Engineering sonogenetic EchoBack-CAR T cells

Longwei Liu¹, Peixiang He², Yuxuan Wang³, Fengyi Ma³, Dulei Li⁴, Zhiliang Bai⁵, Yunjia Qu², Linshan Zhu³, Chi Woo Yoon³, Xi Yu³, Yixuan Huang³, Zhengyu Liang⁶, Yiming Zhang³, Kunshu Liu³, Tianze Guo³, Yushun Zeng³, Qifa Zhou³, H Kay Chung⁷, Rong Fan⁵, Yingxiao Wang⁸

Affiliations

¹ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: longweil@usc.edu.
² Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Acoustic Cell Therapy, Inc., San Diego, CA 92130, USA.
⁵ Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
⁶ Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ywang283@usc.edu.

PMID: 40179881
PMCID: PMC12085297 (available on 2026-05-15)
DOI: 10.1016/j.cell.2025.02.035

Engineering sonogenetic EchoBack-CAR T cells

Longwei Liu et al. Cell. 2025.

. 2025 May 15;188(10):2621-2636.e20.

doi: 10.1016/j.cell.2025.02.035. Epub 2025 Apr 2.

Authors

Affiliations

¹ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: longweil@usc.edu.
² Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Acoustic Cell Therapy, Inc., San Diego, CA 92130, USA.
⁵ Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
⁶ Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ywang283@usc.edu.

PMID: 40179881
PMCID: PMC12085297 (available on 2026-05-15)
DOI: 10.1016/j.cell.2025.02.035

Abstract

Chimeric antigen receptor (CAR) T cell therapy for solid tumors encounters challenges such as on-target off-tumor toxicity, exhaustion, and limited T cell persistence. Here, we engineer sonogenetic EchoBack-CAR T cells using an ultrasensitive heat-shock promoter screened from a library and integrated with a positive feedback loop from CAR signaling, enabling long-lasting CAR expression upon focused-ultrasound (FUS) stimulation. EchoBack-hGD2CAR T cells, targeting disialoganglioside GD2, exhibited potent cytotoxicity and persistence in 3D glioblastoma (GBM) models. In mice, EchoBack-hGD2CAR T cells suppressed GBM without off-tumor toxicity and outperformed their constitutive counterparts. Single-cell RNA sequencing revealed enhanced cytotoxicity and reduced exhaustion in EchoBack-CAR T cells compared with the standard CAR T cells. This EchoBack design was further adapted to target prostate-specific membrane antigen (EchoBack-PSMACAR) for prostate cancer treatment, demonstrating long-lasting tumor suppression with minimal off-tumor toxicity. Thus, the sonogenetic EchoBack-CAR T cells can serve as a versatile, efficient, and safe strategy for solid tumor treatment.

Keywords: CAR T; feedback engineering; immunotherapy; inducible gene expression; promoter library screening; solid tumor; sonogenetics; spatiotemporal CAR regulation; ultrasound controled CAR-T.

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Conflict of interest statement

Declaration of interests Yingxiao Wang is a scientific co-founder and consultant of Cell E&G Inc. and Acoustic Cell Therapy Inc. D.L. is an employee of Acoustic Cell Therapy Inc. A patent related to this study has been filed. These financial interests do not affect the design, conduct, or reporting of this research.

References

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Engineering sonogenetic EchoBack-CAR T cells

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Engineering sonogenetic EchoBack-CAR T cells

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