Acidic extracellular microenvironment (pHe)

The acidic extracellular microenvironment (pHe) is a ubiquitous hallmark of solid tumors, primarily resulting from the metabolic shift to glycolysis (the Warburg effect) and insufficient vascularization leading to hypoxia [1, 5]. While healthy tissues maintain a pHe of approximately 7.4, the tumor microenvironment frequently reaches acidic levels between 6.5 and 6.8 [5, 7]. This acidity functions as a biological driver of malignancy, promoting extracellular matrix degradation, increased invasiveness, and the suppression of anti-tumor immune cells like cytotoxic T-lymphocytes and NK cells [2, 3, 4]. Additionally, the altered pH gradient across the cell membrane contributes to drug resistance through 'ion trapping,' which prevents the cellular uptake of many weak-base chemotherapeutics [15, 16]. Therapeutic strategies targeting this microenvironment include the use of systemic buffers such as sodium bicarbonate to neutralize the pHe and enhance the efficacy of immunotherapies or traditional drugs [4, 8, 13, 14]. More recently, the family of pH-low insertion peptides (pHLIPs) has been developed to exploit this condition for highly selective delivery; these peptides undergo a pH-dependent conformational change that allows them to insert into and cross cell membranes specifically in acidic tissues [1, 7, 9, 10]. This platform enables the targeted delivery of a wide range of payloads, including small-molecule toxins, imaging agents, and oligonucleotides, directly to the cytoplasm of cells within the acidic microenvironment while minimizing exposure to healthy, neutral-pH tissues [10, 11].

Other names

Tumor acidityExtracellular acidosisLow extracellular pHTumor microenvironment acidityAcidic tumor microenvironment

Neutralization of extracellular acidity via buffering, pH-dependent membrane insertion for targeted cargo delivery (e.g., pHLIP), pH-triggered release from nanocarriers, and inhibition of proton/lactate export to normalize pH.