TREM2 scFv‐Engineering Escherichia coli Displaying Modulation of Macrophages to Boost Cancer Radio‐Immunotherapy

Abstract Preoperative neoadjuvant radio‐chemotherapy is a cornerstone in the treatment of low rectal cancer, yet its effectiveness can be limited by the insensitivity of some patients, profoundly impacting their quality of life. Through preliminary research, it is found that TREM2 ⁺ macrophages play a pivotal role in the non‐responsiveness to immunotherapy. To address this challenge, a novel ionizing radiation‐responsive delivery system is developed for the precise expression of anti‐TREM2 single‐chain antibody fragments (scFv) using an engineered probiotic, Escherichia coli Nissle 1917 (EcN), to modulate immunotherapy. The released anti‐TREM2 scFv can be precisely targeted and delivered to the tumor site via the engineered EcN outer membrane vesicles (OMVs), thereby reversing the immunosuppressive tumor microenvironment and enhancing tumor therapeutic efficiency when used in combination with the αPD‐L1 immune checkpoint inhibitor. Additionally, these engineered bacteria can be further modified to enhance the intestinal colonization capabilities through oral administration, thereby regulating the gut microbiota and its metabolic byproducts. Consequently, the ionizing radiation‐responsive drug delivery system based on the engineered bacteria not only introduces a promising new therapeutic option for low rectal cancer but also showcases the potential to finely tune immune responses within the intricate tumor microenvironment, paving the way for innovative strategies in tumor radio‐immunotherapy.