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KCa3.1 channels regulate the tumor infiltration of functionally competent NK cells in head and neck cancer

Abdulaziz O Alshwimi1, Ameet A Chimote1, Marat V Khodoun2,3

  • 1Division of Nephrology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.

Scientific Reports
|October 17, 2025
PubMed

Insights

The KCa3.1 potassium channel is crucial for natural killer (NK) cell anti-tumor activity in head and neck squamous cell carcinoma (HNSCC). Activating this channel enhances NK cell function and boosts anti-tumor immune responses.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • CD8+ T cells and natural killer (NK) cells are key defenders against tumors.
  • Tumor microenvironments can suppress immune cell functions, hindering anti-tumor responses.
  • KCa3.1 potassium channels regulate T cell functions, but their role in NK cells is less understood.

Purpose of the Study:

  • To investigate the role of KCa3.1 channels in human NK cell function within head and neck squamous cell carcinoma (HNSCC).
  • To evaluate KCa3.1 channel activity's impact on NK cell chemotaxis, cytotoxicity, and overall anti-tumor immunity.

Main Methods:

  • Utilized selective KCa3.1 blockers (TRAM-34) and activators (SKA-31) on human NK cells from healthy donors and HNSCC patients.
  • Assessed NK cell chemotaxis and cytotoxicity in vitro.
  • Employed a humanized HNSCC mouse model with Cal27 cells and human peripheral blood mononuclear cells to test SKA-31's in vivo efficacy.

Main Results:

  • KCa3.1 blockade inhibited NK cell chemotaxis, while activation enhanced both chemotaxis and cytotoxicity.
  • In vivo treatment with SKA-31 significantly increased NK cell infiltration (7-fold) and functional activity (23-fold increase in granzyme B-positive NK cells) in HNSCC tumors.
  • SKA-31 demonstrated enhanced anti-tumor immune responses in the HNSCC mouse model.

Conclusions:

  • KCa3.1 channels play a critical role in regulating human NK cell anti-tumor functions, including migration and killing ability.
  • Targeting KCa3.1 channels represents a promising therapeutic strategy for developing novel immunotherapies for HNSCC.
  • Further research into KCa3.1 modulation could enhance NK cell-based cancer treatments.

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