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.
Hsu et al. (Sat,) studied this question.