Molecular-Targeted Fluorescence Guided Surgery in Head and Neck Oncology

Head and neck squamous cell carcinoma (HNSCC) management remains a clinical challenge due to high recurrence rates and persistent difficulties in achieving clear surgical margins. Molecular-targeted fluorescence-guided surgery (FGS) offers a promising solution by enabling real-time visualization of tumor boundaries and critical functional structures. This review synthesizes current evidence on key molecular targets for FGS in HNSCC, including CD44v6, αVβ6 integrin, uPAR, PARP1, and EGFR, as well as emerging strategies for nerve preservation. EGFR-directed probes, such as cetuximab-IRDye800 and panitumumab-IRDye800, demonstrate strong clinical performance for margin and metastatic lymph node assessment, while alternative targets provide complementary advantages for invasive fronts and peripheral tumor regions. Advances in dye chemistry, including near-infrared II fluorophores and small-molecule tracers, address limitations in penetration depth and preoperative logistics. Additionally, nerve-specific agents like ALM-488 (Bevonescein) extend FGS utility to functional preservation. Despite encouraging results, challenges remain in optimizing probe pharmacokinetics, imaging depth, and multispectral integration. Future research should prioritize pragmatic tracer design, standardized imaging protocols, and patient-centered outcomes to enable widespread clinical adoption. Molecular-targeted FGS represents a transformative approach to improving oncologic control and quality of life outcomes in head and neck cancer surgery.