A Nitric Oxide (NO) Nanoreporter for Noninvasive Real‐Time Imaging of Macrophage Immunotherapy

Abstract Macrophage‐centered therapeutic approaches that rely on immune modulation of tumor associated macrophages (TAMs) from a pro‐tumorigenic phenotype (M2) to an anti‐tumorigenic phenotype (M1) have facilitated a paradigm shift in macrophage immunotherapy. However, limited clinical success has been achieved due to the low response rates observed in different types of cancers. The ability to measure immune response in real time is critical in order to differentiate responders from non‐responders; however, there are currently no platforms to monitor real‐time macrophage immunotherapy response. Hence, there is an immediate need to develop imaging techniques that can longitudinally monitor macrophage immunotherapy response. Nitric oxide (NO) produced as a result of activation of macrophages to an anti‐tumorigenic state is considered as a hallmark of M1 and can be a direct indication of response. In this study, a NO nanoreporter (NO‐NR) is reported that enables real‐time monitoring of macrophage immunotherapy drugs in vitro and in vivo. Furthermore, it is observed that sustained inhibition of colony stimulating factor 1 receptor (CSF1R) using a CSF1R inhibitor–NO‐NR system leads to enhanced efficacy and better imaging signal. In conclusion, a first‐of‐its‐kind NO nanoreporter tool is reported that can be used as an activatable imaging agent to monitor macrophage immunotherapy response in real time.