Serum Osteopontin Enhances Hepatocellular Carcinoma Diagnosis and Predicts Anti-PD-L1 Immunotherapy Benefit

Abstract

Background: Osteopontin (OPN), a phosphorylated glycoprotein encoded by SPP1, critical in hepatic inflammation and fibrosis, requires further investigation for its role on hepatocellular carcinoma (HCC) and predictive value for anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy responses. Methods: Publicly available datasets were utilized to explore OPN expression in HCC. A retrospective cohort study involving 316 participants, recruited from January 2015 to March 2017. Serum OPN levels were measured by enzyme-linked immunosorbent assay. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves, a logistic regression model was developed for early HCC diagnosis. Prospective follow-up was conducted from 2017 to 2024 to evaluate overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier analyses. The survival benefit of anti-PD-L1 immunotherapy for patients with OPN patterns was investigated. Results: Serum OPN levels were significantly elevated in HCC compared to chronic liver disease and healthy individuals (both p <0.001). The area under the curve (AUC) for OPN was 0.903, with 88.2% sensitivity and 83.3% specificity, significantly superior to AFP alone (AUC: 0.707). A combined diagnostic model integrating OPN with alpha-fetoprotein (AFP) and aspartate aminotransferase (AST) enhanced accuracy further (AUC: 0.941). High OPN levels indicated higher tumor burden and predicted worse clinical outcomes (mean OS: 49.1 vs 75.1 months; mean DFS: 37.7 vs 60.9 months, respectively; both log-rank p <0.001). Anti-PD-L1 immunotherapy significantly prolonged survival (OS: 62.9 vs 38.0 months, p = 0.009; DFS: 48.7 vs 28.6 months, p = 0.033) in patients with OPN high pattern. Conclusion: Serum OPN demonstrates standalone diagnostic value for HCC and enhances conventional biomarker panels when combined with AFP and AST. OPN high pattern identify patients likely to benefit from anti-PD-L1 immunotherapy, suggesting its dual utility as a diagnostic and predictive biomarker.