N-methyl-D-aspartate (NMDA) ion channels drive calcium-dependent myeloid cell reprogramming to shape cancer immunity and immunotherapy

The field of immunometabolism has highlighted the importance of metabolic signals in regulating immune responses. Various classes of ion channels act as sensors of these metabolic signals, modulating ion influx (e.g., Ca2 + , Na + , K +) and downstream signalling pathways that influence immune cell activation and inflammatory responses. This review focuses on the role of N-methyl-D-aspartate (NMDA) ion channels in promoting an immunosuppressive tumour microenvironment in response to metabolic cues. These ligand-gated cation channels modulate myeloid cell signalling and metabolism, resulting in M2 macrophage polarisation and myeloid-derived suppressor cell (MDSC) activity. Recent studies indicate that combining the ion channel antagonists with anti-PD-1/PD-L1 therapy enhances immunotherapy efficacy, underscoring ion channel signalling as an attractive target to improve treatment outcomes.