Blood profile of Innate Lymphoid Cells in HCC patients is cancer stage specific and undergoes functional switch during immunotherapy

Hepatocellular carcinoma (HCC) is a heterogeneous cancer. Patients differ not only in clinical presentation but also in their immune profiles. Innate lymphoid cells (ILCs), the innate counterparts of T cells, react to changes in the tumor environment, yet their role in HCC has been only partially explored. We studied ILC patterns in the blood of patients with early-stage HCC, advanced disease, patients in follow-up after successful local therapy, and healthy donors. We also monitored ILCs during treatment with the first-line combination of the checkpoint inhibitor atezolizumab and the anti-VEGF-antibody bevacizumab. We found that advanced HCC is marked by low levels of ILC2s and reduced cytotoxic ILC subsets, including NKp80+NK-like cells. These patients also showed a loss of IL-22 production and higher IL-4 production. Patients who later relapsed had fewer IL-13-producing ILC2s and IL-17/IL-22-producing ILC precursors, indicating that the disease stage shapes the systemic immune profile. During immunotherapy, ILC2 levels and checkpoint expression increased, and importantly, ILC2s shifted to a cytotoxic, granzyme-B-producing state. This shift was linked to better response to therapy and lower tumor marker AFP, while non-responders had more IL-4-producing ILC2s and poorer liver function. Trajectory from single-cell sequencing and serum cytokine levels revealed that IL-18 and IL-27 may drive this plasticity of ILC2s toward a cytotoxic phenotype which was specific for HCC patients and not seen in healthy controls. Our study highlights that ILCs respond dynamically to both disease progression and therapy in HCC. These findings support the evaluation of novel ILC-based cell therapies to boost anti-tumor immunity. Publication History Article published online: 26 January 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany