Tumor acidosis is a defining feature of solid tumors and contributes to invasion, metastasis, immune dysfunction, and resistance to chemotherapy and immunotherapy. This review examined whether sodium bicarbonate (NaHCO 3 ), a chemical compound that modifies extracellular pH is associated with tumor behavior and treatment outcomes. We reviewed preclinical and early clinical studies evaluating NaHCO 3 - and NaHCO 3 -containing nanomaterial-based approaches to tumor pH modulation. Studies were included if they reported primary experimental data assessing the effects of NaHCO 3 on tumor pH, tumor behavior, immune function, or therapeutic response. Studies were categorized based on mode of NaHCO 3 delivery. Fourteen studies met inclusion criteria. In eight studies using tumor-bearing mouse models, NaHCO 3 delivered through drinking water consistently elevated extracellular tumor pH without inducing systemic alkalosis. Furthermore, it reduced spontaneous metastases, improved survival, suppression of acid-activated enzymes involved in tissue breakdown, and enhanced anti-tumor immune activity, including improved T-cell function and cytokine production. Four studies using vitro systems or metastatic mouse models with selective localized delivery of NaHCO 3 -incorporating nanoparticles also achieved improved therapeutic outcomes compared with systemic delivery alone. Early clinical data and phase 0 studies of oral NaHCO 3 among humans indicate that long-term administration is feasible but limited by gastrointestinal tolerability. Tumor alkalinization may be a potential add-on to chemotherapy, targeted therapy, and immunotherapy. Localized approaches appear to offer potential advantages in efficiency and tolerability. However, further studies are needed to define optimal dosing strategies, delivery platforms, potential risks, and patient populations most likely to benefit from tumor pH-modulating therapies.
Prabhu et al. (Fri,) studied this question.