Lactate: from friend to foe.

In physiology, lactate supports whole-body energy needs and adaptation. In pathology, it supports selfish tumor survival at the expense of the host.

Symbiotic relationship between cancer cells: Hypoxic cells (Pink) produce lactate, and Normoxic cells (Blue) consume it.

The acidification of the Tumor Microenvironment (TME) is not due to lactate itself being acidic (lactate is actually a base), but rather because lactate is co-exported (to avoid self-poisoning and to regenerate NAD⁺ continuously, the glycolytic cancer cell must export lactate) with a proton (H⁺) via monocarboxylate transporters (MCTs), particularly MCT1 and MCT4. This co-export of lactate and H⁺ leads to the extracellular acidification observed in the TME/ECM, and the intracellular pH remains relatively stable or even slightly alkaline.

A single tumor cell performing high-rate glycolysis can export this acid load. In a dense, poorly perfused tumor mass with billions of cells, the collective export overwhelms the weak buffering capacity and inadequate clearance of the TME. This leads to a sustained drop in extracellular pH (often to pH 6.5-6.9).

This acidity, in turn:

Promotes invasion and metastasis by activating pH-sensitive proteases that degrade the extracellular matrix.

Inhibits immune cell function (e.g., cytotoxic T cells and natural killer cells function poorly in an acidic environment).

Increases genetic instability and drug resistance.

Creates a selection pressure for cancer cells that thrive in acidity.