Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the anti-tumoral activity of NK cells in HCC associated with different etiologies, and the impact of the heterogeneous NK cell subset, e.g., adaptive and conventional subsets, are not understood in detail. By comparatively analyzing the NK-cell repertoire in 60 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD), we show in this study that the NK-cell repertoire is linked to HCC etiology, with increased frequencies of adaptive NK cells in Hepatitis B virus (HBV)-associated HCC. Adaptive NK cells exhibited limited anti-tumoral activity toward liver cancer cells; however, this was not a result of a specific NK-cell impairment in HCC but rather represented an intrinsic feature, since the characteristics of circulating and intra-tumoral adaptive NK cells were conserved between HD, HCC and liver cirrhosis patients. Hence, the expansion of adaptive NK cells with reduced anti-tumoral activity, detectable in HBV-associated HCC, may have implications for tumor surveillance and therapy.

Staphylococcus epidermidis , a dominant human skin commensal from early life, can transition to an opportunistic pathogen, including invasive, biofilm-associated infections linked to medical devices. Neonatal exposure to skin commensals induces a lifelong immunological imprint in the skin, characterized by immunoregulatory responses. We therefore hypothesized that early life exposure to S. epidermidis influences immune responses to invasive biofilm-associated infections later in life. Using a mouse model of biofilm-related S. epidermidis bone infection, we show that neonatal and adult skin colonization altered the immune response to the subsequent infection in adulthood. Neonatal colonization led to increased NK cells and neutrophils compared to no colonization, along with reduced Tregs and Th1 cells, and consistent increase in immune checkpoint receptor PD-1 ⁺ Tregs, T effector, Th1 and Th2 cells across infected bone marrow, blood and spleen. These PD-1-related immune modulations were absent in the adult-colonized group, which had the highest numbers of Tregs, Th1 and Th2 cells of all groups. These findings reveal that early exposure to commensal bacteria strongly impacts the response to invasive infection later in life. Notably, the response depends on the timing of previous exposure. Neonatal colonization drives T cell modulation, resembling neonatal immunity, while adult-colonization increases specific T cell abundance. These differences highlight the essential role of skin colonization in shaping the quality of pathogen immunity to protect against invasive, biofilm-associated infection later in life, emphasizing that immunological studies using uncolonized animal models may not fully capture human immune dynamics.