Intratumoral Bicarbonate Functions as an Adjuvant to Potentiate PD-1 Blockade in Hepatocellular Carcinoma

AntiPD-1 immunotherapy improves survival in advanced hepatocellular carcinoma (HCC), but responses remain limited by the immunosuppressive, acidic tumor microenvironment (TME). We investigated whether intratumoral alkalization with sodium bicarbonate could enhance PD-1 blockade. Bicarbonate-induced intracellular alkalization disrupted mitochondrial membrane potential, triggered rupture, and activated the cGAS–STING pathway via cytosolic mitochondrial DNA release, while simultaneously inducing immunogenic cell death (ICD). In murine models, intratumoral bicarbonate recruited and activated dendritic cells and T cells, suppressing tumor growth and synergizing with antiPD-1 therapy. In a prospective clinical study, 28 patients with advanced-stage and 2 with intermediate-stage HCC received Tislelizumab plus intratumoral 5% sodium bicarbonate. The objective response rate was 93.3% (CR 53.3%, PR 40.0%); median progression-free survival was 31 months, and median overall survival was not reached. Treatment was well tolerated. Biopsies revealed significantly increased CD3⁺, CD4⁺, and CD8⁺ T-cell infiltration with combination therapy versus Tislelizumab alone. In line with our previous work, through this mitochondria-centered mechanism bicarbonate links metabolic reprogramming with innate and adaptive immune activation. Thus, intratumoral bicarbonate functions as a safe and accessible immunometabolic adjuvant that markedly enhances PD-1 blockade efficacy in HCC.