Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, with limited therapeutic success in advanced stages. Immune cell therapy utilizing cytokine-induced killer (CIK) cells has emerged as a promising strategy due to its MHC-unrestricted cytotoxicity and favorable safety profile.

However, enhancing the responsiveness of tumor cells to immune effectors remains a clinical challenge. All-trans retinoic acid (ATRA), a derivative of vitamin A, has demonstrated the ability to modulate tumor cell phenotypes and induce expression of stress ligands which are key elements in immune recognition.
This study explores whether ATRA can sensitize HCC cells to immune-mediated cytotoxicity by upregulating surface molecules recognized by CIK cells. Using a human HCC cell line (HepG2), we assessed the impact of ATRA pretreatment on cellular proliferation, surface ligand expression, and susceptibility to CIK cell-mediated lysis. The functional activity of expanded CIK cells was evaluated in vitro and further tested in a subcutaneous xenograft model in immunodeficient mice.
Initial findings suggest that ATRA pretreatment reduces HCC cell proliferation and enhances immunogenic features associated with improved recognition by CIK cells. Co-culture experiments revealed synergistic effects on tumor cell apoptosis and cell cycle arrest. In vivo application of the combined approach indicated reduction in tumor volume and evidence of immune cell infiltration within the tumor site.
These results highlight the potential of pharmacological priming strategies, such as ATRA treatment, to enhance the therapeutic efficacy of CIK-based immune cell therapy.  By promoting immune susceptibility of tumor cells, this approach may offer a complementary modality to improve clinical outcomes in HCC. Further mechanistic studies and translational assessments are warranted to refine this combination therapy for future application.