Radionuclide imaging and therapy directed towards the tumor microenvironment: a multi-cancer approach for personalized medicine

Targeted radionuclide theranostics is becoming more and more prominent in clinical oncology. Currently, most nuclear medicine compounds researched for cancer theranostics are directed towards targets expressed in only a small subset of cancer types, limiting clinical applicability. The identification of cancer-specific targets that are (more) universally expressed will allow more cancer patients to benefit from these personalized nuclear medicine–based interventions. A tumor is not merely a collection of cancer cells, it also comprises supporting stromal cells embedded in an altered extracellular matrix (ECM), together forming the tumor microenvironment (TME). Since the TME is less genetically unstable than cancer cells, and TME phenotypes can be shared between cancer types, it offers targets that are more universally expressed. The TME is characterized by the presence of altered processes such as hypoxia, acidity, and increased metabolism. Next to the ECM, the TME consists of cancer-associated fibroblasts (CAFs), macrophages, endothelial cells forming the neo-vasculature, immune cells, and cancer-associated adipocytes (CAAs). Radioligands directed at the altered processes, the ECM, and the cellular components of the TME have been developed and evaluated in preclinical and clinical studies for targeted radionuclide imaging and/or therapy. In this review, we provide an overview of the TME targets and their corresponding radioligands. In addition, we discuss what developments are needed to further explore the TME as a target for radionuclide theranostics, with the hopes of stimulating the development of novel TME radioligands with multi-cancer, or in some cases even pan-cancer, application.