Scheme 1

Schematic diagram of CFH/OM-L reversing EMT process of CAFs activation derived from hepatic stellate cells (HSCs) and consequent boosting hepatocellular carcinoma therapy with IC-ML. After accumulation at hepatocellular carcinoma sites, CFH/OM-L actively enters into TGF-β1-activated CAFs via high affinity between CFH peptide and tenascin-C. CFH/OM-L can educate activated CAFs into quiescent HSCs through EMT reversion, which is proofed by the upregulation of E-cadherin and the downregulation of vimentin, N-cadherin, and snail protein. The reduction of CAFs leads to TME reprogramming, such as collagen reduction, M1 tumor-associated macrophages (TAMs) polarization, NK cells activation, and so on. The CFH/OM-induced TME activation not only damages tumorigenesis but also assists IC-ML to penetrate deeply, thereby enhancing the comprehensive anticancer efficacy