Ultrasound Control of Genomic Regulatory Toolboxes for Cancer Immunotherapy

• Published in: Nature communications 2024-12, Vol.15 (1), p.10444-16
• Main Authors: Wu, Yiqian, Huang, Ziliang, Liu, Yahan, He, Peixiang, Wang, Yuxuan, Yan, Liyanran, Wang, Xinhui, Gao, Shanzi, Zhou, Xintao, Yoon, Chi Woo, Sun, Kun, Situ, Yinglin, Ho, Phuong, Zeng, Yushun, Yuan, Zhou, Zhu, Linshan, Zhou, Qifa, Zhao, Yunde, Liu, Thomas, Kwong, Gabriel A., Chien, Shu, Liu, Longwei, Wang, Yingxiao
• Format: Article
• Language: English
• Subjects: 13/31; 13/44; 14/19; 38/1; 38/39; 38/5; 38/77; 38/88; 42/109; 631/250/251; 631/337/4041; 631/67/1059; Animals; Antigens; Cancer; Cancer immunotherapy; Cancer therapies; Cell Line, Tumor; Cell therapy; Chimeric antigen receptors; Clustered Regularly Interspaced Short Palindromic Repeats; Controllability; CRISPR; CRISPR-Cas Systems; Dependovirus - genetics; Disruption; Epigenetics; Gene Editing - methods; Genomics; Genomics - methods; Humanities and Social Sciences; Humans; Hyperthermia; Immunotherapy; Immunotherapy - methods; Immunotherapy, Adoptive - methods; Lymphocytes; Lymphocytes T; Mice; multidisciplinary; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - metabolism; Science; Science (multidisciplinary); Solid tumors; Telomeres; Transgenes; Tumors; Ultrasonic imaging; Ultrasonic Waves; Ultrasound
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54477-7

There remains a critical need for the precise control of CRISPR (clustered regularly interspaced short palindromic repeats)-based technologies. Here, we engineer a set of inducible CRISPR-based tools controllable by focused ultrasound (FUS), which can penetrate deep and induce localized hyperthermia for transgene activation. We demonstrate the capabilities of FUS-inducible CRISPR, CRISPR activation (CRISPRa), and CRISPR epigenetic editor (CRISPRee) in modulating the genome and epigenome. We show that FUS-CRISPR-mediated telomere disruption primes solid tumours for chimeric antigen receptor (CAR)-T cell therapy. We further deliver FUS-CRISPR in vivo using adeno-associated viruses (AAVs), followed by FUS-induced telomere disruption and the expression of a clinically validated antigen in a subpopulation of tumour cells, functioning as “training centers” to activate synthetic Notch (synNotch) CAR-T cells to produce CARs against a universal tumour antigen to exterminate neighboring tumour cells. The FUS-CRISPR(a/ee) toolbox hence allows the noninvasive and spatiotemporal control of genomic/epigenomic reprogramming for cancer treatment. There remains a critical need for precise control of CRISPR-based technologies. Here, the authors develop a focused ultrasound (FUS)-controllable CRISPR toolbox, allowing the noninvasive and spatiotemporal control of genomic/epigenomic reprogramming for cancer treatment combined with CAR-T therapy.