with HCC, ICC has a stiffer ECM and a worse prognosis. Therefore, ICC is selected to investigate mechanisms underlying the influence of ECM stiffness on cancer progression and application of the integrated anticancer strategy targeting ECM stiffness. In summary, immunofluorescence results for 181 primary liver cancer tissue chips (ICC, n = 91; HCC, n = 90) and analysis of TCGA mRNA‐sequencing demonstrate that ECM stiffness can affect phenotypes of primary liver cancers. The YAP1/ABHD11‐AS1/STAU2/ZYX/p‐YAP1 pathway is a useful entry point for exploration of specific mechanisms of mechanical signal conduction from the ECM in ICC cells and their impact on cancer progression. Moreover, a synergistic anticancer strategy targeting ECM stiffness (ICCM@NPs + siABHD11‐AS1@BAPN) is constructed by integrating ECM softening and blocking intracellular mechanical signal transduction in ICC and can provide insights for the treatment of cancers characterized by stiff ECM.