EGFR-targeted Near-Infrared Photoimmunotherapy for EGFR-expressing advanced solid tumors: A scoping review of barriers and enablers to clinical translation

Abstract Background Epidermal growth factor receptor (EGFR)-targeted near-infrared photoimmunotherapy (NIR-PIT) is an emerging drug-device modality that enables spatially selective tumor cell killing through antibody-photoabsorber conjugation and localized light activation. Although clinical translation has advanced in selected settings, particularly head and neck squamous cell carcinoma (HNSCC), barriers and enablers influencing broader implementation across solid tumors have not been systematically mapped. This review focuses specifically on the IR700 (IRDye700DX)-based conjugate cetuximab sarotalocan (RM-1929/ASP-1929), which is the only NIR-PIT construct to have advanced into clinical use, while acknowledging the broader and rapidly expanding photoimmunotherapy landscape. Objective To synthesize and characterize the biological, technical, clinical, and system-level factors that facilitate or hinder the clinical translation of EGFR-targeted NIR-PIT across EGFR-expressing advanced solid tumors. Methods A scoping review was conducted in accordance with PRISMA-ScR guidelines. Comprehensive searches of PubMed, Embase, Scopus, ClinicalTrials.gov, and the Cochrane Library identified 28 eligible studies, including preclinical investigations, early-phase clinical trials, observational studies, and case reports or series. Data were charted and synthesized thematically, with study quality appraised to inform interpretation. Results Preclinical studies consistently demonstrated light-dependent, EGFR-selective cytotoxicity and identified non-linear dose–response relationships that support standardized light dosing strategies. Clinical translation has been most successful in recurrent or unresectable HNSCC, facilitated by tumor accessibility, multidisciplinary workflows, and regulatory approval in Japan. Technical enablers included endoscopic and navigation-assisted light delivery, real-time fluorescence imaging, and the feasibility of repeat treatment without cumulative toxicity. Key barriers included limited light penetration, anatomical constraints, reliance on specialized equipment, and restricted applicability to deep-seated or diffuse disease. Although most adverse events were localized and manageable, rare but serious complications reported across multiple case studies represent an important translational challenge. Evidence outside HNSCC remains sparse and is largely confined to preclinical models. Conclusions EGFR-targeted NIR-PIT has achieved meaningful clinical translation within a narrow but well-defined therapeutic niche, supported by strong mechanistic rationale and growing real-world experience. Broader adoption is constrained by biological, technical, regulatory and system-level barriers, as well as gaps in comparative effectiveness, long-term outcomes, and health-economic evidence. Addressing these challenges through targeted clinical trials, improved patient selection, and implementation-focused research will be essential to advance NIR-PIT toward wider clinical integration.