Extracellular tumor microenvironment pH buffering system (TME pH system)

The extracellular tumor microenvironment (TME) pH buffering system is a critical physiological target characterized by the regulation of proton concentrations in the space surrounding malignant cells (Vaupel & Multhoff, 2021). In most solid tumors, metabolic reprogramming—specifically the Warburg effect—leads to the overproduction of lactic acid and protons, resulting in a chronically acidic extracellular environment with a pH typically ranging from 6.5 to 6.9 (Gatenby & Gillies, 2004). This acidosis serves as a driver for cancer progression by promoting extracellular matrix degradation and facilitating local invasion and distant metastasis (Robey et al., 2009). Furthermore, the acidic TME acts as a potent immunosuppressive barrier, impairing the function of cytotoxic T lymphocytes while favoring pro-tumorigenic immune cells (Pilon-Thomas et al., 2016). Therapeutic interventions targeting this system involve the use of systemic buffering agents, such as sodium bicarbonate, or targeted delivery systems like pH-low insertion peptides (pHLIP) to neutralize acidity (Reshetnyak et al., 2006). By restoring a more neutral pH, these treatments aim to sensitize tumors to conventional therapies and enhance the efficacy of immune checkpoint inhibitors (Pilon-Thomas et al., 2016).

Other names

Tumor extracellular acidosisAcidic tumor microenvironmentTME acidityExtracellular proton concentrationTumor pHe

Direct neutralization of extracellular protons or systemic administration of buffering agents to increase the pH of the tumor microenvironment, thereby reversing acidosis-induced immunosuppression and chemoresistance (Pilon-Thomas et al., 2016; Robey et al., 2009).