Precision at the Margin: Innovations and Challenges in Intraoperative Molecular Imaging for Thoracic Surgery

Tumor localization during pulmonary surgery has become increasingly challenging with the earlier detection of smaller and smaller lung nodules. Concomitantly, minimally invasive surgical (MIS) techniques have been increasingly adopted within the field of thoracic surgical oncology. Surgeons face growing challenges not only with locating these small tumors, but also with immediate margin assessment, reduced tactile feedback, and nodal assessment. Intraoperative molecular imaging (IMI) has emerged as a promising adjunct to address these challenges by enabling real-time visualization of malignant tissue during pulmonary resection. In its current form, IMI integrates systemically administered, tumor-targeting near-infrared fluorophores with fluorescence-capable imaging platforms to enhance intraoperative decision-making. Early clinical experiences in thoracic surgery suggest particular utility in the localization of small or nonpalpable pulmonary nodules and for improved margin assessment during MIS. Despite encouraging preliminary data, widespread adoption of IMI remains limited by biologic variability in target expression, optical depth constraints, false-positive fluorescence in inflammatory tissue, and challenges in workflow integration. Applications for nodal evaluation, staging, and longer-term oncologic outcome improvement remain investigational. Addressing these multifaceted barriers will be essential for the translation of IMI from a promising, experimental adjunct to a more broadly implementable surgical technology. This work summarizes the current state of IMI in thoracic surgical oncology, highlighting key translational studies, established and emerging clinical applications, and critical limitations within the current landscape. The authors also outline future directions for the field, including quantitative fluorescence interpretation, standardized reporting, and outcomes-driven clinical trials evaluating margin adequacy, recurrence, staging impact, and cost-effectiveness to support widespread evidence-based implementation.