Fibroblast activation protein-targeted radioligand therapy in various types of cancer: Background, clinical studies, and future development

Cancer is the leading cause of mortality worldwide. The proliferation and viability of cancer cells are intricately related to the complex tumor microenvironment in which they reside. Cancer-associated fibroblasts (CAFs) play a pivotal role in multiple stages of tumorigenesis, including tumor growth, invasion, metastasis, and resistance to treatment, through intricate crosstalk with tumor and immune cells. Targeted radionuclide therapy involves the systemic administration of small molecule drugs labeled with β-emitting or α-emitting radioisotopes, allowing precise targeting of tumor sites and delivering radiation directly to the tumor. Prostate-specific membrane antigen-targeted radioligand therapy (RLT) and somatostatin receptor-targeted peptide receptor radionuclide therapy (PRRT) have demonstrated favorable safety profiles and significant antitumor efficacy, leading to their approval by the Food and Drug Administration. Recently, the utilization of theranostic approaches that target overexpressed fibroblast activation proteins (FAPs) within the CAFs of the tumor stroma has demonstrated encouraging preliminary outcomes. This review aims to provide a concise summary of current clinical research outcomes and the applications of RLT based on FAP inhibitors in the context of solid tumors.