Deleu_2025_Semin.Nucl.Med__

Fibroblast activation protein (FAP), selectively expressed on activated fibroblasts in proliferating tissues, is emerging as a promising target in oncology. In lung cancer, the leading cause of cancer-related deaths worldwide, [(18)F]FDG PET/CT has set the bar high and earned widespread recognition in clinical guidelines for its essential role in staging and follow-up. Yet, FAP-targeted imaging agents like FAPI PET/CT have demonstrated significant potential due to their high tumor specificity, rapid tracer uptake, and low background activity. This review focuses on the role of FAPI PET/CT in lung cancer, highlighting its applications in staging, biomarker evaluation, and clinical management. FAP expression correlates with cancer associated fibroblast-driven tumorigenesis in lung cancer, showing higher expression in nonsmall cell lung cancer (NSCLC) than in small cell lung cancer (SCLC) subtypes. Studies reveal that FAPI PET/CT provides comparable or superior detection rates for primary tumors and metastases compared to [(18)F]FDG PET/CT, particularly in brain, pleural, and bone lesions. It also enhances accuracy in lymph node staging, influencing disease management by enabling surgical resection in cases misclassified by [(18)F]FDG PET/CT. Despite these advantages, several challenges remain, such as differentiating benign from malignant lesions, assessing FAPI's prognostic implications or its role in treatment response monitoring. Future directions include exploring FAPI-based theranostics, standardizing radiopharmaceuticals, and conducting well-designed, adequately powered prospective trials. FAPI PET/CT represents a transformative diagnostic tool, complementing or potentially surpassing [(18)F]FDG PET/CT in precision lung cancer care.