FAP-Targeted Radionuclide Therapy: Mechanisms, Clinical Applications, and Combination Strategies

Area of Science:

• Oncology
• Radiopharmaceutical Science
• Molecular Imaging

Background:

• Fibroblast activation protein (FAP) is highly expressed in the tumor microenvironment of many solid malignancies, primarily on cancer-associated fibroblasts.
• FAP-targeted PET imaging has seen rapid clinical expansion, leading to exploration of FAP-targeted radionuclide therapy (FAP-TRT) as a stromal-directed strategy.

Purpose of the Study:

• To review the biological rationale, mechanistic basis, radiopharmaceutical development, and emerging clinical evidence for FAP-TRT.
• To highlight ligand-engineering strategies for improved tumor retention and absorbed dose.
• To summarize current clinical data, focusing on dosimetry, safety, and early efficacy signals.

Main Methods:

• Review of biological rationale and mechanistic basis of FAP-TRT.
• Analysis of radiopharmaceutical development and ligand-engineering strategies.
• Summary of emerging clinical data, including safety, dosimetry, and efficacy.

Main Results:

• FAP-TRT faces challenges including stromal heterogeneity, variable FAP expression, and limited radioligand tumor retention.
• Ligand engineering strategies aim to enhance tumor residence time and absorbed dose.
• Early clinical data suggest feasibility but highlight the need for improved ligand design.

Conclusions:

• FAP-TRT is a feasible theranostic approach for solid malignancies.
• Improved ligand design and biologically informed clinical development are crucial for FAP-TRT's success.
• Future directions include disease-focused development and combination strategies with other therapies.