Bicarbonate transport as regulator of antitumour immunity in pancreatic cancer

Abstract

Bicarbonate transport is a pre-existing mechanism of pH regulation in pancreatic ductal cells. In a recent study, Cappellesso et al. demonstrated that pancreatic ductal adenocarcinoma metabolic rewiring creates an acidic environment, enhanced by bicarbonate import into cancer cells via SLC4A4. This acidity favours protumourigenic immunosuppression. Targeting SLC4A4 neutralises environmental pH and restores antitumour immunity, sensitising tumours to immune checkpoint blockade.

Keywords: T-cells; acidosis; cancer; immunotherapy; metabolism; tumour microenvironment.

Fig. 1

PDAC cancer cells retain the expression of SLC4A4, which imports bicarbonate (${\mathrm{HCO}}_3^{-}$), contributing to maintaining an acidic tumour microenvironment (TME) by increasing intracellular glycolysis and extrusion of protons (H⁺) and lactate via the monocarboxylate transporters (MCTs). Increased H⁺/lactate creates an immunosuppressive TME with Treg cells and M2‐like macrophages. Genetic depletion (sgSlc4a4) or inhibition of Slc4a4 with a non‐specific inhibitor 4,4′‐diisothiocyano‐2,2′‐stilbenedisulfonic acid (DIDS) reduces H⁺/lactate in the TME and restores CD8⁺ T‐cell infiltration and increased antitumour activation (M1‐like macrophages and IFNɣ expressing CD8⁺ T cells). Figure created with BioRender.com.