X-Ray Guided in Situ Genetic Engineering of Macrophage for Sustained Cancer Immunotherapy.

Effective repolarization of macrophages has emerged as a promising approach for anti-cancer 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 was established. Under X-ray irradiation, X-CC9 selectively enhanced M2-to-M1 repolarization within the tumor microenvironment, and significantly improved anti-tumor efficacy with robust immune responses in two animal models. This strategy provides an ideal method for improving the safety of the macrophage polarization and may constitute a promising immunotherapy strategy. This article is protected by copyright. All rights reserved.