X‐ray‐Guided In Situ Genetic Engineering of Macrophages for Sustained Cancer Immunotherapy

• Published in: Advanced materials (Weinheim) Vol. 35; no. 14; pp. e2208059 - n/a
• Main Authors: Zhao, Caiyan, Cheng, Yaya, Huang, Pei, Wang, Changrong, Wang, Weipeng, Wang, Mengjiao, Shan, Wenbo, Deng, Hongzhang
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01-04-2023
• Subjects: Animals; Anticancer properties; Cell Line, Tumor; CRISPR‐Cas9; Genetic Engineering; immunomodulation; Immunotherapy; Macrophages; Materials science; Neoplasms - therapy; Pharmacology; Remote control; Tumor Microenvironment; X-Rays; immunomodulation; macrophages; CRISPR-Cas9; genetic engineering; X-rays
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.202208059

Effective repolarization of macrophages has emerged as a promising approach for anticancer therapy. However, there are very few studies on the effect of reprogramming macrophages from M2 phenotype to M1 phenotype without reconversion while maintaining an activated M1 phenotype. Moreover, these immunomodulatory methods have serious drawbacks due to the activation of normal monocytic cells. Therefore, it remains a challenge to selectively reprogram tumor‐associated macrophages (TAMs) without systemic toxicities. Here, X‐ray‐guided and triggered remote control of a CRISPR/Cas9 genome editing system (X‐CC9) that exclusively activates therapeutic agents at tumor sites is established. Under X‐ray irradiation, X‐CC9 selectively enhances M2‐to‐M1 repolarization within the tumor microenvironment, and significantly improves antitumor efficacy with robust immune responses in two animal models. This strategy provides an ideal method for improving the safety of macrophage polarization and may constitute a promising immunotherapy strategy.
An X‐ray‐guided and triggered remote control of the CRISPR/Cas9 genome‐editing strategy is reported, to specifically and permanently repolarize TAMs toward M1 phenotype without reconversion by blocking CSF1‐R and SIRPα expressions both in vitro and in vivo, thereby inducing the phagocytosis of tumor cells and eliciting robust antitumor immunity, while reducing systemic toxicities.