The Role of 18F-FDG PET/CT in Monitoring Immunotherapy Response in Non-Small Cell Lung Cancer: Current Evidence and Challenges: A Narrative Review.

Background/Objectives: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have transformed treatment paradigms, but assessing response remains challenging due to atypical patterns such as pseudoprogression, hyperprogression and dissociated response. Conventional evaluation criteria, such as RECIST 1.1, may not fully capture these patterns, leading to potential misclassification and premature therapy discontinuation. This review explores the role of 18F-FDG PET/CT in assessing immunotherapy response and highlights novel imaging criteria to enhance clinical decision-making. Methods: A systematic literature review was conducted across PubMed, Web of Science, Scopus, and Cochrane Library, selecting relevant studies published between 2013 and 2024. The review focuses on the strengths and limitations of PET-based imaging in monitoring NSCLC immunotherapy outcomes. Specific attention was given to evolving evaluation frameworks, including iRECIST, PERCIST, imPERCIST, and iPERCIST, as well as metabolic biomarkers such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Results: Compared with anatomical-based assessment, metabolic imaging using 18F-FDG PET/CT may offer deeper insights into tumor behavior during immunotherapy. PET-derived parameters seem to improve the detection of immune-related response patterns, providing a more refined approach to differentiate true progression from pseudoprogression. Emerging evidence indicates that metabolic biomarkers such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) could serve as useful predictors of therapeutic efficacy and support treatment adaptation. Nevertheless, current findings are mainly based on small, heterogeneous, and predominantly retrospective studies, with variable PET timing and threshold definitions that limit the generalizability of these results. Conclusions: 18F-FDG PET/CT represents a promising complementary tool for assessing immunotherapy response in NSCLC. Its integration with advanced imaging criteria and metabolic tumor biomarkers may enhance response evaluation and assist clinical decision-making. Nonetheless, the current evidence remains preliminary, and further standardization and large prospective validation studies are required before its routine implementation in clinical practice.