Acidity Modulation in Tumor Microenvironments

Solid tumours frequently develop a reversed pH gradient in which extracellular pH (pHe) falls to values as low as 6.5–6.9 while intracellular pH (pHi) is maintained at neutral or slightly alkaline levels. This imbalance stems from accelerated glycolytic metabolism, poor perfusion and hypoxia, leading to excess proton production. Cancer cells employ proton extrusion mechanisms—such as monocarboxylate transporters, sodium–hydrogen exchangers and vacuolar ATPases—to survive acidic stress. Extracellular acidification alters cell–matrix interactions, promotes invasive and metastatic phenotypes, impairs drug uptake and suppresses antitumour immunity. Emerging interventions aim to normalise pH through buffering agents, proton-pump inhibitors, nanoparticle-based delivery systems and metabolic reprogramming. A comprehensive understanding of acidity modulation in the tumour microenvironment unveils novel therapeutic targets and informs strategies to overcome treatment resistance.

Research from Nature Portfolio

Recent studies have combined computational modelling with functional assays to map pH-dependent cancer vulnerabilities. One approach reconstructed pH-sensitive enzyme activity profiles within genome-scale metabolic networks, demonstrating that intracellular alkalinisation enhances glycolysis and hypoxia adaptation, whereas acidification undermines these processes and limits proliferation. This framework also pinpointed metabolic enzymes whose inhibition is magnified under acidic conditions, suggesting pH-guided therapeutic opportunities. Another investigation revealed that extracellular acidity activates autocrine TGF-β2 signalling, which in turn drives lipid droplet formation, partial epithelial-to-mesenchymal transition and resistance to anoikis. This mechanism supports metastatic dissemination by regulating fatty acid uptake, storage and oxidation, thus linking acid stress to lipid metabolism and cell motility.

Acidity Modulation in Tumor Microenvironments publication trend

The graph below shows the total number of articles in acidity modulation in tumor microenvironments across all publications each year (not limited to Nature Index journals).

Technical terms

Tumour microenvironment: The local cellular and non-cellular surroundings of a tumour, including stromal cells, immune infiltrates and extracellular matrix.

Extracellular pH (pHe): The acidity level outside cells, which in solid tumours is often lower than in healthy tissues.

Intracellular pH (pHi): The acidity level within cells, tightly regulated to sustain enzymatic activities and metabolic homeostasis.

Monocarboxylate transporter (MCT): A membrane protein that exports lactate and protons from cells, contributing to extracellular acidification.

Vacuolar ATPase (V-ATPase): A proton pump that acidifies intracellular organelles and supports proton export at the cell surface.

Epithelial-to-mesenchymal transition (EMT): A process through which epithelial cells acquire motile, invasive properties characteristic of mesenchymal cells.

References

1. pH sensing and regulation in cancer. Frontiers in Physiology (2013).
2. Systems analysis of intracellular pH vulnerabilities for cancer therapy. Nature Communications (2018).
3. TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells. Nature Communications (2020).
4. Manipulating extracellular tumour pH: an effective target for cancer therapy. RSC Advances (2018).
5. Unravelling the Interplay between Extracellular Acidosis and Immune Cells. Mediators of Inflammation (2018).