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A membrane-bound IL-2 promotes CAR-NK cell proliferation, anti-apoptosis and anti-tumor activity

Changjiang Guo1, Shizhuang Cheng1, Feiyan Cui1

  • 1Henan Engineering Technology Research Center for Advanced SynBio Medicine and Clinical Innovation Translation, School of Life Sciences and Technology, Henan Medical University, Xinxiang, Henan Province, PR China; Henan Engineering Research Center of Innovation for Synthetic Biology, School of Life Sciences and Technology, Henan Medical University, Xinxiang, Henan Province, PR China.

Biochemical and Biophysical Research Communications
|August 22, 2025
PubMed

Insights

Engineered natural killer (NK) cells for cancer therapy can now persist longer. Membrane-bound cytokines, specifically mbIL2, enable CAR-NK cells to survive and fight tumors without external cytokine support.

Area of Science:

  • Immunotherapy
  • Cellular Engineering
  • Oncology

Background:

  • Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells show potential for off-the-shelf cancer immunotherapy.
  • Clinical use is limited by poor cell persistence and toxicity from external cytokine support.

Purpose of the Study:

  • To develop membrane-bound cytokine (mbCytokine) modules for autonomous survival signaling in CAR-NK cells.
  • To overcome cytokine dependency and improve the persistence and efficacy of CAR-NK cell therapy.

Main Methods:

  • Engineered CAR-NK92 cells with membrane-bound cytokine modules (mbCytokines) by fusing IL-2, IL-15, or Neo-2/15 to their cognate receptor α-chains.
  • Assessed cell proliferation, apoptosis resistance, and cytotoxicity under serum-free conditions.
  • Investigated the mechanistic effects of mbIL2 on NK cell survival and function during tumor engagement.

Main Results:

  • Self-sustaining CAR-NK92 cells were generated, bypassing the need for external cytokines.
  • Membrane-bound IL-2 (mbIL2) demonstrated superior efficacy, promoting proliferation and apoptosis resistance.
  • mbIL2-engineered CAR-NK cells showed enhanced cytotoxicity against MICA/B-expressing tumor cells.
  • mbIL2 mitigated activation-induced apoptosis and suppressed NK cell exhaustion.

Conclusions:

  • mbIL2 is a critical enhancer of CAR-NK cell persistence and antitumor function.
  • This mbCytokine strategy offers a clinically translatable approach to overcome limitations in current CAR-NK cell therapies.
Keywords:
Anti-apoptosisAutonomous proliferationCAR-NK cellsMembrane-bound IL-2 or IL-15Tumor cytotoxicity

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