The cellular senescence score (CSS) is a comprehensive biomarker to predict prognosis and assess senescence and immune characteristics in hepatocellular carcinoma (HCC).

Cellular senescence, an emerging hallmark of cancer, has garnered increasing attention in recent years. However, its role in hepatocellular carcinoma (HCC) is still not well understood. Furthermore, there is a lack of comprehensive biomarkers to predict prognosis and assess senescence and immune characteristics in HCC patients. To address these gaps, we conducted functional studies on bleomycin-induced senescent Hepa1-6 cells and developed the Cellular Senescence Score (CSS) based on four core cellular senescence-related genes. We found that the cellular senescence signaling pathway was enriched among the risk genes associated with unfavorable prognosis in HCC patients. The senescence associated secretory phenotype (SASP) derived from senescent Hepa1-6 cells induced an increase in CD3 CD8 CD279 T cells. The senescent Huh7 cells expressed higher levels of pro-angiogenic genes compared to their immortal counterparts. The CSS was constructed on the basis of BMI1, EZH2, NPM1, and ME1. HCC Patients in the high-CSS group had significantly shorter overall survival compared to those in the low-CSS group. In contrast to the low-CSS group, the high-CSS group exhibited more senescence characteristics at both the overall tumor microenvironment and single-cell levels. Three distinct senescence patterns were identified in hepatoma cells: oxidative stress related senescence, metabolism related senescence, and immune related senescence. The high-CSS group showed elevated TP53 mutation rate, diminished immune cell infiltration, and enhanced expression levels of immune checkpoint molecules compared to the low-CSS group. Moreover, the high-CSS group displayed a greater proportion of patients responsive to immune checkpoint therapy compared to the low-CSS group. In summary, the impacts of cellular senescence on HCC are multifaceted, and the tumor-promoting effects may be caused by SASP remodeling the HCC microenvironment rather than by the senescent hepatoma cells themselves. The CSS is a promising biomarker capable of predicting prognosis and assessing senescence and immune characteristics in HCC.