A Single-Cell-Derived CD8+ T-Cell State Plasticity Score for Prognostic Stratification and Characterization of Immune Responsiveness in Hepatocellular Carcinoma

Abstract

Background T cells play a central role in antitumor immunity. Emerging evidence indicates that T-cell plasticity and differentiation states are associated with clinical outcomes and responses to cancer immunotherapy. CD8⁺ T cells that retain differentiation potential are thought to sustain effective antitumor immunity. However, robust quantitative metrics for assessing tumor-infiltrating CD8+ T-cell state plasticity and defining its clinical significance in hepatocellular carcinoma remain lacking. Methods We integrated publicly available single-cell RNA-sequencing datasets from HCC cohorts to characterize CD8⁺ T-cell states using unsupervised pseudotime reconstruction and supervised ordinal transcriptional modeling. We used genes showing progressive changes along the inferred state axis and enriched in CD8⁺ T cells to develop a T-cell State Plasticity score using Cox proportional hazards and LASSO regression in the training cohort. The model was evaluated in independent bulk transcriptomic cohorts. Results Supervised psupertime analysis validated the predefined Tcm–Tem–Tpex–Ttex ordinal axis in held-out cells, supporting the existence of an ordered CD8⁺ T-cell state continuum in HCC. The CD8+ T-cell State Plasticity score robustly stratified clinical outcomes across multiple large HCC cohorts. High-risk scores, indicative of reduced CD8+ T-cell state plasticity, were associated with adverse clinical outcomes and an immunosuppressive tumor immune microenvironment. Conclusion CD8+ T-cell states are associated with tumor immune characteristics and clinical outcomes in HCC. This single-cell–derived T cell plasticity scoring system provides a quantitative framework for prognostic prediction and immune landscape evaluation, with potential implications for clinical decision-making.