A novel cabozantinib-sulfasalazine combination targeting ferroptosis to overcome resistant immunotherapy in advanced hepatocellular carcinoma

Advanced hepatocellular carcinoma (HCC) frequently develops resistance to immunotherapy, resulting in limited treatment options and poor prognosis. Ferroptosis, an iron-dependent regulated form of cell death, may help overcome drug resistance, and cabozantinib has shown clinical efficacy in advanced HCC. In this single-arm retrospective study at the First Affiliated Hospital, Zhejiang University School of Medicine, 60 patients with immunotherapy-refractory HCC received cabozantinib combined with sulfasalazine (1,500 mg/day in three divided oral doses) between August 2021 and August 2024. Tumor response was assessed using RECIST v1.1, while progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier methods and exploratory Cox regression. The combination achieved an objective response rate of 40% (95% CI: 28–53%) and a disease control rate of 70% (95% CI: 58–81%), with median PFS of 8.5 months (95% CI: 6.9–10.1) and median OS of 15.3 months (95% CI: 12.9–17.7). Adverse events were mostly grade 1–2 and manageable, consistent with cabozantinib’s known safety profile. These findings suggest encouraging antitumor activity, tolerability, and a potential synergistic effect, though the retrospective single-center design may introduce bias. Prospective randomized studies are warranted to confirm these results and further explore this combination’s potential in overcoming immunotherapy resistance.