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 (ChiCTR2100053537), 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.