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Updated: Jul 17, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Navigating chimeric antigen receptor-engineered natural killer cells as drug carriers via three-dimensional mapping
Shigao Huang1, Fuqiang Xing2, Yeneng Dai3
1Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China; Department of Cell Biology of National Translational Science Center for Molecular Medicine and Department of Radiation Oncology of Xijing Hospital, Fourth Military Medical University, Xi' an, China.
Abstract:
Chimeric antigen receptor (CAR)-modified natural killer (NK) cells are recognized as promising immunotherapeutic agents for cancer treatment. However, the efficacy and trafficking of CAR-NK cells in solid tumors are hindered by the complex barriers present in the tumor microenvironment (TME). We have developed a novel strategy that utilizes living CAR-NK cells as carriers to deliver anticancer drugs specifically to the tumor site. We also introduce a time-lapse method for evaluating the efficacy and tumor specificity of CAR-NK cells using a two-photon microscope in live mouse models and three-dimensional (3D) tissue slide cultures. Our results demonstrate that CAR-NK cells exhibit enhanced antitumor immunity when combined with photosensitive chemicals in both in vitro and in vivo tumor models. Additionally, we have successfully visualized the trafficking, infiltration, and accumulation of drug-loaded CAR-NK cells in deeply situated TME using non-invasive intravital two-photon microscopy. Our findings highlight that tumor infiltration of CAR-NK cells can be intravitally monitored through the two-photon microscope approach. In conclusion, our study demonstrates the successful integration of CAR-NK cells as drug carriers and paves the way for combined cellular and small-molecule therapies in cancer treatment. Furthermore, our 3D platform offers a valuable tool for assessing the behavior of CAR cells within solid tumors, facilitating the development and optimization of immunotherapeutic strategies with clinical imaging approaches.
Insights
Chimeric antigen receptor (CAR)-NK cells deliver drugs to tumors, enhancing cancer immunity. A new imaging method tracks these CAR-NK cells in real-time, aiding combined therapies.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR)-modified natural killer (NK) cells show promise for cancer treatment.
- Solid tumor barriers in the tumor microenvironment (TME) limit CAR-NK cell efficacy and trafficking.
- Novel strategies are needed to improve CAR-NK cell delivery and function in solid tumors.
Purpose of the Study:
- To develop CAR-NK cells as drug carriers for targeted cancer therapy.
- To establish a time-lapse imaging method for evaluating CAR-NK cell efficacy and tumor specificity.
- To visualize CAR-NK cell trafficking and infiltration in the TME.
Main Methods:
- Development of living CAR-NK cells as drug carriers.
- Utilizing time-lapse two-photon microscopy for in vivo and 3D culture imaging.
- Combining CAR-NK cells with photosensitive chemicals for enhanced antitumor effects.
Main Results:
- CAR-NK cells successfully delivered anticancer drugs specifically to tumor sites.
- Enhanced antitumor immunity observed when CAR-NK cells were combined with photosensitive chemicals.
- Intravital two-photon microscopy visualized CAR-NK cell trafficking, infiltration, and accumulation in deep TME.
Conclusions:
- CAR-NK cells can be effectively utilized as drug carriers for combined cellular and small-molecule cancer therapies.
- The developed time-lapse two-photon microscopy approach enables real-time monitoring of CAR-NK cell tumor infiltration.
- A 3D platform aids in assessing CAR cell behavior in solid tumors, supporting immunotherapeutic strategy development.
