The Evolution of FAP-Targeted CAR T-Cell Therapy in Solid Tumors: From Immunotherapy to Immunotheranostic Applications

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of hematologic malignancies but has demonstrated limited efficacy in solid tumors, mainly due to the complex and immunosuppressive tumor microenvironment (TME). Among the strategies to overcome this challenge, targeting the tumor stroma rather than the tumor cells themselves has gained increasing interest. In this context, fibroblast activation protein alpha (FAP), a cell surface protease overexpressed by cancer-associated fibroblasts, represents a promising target. With the aim of remodeling the TME, enhancing immune infiltration, and suppressing tumor growth, numerous FAP-directed CAR T-cell therapies have been developed in the last decade, leading to the clinical translation of two candidates. To improve the flexibility and safety profile of CAR T-cell therapies, several groups have designed more controllable and modular approaches, including adapter CAR T-cell systems, which enable on-demand activation of effector cells through the administration of an adapter molecule. In parallel, the development of FAP-targeted radiotracers, particularly FAP inhibitors (FAPIs), has enabled high-contrast imaging of solid tumors and introduced attractive opportunities for radioligand therapy. The convergence of these advances has given rise to immunotheranostic strategies that integrate CAR T-cell immunotherapy and radioligand delivery within a unified framework. This review traces the evolution of FAP-directed CAR T-cell strategies, from conventional designs to adapter-based and theranostic platforms, and examines how modular adapters bring immunotherapy and radioligand delivery together within a single immunotheranostic framework, across preclinical and clinical settings.