Abstract by Simona Mattiussi

Cancer represents a growing global health challenge, with progressively increasing incidence and mortality rates that significantly affect life expectancy worldwide. Despite major advances in oncology, early detection, accurate treatment monitoring, and effective therapeutic strategies for solid tumors remain difficult to achieve. To address these challenges, theranostics has emerged as an innovative approach in nuclear medicine, integrating molecular imaging with targeted radionuclide therapy to enable precision medicine, improve patient selection, and reduce systemic toxicity. A major limitation of conventional cancer therapies lies in tumor heterogeneity and the complex role of the tumor microenvironment, which actively promotes tumor growth and therapeutic resistance. Targeting stromal components rather than cancer cells alone has therefore gained increasing interest. Fibroblast activation protein (FAP), highly expressed in cancer-associated fibroblasts across a wide range of solid tumors and minimally present in normal tissues, has emerged as a promising universal target. Although FAP-targeted inhibitors have demonstrated excellent performance in PET imaging, their clinical translation into effective therapeutic agents remains constrained by insufficient tumor retention and suboptimal pharmacokinetic properties. In parallel, immunotherapeutic strategies such as chimeric antigen receptor (CAR) T-cell therapy have shown remarkable success in hematological malignancies but face significant obstacles in solid tumors, including toxicity and immunosuppressive tumor environments. Switchable CAR platforms, such as Universal CAR T-cell technology, together with combination approaches involving targeted radionuclide therapy, offer new possibilities to enhance safety, control, and antitumor efficacy.
This Ph.D. thesis focuses on the development and optimization of novel small-molecule compounds that target FAP to enhance their use as theranostic agents. The research investigates FAP inhibitors for PET imaging, assesses structural strategies to improve tumor uptake and retention time, and explores pretargeting approaches that integrate nuclear and near-infrared fluorescence imaging. Additionally, a FAP-based targeting module is developed for the combined delivery of radionuclides and Universal CAR T-cell immunotherapy. In conclusion, the work presented in this Ph.D. project significantly advance the field of FAP-targeted theranostics.