Selenoprotein P Deficiency Drives Hepatocellular Carcinoma Progression via Induction of Neutrophil Senescence and Immunosuppressive Microenvironment

The tumor immune microenvironment (TIME) is critically shaped by immunosuppressive neutrophils, yet the molecular mechanisms underlying the functional reprogramming of these neutrophils remain poorly understood. Here, through integrative analysis of single-cell RNA sequencing (scRNA-seq) we showed the presence, in hepatocellular carcinoma (HCC) mice, of a novel subpopulation of senescent-like neutrophils that exhibit hepatic depletion of Sepp1 in concert with the accumulation of the cellular senescence marker Cdkn1a, the immunosuppressive proteins S100a8 and 9, and the pro-angiogenic factor Vegfa. Furthermore, we demonstrated that the hepatic depletion of Sepp1, in combination with this unique subset of senescent neutrophils, drives immunosuppressive activity and further accelerates tumor growth. Mechanistically, the loss of tumor cell-derived Sepp1 impaired selenium uptake in tumor-infiltrating neutrophils (TINs) by disrupting Lrp8 receptor-mediated transport, thereby suppressing intracellular selenium metabolism. This metabolic perturbation led to reduced hydrogen selenide (H2Se) production and accumulation of S-adenosylmethionine (SAM), resulting in increased levels of trimethylation of lysine 4 on histone H3 protein (H3K4me3) modification in neutrophils and collectively establishing a pro-senescence chromatin landscape in tumor-associated neutrophils. Furthermore, we demonstrated that selenium supplementation not only restores Sepp1 expression but also is essential to reshaping anti-tumor immunity in HCC mice, including reversal of the senescent-like phenotype and providing synergistic effects with anti-Programmed cell death 1 (anti-PD-1) therapy. Collectively, our findings identify SEPP1 as a master regulator acting against neutrophil senescence and the potent immunosuppressive effects of senescence in HCC. We discuss the therapeutic potential of strategies to modulate senescent-like neutrophils and underscore the potential utility of selenium supplementation as an adjuvant to enhance immunotherapy efficacy in liver cancer.