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Updated: Mar 7, 2026
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
NIR-II Nanomedicine Engineered CAR-NK Cells for Precision Navigation and Potentiating Lung Cancer Immunotherapy by
Yeneng Dai1,2, Qihang Ding3, Ze Chen1
1Cancer Centre, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR 999078, China.
Abstract:
Despite the prominent success against hematologic malignancies in clinical settings, chimeric antigen receptor NK (CAR-NK) cell immunotherapy is still hindered in lung cancer tumors owing to insufficient infiltration and poor immune activation induced by the immunosuppressive tumor microenvironment (TME). Herein, a nanoengineered CAR-NK biohybrid (CK-PSI) was constructed by conjugating nanomedicine (PSI NPs) containing a near-infrared II (NIR-II) polymer and a specific small-molecule inhibitor of Smad3 (SIS3) to the surface of metabolic glycan-engineered CAR-NK cells via a bioorthogonal reaction. Anti-B7H3 CAR modification on cell vectors offers selectively targeted delivery of hitchhiking NIR-II nanomedicine into lung cancer tumors, simultaneously enabling real-time tracking of CAR-NK cells and precise localization of deep-seated tumors through NIR-II fluorescence imaging. NIR-II excitation mild photothermal therapy not only destroys tumor cells by thermal ablation but also promotes the infiltration and penetration of CK-PSI through the rupture of physical barriers within tumor tissues. More importantly, the in situ release of the Smad3 inhibitor further reduces extracellular matrix (ECM) deposition through TGF-β signaling pathway blockade in the TME, thereby boosting the infiltration and immune activation of CAR-NK cells. The bioorthogonal nanohybrid with NIR-II phototheranostic triggered cell localization and immunomodulatory capabilities provides a new paradigm for potentiating the infiltration and immune activation efficiency of CAR-NK cells against solid tumors.
Insights
This study engineered a novel CAR-NK cell therapy to overcome lung cancer
Area of Science:
- Immunotherapy
- Nanomedicine
- Cancer Research
Background:
- Chimeric antigen receptor NK (CAR-NK) cell therapy shows promise in hematologic cancers but faces challenges in solid tumors like lung cancer.
- Key limitations include poor CAR-NK cell infiltration and suppressed immune activation within the immunosuppressive tumor microenvironment (TME).
- The TME presents physical and biological barriers that impede effective CAR-NK cell delivery and function.
Purpose of the Study:
- To develop a nanoengineered CAR-NK cell biohybrid (CK-PSI) to enhance CAR-NK cell infiltration and immune activation in lung cancer.
- To utilize near-infrared II (NIR-II) imaging for real-time tracking and precise localization of CAR-NK cells within tumors.
- To combine photothermal therapy and targeted drug delivery to overcome TME-mediated suppression.
Main Methods:
- Constructed CK-PSI by conjugating NIR-II polymer and Smad3 inhibitor (SIS3) loaded nanoparticles (PSI NPs) to metabolically engineered CAR-NK cells via bioorthogonal reaction.
- Incorporated anti-B7H3 CAR for targeted delivery of nanomedicine to lung cancer cells.
- Utilized NIR-II fluorescence imaging for tracking and mild photothermal therapy for tumor ablation and enhanced infiltration.
Main Results:
- The CK-PSI biohybrid enabled targeted delivery and real-time tracking of CAR-NK cells in lung tumors using NIR-II imaging.
- NIR-II triggered photothermal therapy destroyed tumor cells and facilitated CK-PSI penetration by disrupting tumor barriers.
- In situ release of Smad3 inhibitor blocked TGF-β signaling, reducing extracellular matrix deposition and significantly boosting CAR-NK cell infiltration and immune activation.
Conclusions:
- The developed nanoengineered CAR-NK biohybrid (CK-PSI) effectively enhances CAR-NK cell infiltration and immune activation against lung cancer.
- The combination of NIR-II phototheranostics and targeted immunomodulation offers a promising strategy for solid tumor immunotherapy.
- This approach represents a new paradigm for improving CAR-NK cell efficacy in challenging solid tumor environments.
