Abstract Background: Hepatocellular carcinoma (HCC) is among the most prevalent and fatal cancers globally, but viable therapeutic alternatives are scarce. Natural killer (NK) cells are components of the innate immune system that exhibit significant anti-cancer properties. Recent findings indicate that activation with interleukins IL-15 and IL-18 promotes the production of NK cells exhibiting augmented effector capabilities and potential “memory-like” characteristics. This study examined the cytotoxic efficacy of IL-15/18-stimulated NK cells against human HCC tissue in vitro. Methods: NK cells were collected from healthy donors and patients with HCC, followed by in vitro activation with IL-15 and IL-18. The cytotoxic efficacy of activated NK cells was assessed in co-culture with human HCC cells. This study demonstrated that IL-6 and IL-1α participated in regulating the anti-tumor efficacy of IL-15/18-activated NK cells. Results: The results indicate that NK cells from patients with HCC and healthy donors exhibited comparable expression levels of both activating and inhibiting NK cell receptors. The expansion of NK cells from HCC patients was inferior compared to that of healthy donors in response to IL15/18 (p 0.001 on day 5). In vitro, NK cells from both groups of persons exhibited significant cytotoxicity against HCC targets, and this was associated with the inhibitory effects of activated NK cells on the production of IL-6 and IL-1alpha. Lower levels of spontaneous HCC formation were observed in a spontaneous model of HCC after IL-15/18 activated NK cells that trafficked to the liver (p 0.01). Conclusion: IL-15/18-activated NK cells from both healthy donors and HCC patients exhibit comparable levels of anti-tumor efficacy against HCC cells. These results indicate that IL-15/18 activation augments the therapeutic efficacy of NK cells, endorsing their application as a promising immunotherapeutic approach for hepatocellular carcinoma. Citation Format: Ola Sayed Ahmed, Refaat Gabre, Amr Iamail Abdelraouf, Hisham Imam, Maha Genhia. Regulatory immunotherapy utilizing activated natural killer cells and antitumor response for hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3716.
Ahmed et al. (Fri,) studied this question.