An Image-Guided Combination Strategy: Immediate Hepatic Arterial Infusion of Nivolumab Following Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma

Background: Transarterial chemoembolization (TACE) is an established image-guided, minimally invasive therapy for unresectable hepatocellular carcinoma (HCC). However, post-embolization hypoxia often triggers compensatory angiogenesis and an immunosuppressive microenvironment, limiting long-term efficacy. We hypothesized that the immediate image-guided hepatic arterial infusion (HAI) of a PD-1 inhibitor following TACE could synergistically enhance local tumor control. Methods: In this retrospective, propensity-score-matched study, 226 patients with unresectable HCC (January 2021–June 2024) were analyzed. After 1:1 matching, 84 pairs were included: Study Group (TACE + HAI-nivolumab) and Control Group (TACE alone). Nivolumab (3 mg/kg) was infused via the hepatic artery under fluoroscopic guidance immediately after embolization. Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included objective response rate (ORR) by mRECIST and changes in serum angiogenesis/immune biomarkers. Results: The Study Group demonstrated significantly longer median OS (16.2 vs. 12.8 months; HR 0.62, 95% CI: 0.44–0.88, p = 0.007) and median PFS (9.8 vs. 6.5 months; p < 0.001). ORR was higher with combination therapy (58.3% vs. 36.9%, p = 0.006). Mechanistically, HAI-nivolumab suppressed the post-TACE surge in VEGF and Ang-2 (p < 0.001) and increased the peripheral CD4+/CD8+ T-cell ratio. Grade 3/4 adverse events were comparable between groups (14.3% vs. 10.7%, p = 0.485). Conclusions: The image-guided combination of TACE with immediate HAI of nivolumab is associated with improved survival and tumor response in unresectable HCC. This strategy may counteract the adverse post-embolization microenvironment by simultaneously inhibiting angiogenesis and reactivating local immunity, representing an advanced image-guided combination therapy with strong translational relevance.