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

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

  • Biochem Biophys Res Commun. 2025 Aug 18:781:152495. doi: 10.1016/j.bbrc.2025.152495.
Changjiang Guo 1,  Shizhuang Cheng 2,  Feiyan Cui 2,  Yifan Qian 2,  Qianqian Bao 2,  Yizhuo Sun 2,  Lingtong Zhi 2,  Zhiyuan Niu 2,  Mingfeng Li 2,  Wuling Zhu 3
Affiliations

Affiliations

  • 1 Henan 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. Electronic address: changjiangguo@xxmu.edu.cn.
  • 2 Henan 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.
  • 3 Henan 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. Electronic address: wuling_zhu@163.com.
PMID: 40845437 DOI: 10.1016/j.bbrc.2025.152495
Abstract

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells hold promise for off-the-shelf Cancer Immunotherapy, yet their clinical application is hindered by poor persistence due to cytokine dependency and systemic toxicity from exogenous cytokine support. Here, we developed membrane-bound cytokine (mbCytokine) modules to enable autonomous survival signaling in CAR-NK cells. By fusing IL-2, IL-15, or the potent mimic Neo-2/15 to their cognate receptor α-chains (IL-2Rα or IL-15Rα), we generated self-sustaining CAR-NK92 cells that bypass reliance on external cytokines. Among these constructs, membrane-bound IL-2 (mbIL2) demonstrated superior efficacy, driving robust proliferation and resistance to Apoptosis under serum-free conditions. Notably, mbIL2-armored CAR-NK cells exhibited enhanced cytotoxicity against MICA/B-expressing tumor cells. Mechanistically, mbIL2 mitigated activation-induced Apoptosis and suppressed exhaustion during tumor engagement, thereby sustaining NK cell viability. These findings establish mbIL2 as a critical enhancer of CAR-NK cell persistence and antitumor function, offering a clinically translatable strategy to overcome the limitations of cytokine-dependent therapies.

Keywords

Anti-apoptosis; Autonomous proliferation; CAR-NK cells; Membrane-bound IL-2 or IL-15; Tumor cytotoxicity.

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