2. Academic Validation
  3. High Extracellular K+ Skews T-Cell Differentiation Towards Tumour Promoting Th2 and Treg Subsets

High Extracellular K+ Skews T-Cell Differentiation Towards Tumour Promoting Th2 and Treg Subsets

  • Eur J Immunol. 2025 Feb;55(2):e202451440. doi: 10.1002/eji.202451440.
Brandon Han Siang Wong 1 2,  Zhi Sheng Poh 1,  James Tan Chia Wei 1,  Kottaiswamy Amuthavalli 1,  Ying Swan Ho 3,  Shuwen Chen 3,  Shi Ya Mak 3,  Xuezhi Bi 3,  Richard D Webster 4,  Vishalkumar G Shelat 1 5,  K George Chandy 1,  Navin Kumar Verma 1 6 7
Affiliations

Affiliations

  • 1 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • 2 Interdisciplinary Graduate Programme, NTU Institute for Health Technologies (HealthTech NTU), Nanyang Technological University, Singapore, Singapore.
  • 3 Bioprocessing Technology Institute, Agency for Science Technology and Research (A*STAR), Singapore.
  • 4 School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
  • 5 Department of General Surgery, Tan Tock Seng Hospital, Singapore.
  • 6 National Skin Centre, Singapore.
  • 7 Skin Research Institute of Singapore, Singapore.
PMID: 39651799 DOI: 10.1002/eji.202451440
Abstract

Potassium ions (K+) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K+ concentration to 50 mM (high-[K+]e). Here, we demonstrate that high-[K+]e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K+]e also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and iTreg subsets that promote tumour growth while restricting antitumour Th1 and Th17 subsets. Similar phenotypes were noted in T-cells present within the necrosis-prone core versus the outer zones of hepatocellular carcinoma (HCC)/colorectal carcinoma (CRC) tumours as analysed by GeoMx digital spatial profiling and flow-cytometry. Our results thus expand the understanding of the contribution of high-[K+]e to the immunosuppressive milieu in the TME.

Keywords

T‐cell exhaustion; T‐lymphocytes; immune suppression; metabolomics.

Figures
Products