{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:01:41Z","timestamp":1785438101339,"version":"3.56.0"},"reference-count":104,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P01CA254859"],"award-info":[{"award-number":["P01CA254859"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P01CA254859"],"award-info":[{"award-number":["P01CA254859"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Intraoperative molecular imaging (IMI) enables real-time visualization of tumor biology during surgery using fluorescent probes and near-infrared imaging systems. As lung cancer screening increases detection of small and nonpalpable pulmonary nodules, conventional localization and margin assessment techniques remain limited, particularly during minimally invasive surgery. This review summarizes the technical foundations, imaging agents, clinical applications, and future directions of IMI in thoracic oncology. Methods: We performed a narrative review to synthesize current evidence regarding the technical foundations, molecular imaging agents, clinical applications, and future directions of intraoperative molecular imaging in thoracic oncology. Given the multidisciplinary scope of the field, a narrative approach was selected to integrate mechanistic, translational, and clinical evidence rather than to answer a single narrowly defined clinical question. Results: IMI generates dynamic intraoperative contrast based on preferential probe accumulation or activation within malignant tissue. Current approaches include non-specific fluorophores such as indocyanine green, activatable probes targeting tumor-associated proteases or acidic microenvironments, and receptor-targeted agents such as pafolacianine. Across prospective studies and multicenter trials, IMI improved localization of nonpalpable lesions, identified occult synchronous malignancies, and enhanced intraoperative margin assessment, frequently altering surgical management. Phase 2 and 3 studies of folate receptor-targeted imaging demonstrated clinically significant findings in a substantial proportion of patients, including lesions not detected by conventional imaging or palpation. However, performance remains dependent on tumor biology, target expression, lesion depth, and optical constraints. Conclusions: IMI represents an emerging transition from anatomy-guided toward biology-informed thoracic surgery by providing real-time molecular information during resection. Current evidence supports its role as a complementary intraoperative technology that augments conventional imaging and surgical techniques, particularly for small, peripheral, and nonpalpable lesions.<\/jats:p>","DOI":"10.3390\/cancers18142220","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T09:46:47Z","timestamp":1783676807000},"page":"2220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intraoperative Molecular Imaging in Thoracic Oncology: Expanding the Observable Disease Space"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2061-243X","authenticated-orcid":false,"given":"Eliana","family":"Marostica","sequence":"first","affiliation":[{"name":"Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2413-7082","authenticated-orcid":false,"given":"Sunil","family":"Singhal","sequence":"additional","affiliation":[{"name":"Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e354","DOI":"10.1016\/S1470-2045(19)30317-1","article-title":"Latest Developments in Molecular Tracers for Fluorescence Image-Guided Cancer Surgery","volume":"20","author":"Hernot","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e186","DOI":"10.1016\/S1470-2045(20)30600-8","article-title":"Real-Time Fluorescence Imaging in Intraoperative Decision Making for Cancer Surgery","volume":"22","author":"Lauwerends","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e468","DOI":"10.1016\/j.jtcvs.2023.02.025","article-title":"ELUCIDATE Study Group Pafolacianine for Intraoperative Molecular Imaging of Cancer in the Lung: The ELUCIDATE Trial","volume":"166","author":"Sarkaria","year":"2023","journal-title":"J. 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