Beyond gastric acid: pharmacologic modulation of the tumor microenvironment by vonoprazan and its drug-interaction implications for chemotherapy and immunotherapy.

purposeVonoprazan, a potassium-competitive acid blocker, possesses distinct pharmacokinetic and pharmacodynamic properties, including a high pKa , prolonged systemic exposure, and sustained hypochlorhydria, that may have implications beyond gastric acid suppression for anticancer drug interactions and the tumor microenvironment.

methodsWe critically reviewed preclinical and clinical literature to evaluate vonoprazan's potential effects across two proposed biological axes: the intracellular/organelle axis, involving potential lysosomal drug sequestration, pH regulation, autophagy, and apoptotic signaling, and the systemic microbiome axis, involving acid-suppression-associated microbial alterations and potential consequences for antitumor immunity.

resultsVonoprazan enhanced cisplatin cytotoxicity in MCF-7 breast cancer cells and attenuated cisplatin-associated nephrotoxicity in rats, while altering autophagy-related markers. Separate cancer-cell studies found no increase in VEGF expression under the tested conditions, in contrast to several proton pump inhibitors. Conversely, a retrospective NSCLC cohort associated vonoprazan exposure with higher hazards of progression and death during immune checkpoint inhibitor therapy, although causality was not established. A 2026 pharmacovigilance analysis also identified increased cholangitis reporting among immune checkpoint inhibitor-exposed reports with co-reported vonoprazan, although causality was not established. Clinical evidence for microbiome alterations is emerging, but their relevance to anticancer treatment outcomes remains uncertain.

conclusionAvailable evidence supports a context-dependent pharmacologic framework rather than a uniform oncologic effect. Direct evidence for tumor-cell accumulation and vonoprazan-specific effects on V-ATPase activity in tumors remains limited. Prospective clinical and translational studies are needed to determine the clinical relevance of these potential interactions and to define appropriate use alongside anticancer therapies.