protein transduction exploits the ability of some cell - penetrating peptide sequences to enhance the uptake of proteins and other macromolecules by mammalian cells . previously developed hydrophobic cpps , named membrane translocating sequence , membrane translocating motif and macromolecule transduction domain , are able to deliver biologically active proteins into a variety of cells and tissues . various cargo proteins fused to these cpps have been used to test the functional and / or therapeutic efficacy of protein transduction . for example , recombinant proteins consisting of suppressor of cytokine signaling 3 protein fused to the fibroblast growth factor 4 - derived mtm were developed to inhibit inflammation and apoptosis . however , cp - socs3 fusion proteins expressed in bacteria were hard to purify in soluble form . to address these critical limitations , cpp sequences called advanced mtds have been developed in this art . this is accomplished by analyzing previous developed hydrophobic cpp sequences to identify specific critical factors that affect intracellular delivery potential and constructing artificial amtd sequences satisfied for each critical factor . in addition , solubilization domains have been incorporated into the amtd - fused socs3 recombinant proteins to enhance solubility with corresponding increases in protein yield and cell -/ tissue - permeability . these recombinant socs3 proteins fused to amtd / sd having much higher solubility / yield and cell -/ tissue - permeability have been named as improved cell - permeable socs3 proteins . previously developed cp - socs3 proteins fused to mtm were only tested or used as anti - inflammatory agents to treat acute liver injury . in the present art , icp - socs3 proteins have been tested for use as anti - cancer agents in the treatment of hepatocellular carcinoma . since socs3 is frequently deleted in and loss of socs3 in hepatocytes promotes resistance to apoptosis and proliferation , we reasoned that icp - socs3 could be used as a protein - based intracellular replacement therapy for the treatment of hepatocellular carcinoma . the results support this reasoning : treatment of hepatocellular carcinoma cells with icp - socs3 results in reduced cancer cell viability , enhanced apoptosis and loss of cell migration / invasion potential . furthermore , icp - socs3 inhibits the growth of hepatocellular carcinoma in a subcutaneous xenografts model . in the present invention with icp - socs3 fused to an empirically determined combination of newly developed amtd and customized sd , macromolecule intracellular transduction technology enabled by the advanced mtd may provide novel protein therapy against hepatocellular carcinoma .