Abstract B037: COX-2 inhibitor enhances cabozantinib/Anti-PD1 efficacy in hepatocellular carcinoma

Abstract Combination strategies that integrate targeted therapies with immune checkpoint inhibitors (ICIs) have improved the therapeutic landscape for advanced hepatocellular carcinoma (HCC). Clinically, the Phase III COSMIC-312 trial demonstrated that cabozantinib plus atezolizumab prolonged progression-free survival without extending overall survival, underscoring the persistence of tumor-intrinsic resistance mechanisms and the urgent need for more effective combination approaches. In this mechanistic and translational study, we comprehensively evaluated the therapeutic and immunological effects of cabozantinib, celecoxib (Cox-2 inhibitor), and anti–programmed death-1 (anti-PD1), administered individually or in combination, in orthotopic and spontaneous metastatic HCC models designed to better recapitulate human disease. Cabozantinib induced hallmark features of immunogenic cell death (ICD) but concurrently activated COX-2/PGE2 signaling, generating an immunosuppressive milieu that limited its therapeutic potential. Celecoxib selectively suppressed PGE2 production while preserving ICD, leading to enhanced dendritic cell activation and stronger cytotoxic T-cell responses. Notably, the triplet regimen of cabozantinib, celecoxib, and anti-PD1 delivered the most pronounced therapeutic benefit, with robust inhibition of primary tumor progression, significant reduction of spontaneous lung metastases, and marked depletion of regulatory T cells. These results demonstrate that celecoxib effectively counters COX-2/PGE2–driven immunosuppression without disrupting ICD, thereby restoring and amplifying the antitumor efficacy of cabozantinib–anti-PD1 therapy. Taken together, these results provide a compelling and clinically actionable rationale for clinical trials evaluating the addition of a COX-2 inhibitor to targeted therapy–ICI combinations to enhance efficacy in advanced HCC. Citation Format: Yu-Chen Hsu, Meng-Chuan Wu, Meng-Tzu Weng, Ying-Te Lee, Ching-I Lin, Huei-Chi Chou, Hsuan-Shu Lee, Li-Fang Wang, Jin-Chuan Sheu, Chien-Hung Chen Chen. COX-2 inhibitor enhances cabozantinib/Anti-PD1 efficacy in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B037.