The addition of celecoxib enhances the therapeutic benefit of cabozantinib and anti-PD1 in hepatocellular carcinoma.

Combination therapy with targeted agents and immune checkpoint inhibitors (ICIs) represents a major advance in the treatment of advanced hepatocellular carcinoma (HCC), yet clinical efficacy remains modest. In the phase III COSMIC-312 trial, cabozantinib plus atezolizumab prolonged progression-free survival but did not improve overall survival, indicating the presence of tumor-intrinsic resistance mechanisms. In this study, we investigated the therapeutic and immunological effects of cabozantinib, celecoxib, and anti-programmed death-1 (anti-PD1), administered individually or in combination, in orthotopic and spontaneous metastatic HCC mouse models. Cabozantinib demonstrated hallmarks of immunogenic cell death (ICD) but concurrently activated COX-2/PGE₂-mediated immunosuppression, thereby limiting its antitumor efficacy. Celecoxib selectively inhibited PGE₂ production without affecting ICD, thereby enhancing dendritic cell activation and strengthening cytotoxic T-cell responses. Notably, triple therapy with cabozantinib, celecoxib, and anti-PD1 produced the most potent therapeutic outcome, markedly suppressing primary tumor growth, reducing lung metastases, and depleting regulatory T cells. These results reveal that celecoxib mitigates COX-2/PGE₂-driven immunosuppression while preserving ICD, thereby augmenting the efficacy of cabozantinib-anti-PD1 immunotherapy. This combination provides a strong mechanistic rationale for clinical translation and may inform future strategies to improve the durability of immune-based treatments for advanced HCC. This strategy may also guide future clinical trial designs and support the development of more effective, personalized therapies for patients with advanced HCC.