Abstract

Background The hepatocellular carcinoma (HCC) immune microenvironment is heavily influenced by immunosuppressive neutrophils, yet the mechanisms driving their senescence-associated reprogramming remain elusive. Objectives To elucidate the role of Selenoprotein P (Sepp1)-mediated selenium metabolism in driving the accumulation and immunosuppressive function of senescent-like neutrophils in HCC, and its impact on tumour immune evasion. Design We performed integrative single-cell RNA sequencing analyses in HCC mouse models, coupled with functional, metabolic and epigenetic assays to characterise neutrophil subpopulations and dissect the regulatory pathways linking Sepp1 and selenium metabolism to neutrophil senescence-associated reprogramming and tumour progression. Results We identified a distinct subpopulation of senescent-like tumour-infiltrating neutrophils marked by hepatic depletion of Sepp1, elevated Cdkn1a, S100a8/9 and Vegfa. Loss of tumour-derived Sepp1 impaired selenium uptake via Lrp8-mediated transport, suppressing intracellular selenium metabolism and hydrogen selenide production. This led to S-adenosylmethionine accumulation and increased histone H3 protein of trimethylation of lysine 4 histone modification, driving a prosenescence chromatin landscape. Selenium supplementation reversed these effects, restoring Sepp1 expression, reducing neutrophil senescence-associated reprogramming and reinvigorating anti-tumour immunity. Moreover, selenium synergised with anti-programmed cell death 1 therapy to suppress tumour growth. Conclusions Sepp1 is a key regulator of neutrophil senescence-associated reprogramming and immune suppression in HCC through selenium-dependent epigenetic remodelling. Targeting senescent-like neutrophils via selenium supplementation holds therapeutic promise to enhance immunotherapy efficacy in liver cancer.