Elevated IL-17A level is associated with poor overall survival following immune checkpoint inhibitors combined with targeted therapy in hepatocellular carcinoma with hyperbilirubinemia

Background: Combination therapy with programmed death-1 (PD-1) inhibitors and targeted therapy is a first-line treatment for advanced hepatocellular carcinoma (HCC). Patients with hyperbilirubinemia (total bilirubin > upper limit of normal) are often excluded from such regimens. This study aimed to evaluate the efficacy and safety of PD-1 inhibitor plus targeted therapy in this patient population and to identify plasma protein biomarkers associated with prognosis. Methods: We enrolled 201 patients with advanced HCC who received PD-1 inhibitor plus targeted therapy. After propensity score matching (1:1), 60 pairs of patients with hyperbilirubinemia and normal bilirubin were compared in terms of objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Baseline plasma samples from 72 patients (28 with hyperbilirubinemia, 44 with normal bilirubin) were analyzed using Olink proteomics to quantify 92 inflammatory proteins. Differentially expressed proteins were identified, and the functional pathways were examined. The prognostic value of key proteins was assessed using Cox regression and Kaplan-Meier survival analysis. Results: The combination therapy was well tolerated in the hyperbilirubinemia group, with no increase in severe hepatotoxicity. ORR (7.0% vs. 20.7%, P = 0.043) and DCR (50.9% vs. 72.4%, P = 0.022) were significantly lower in the hyperbilirubinemia group. Median OS was significantly shorter in the hyperbilirubinemia group (HR = 0.54, 95% CI 0.35-0.84, P = 0.0065). Proteomic analysis revealed 36 differentially expressed proteins. Univariate Cox regression indicated that elevated plasma IL-17A was significantly associated with poorer OS in the hyperbilirubinemia subset (HR = 1.63, 95% CI 1.04-2.55, P = 0.033). Further stratification by median IL-17A levels showed that hyperbilirubinemia patients with high IL-17A had significantly worse OS (HR = 2.89, 95% CI 1.03-8.07, P = 0.035), whereas IL-17A levels had no significant impact in patients with normal bilirubin (P = 0.870). A formal interaction test confirmed that the detrimental effect of high IL-17A was amplified in the presence of hyperbilirubinemia (HR = 2.72, 95% CI 1.28-5.75, P = 0.009). Conclusion: PD-1 inhibitor combined with targeted therapy is safe and feasible in advanced HCC patients with hyperbilirubinemia, although efficacy is inferior to that in patients with normal bilirubin. Elevated plasma IL-17A may serve as a biomarker for poor prognosis and a potential therapeutic target in this population.