Lung cancer remains the most frequently diagnosed cancer and the leading cause of cancer-related death worldwide, despite preventive measures and screening programs that facilitate earlier disease detection.1 Approximately 85% of all lung cancers are of the nonsmall cell histological subtype, with nearly 50% presenting as metastatic disease at diagnosis.2 [18F]FDG PET/CT has set the standard as a pan-cancer imaging modality and is widely accepted for clinical staging of lung cancer, particularly due to its superiority in detecting metastases compared to conventional imaging techniques.3 Moreover, the evolution of the metabolic activity in lung cancer lesions has been validated as a biomarker for treatment response.4 However, [18F]FDG PET/CT is not without limitations. First, it requires fasting and involves lengthy preparation and imaging procedures, which can impose a significant burden on already ill patients. Second, it should be complemented with a triple phase contrast-enhanced CT for preoperative assessment, MRI to rule out brain metastases, and pathological confirmation of often nonspecific hypermetabolic mediastinal lymph nodes.5 Given these limitations, the search for novel tracers targeting other aspects of lung cancer biology beyond glucose metabolism, remains an active area of research.6

One promising target is the cell surface antigen recognized by the monoclonal antibody (mAb) F19, which was first described in 1986 on human astrocytoma cells.7 It was designated ‘fibroblast activation protein’ (FAP) by the same author, referring to the almost exclusive expression in proliferating tissues such as reactive stromal fibroblasts of epithelial cancers (cancer associated fibroblasts, CAFs) and regenerative tissue.8 This selective pathologic upregulation, alongside its near absence in normal tissues, has drawn significant attention from researchers as a promising pan-cancer target.9,10 As early as 2003, Scott et al.11 identified the therapeutic potential of FAP targeting and conducted a phase I dose-escalation study of a humanized version of the mAb F19 (sibrotuzumab) in patients with advanced or metastatic colorectal carcinoma or nonsmall cell lung cancer. Advances in FAP-targeted radiopharmaceuticals and specifically small molecule FAP inhibitors (FAPIs) have accelerated research, enabling molecular imaging and the development of radiotheranostic pairs.12,13 A 2022 bibliometric analysis highlighted a rapidly expanding research interest in FAPI theranostics, primarily focused on imaging applications across various cancer types.14

A recent review summarized the available literature up to January 2024, comparing [18F]FDG and FAPI PET/CT in lung cancer diagnosis.15 The authors concluded that FAPI PET/CT has a demonstrated clinical value in detecting and staging of lung cancer, offering novel insights and enhanced precision compared to [18F]FDG. This review aims to provide an updated overview of the available literature on FAPI PET/CT in lung cancer, focusing on its role in staging, its potential as prognostic biomarker, and its impact on the clinical management of lung cancer patients.

A PubMed/MEDLINE search was conducted up to January 7, 2025, using the query: ("lung cancer"[Title/Abstract] OR "NSCLC"[Title/Abstract] OR "nonsmall cell lung cancer"[Title/Abstract] OR "small cell lung cancer"[Title/Abstract] OR "SCLC"[Title/Abstract] OR "lung tumor"[Title/Abstract]) AND ("FAP"[Title/Abstract] OR "FAPI"[Title/Abstract] OR "FAPI PET"[Title/Abstract]). This approach ensured comprehensive coverage of all possible FAPI tracers used for PET imaging in different lung tumor types. Due to the similar biodistribution patterns observed across all known small molecule FAP inhibitors, a subdivision by specific FAPI radiopharmaceuticals was not made in this review. Consequently, all FAPI radiopharmaceuticals are collectively referred to as ‘FAPI’ below.