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<p>Intraoperative molecular imaging (IMI) has emerged as a valuable tool for the surgical management of non-small cell lung cancer (NSCLC), enabling detection of otherwise imperceptible pulmonary nodules. However, current IMI tracers target tumor-specific receptors that are heterogeneously expressed across different NSCLC subtypes, limiting their universal applicability. This study investigated fibroblast activation protein (FAP), selectively expressed by cancer-associated fibroblasts (CAFs) in the tumor microenvironment but absent in normal lung parenchyma, as a potential universal target for fluorescence-guided surgery in NSCLC patients. We demonstrated that a FAP-targeted near-infrared fluorophore (FAPL-S0456) specifically bound to FAP-expressing fibroblasts in vitro with high affinity (Kd ~ 12.1 × 10⁻⁷ M). In heterotopic flank xenograft models combining NSCLC cells with FAP+ fibroblasts, FAPL-S0456 selectively labeled tumors containing FAP-expressing CAFs with excellent signal-to-background ratios (up to 12.67 ± 4.5), while showing no uptake in tumors with FAP-negative fibroblasts or cancer cells alone. These findings were replicated in orthotopic pulmonary xenograft models, where FAPL-S0456 precisely identified FAP+/αSMA+ regions within tumors. Biodistribution studies confirmed no fluorescence in normal lung tissue, with renal clearance as the primary excretion pathway. FAPL-S0456 demonstrates high specificity for FAP-expressing CAFs within the NSCLC tumor microenvironment, with negligible binding to normal tissues. This approach offers a potential universal strategy for fluorescence-guided surgery in NSCLC patients, regardless of tumor histological subtype, by targeting the stromal component rather than heterogeneously expressed tumor cell receptors. The ability to visualize CAF-rich regions may enhance complete surgical resection and potentially improve outcomes for NSCLC patients. FAP targeted labeling of CAFs during intraoperative molecular imaging allows for accurate localization and resection of lung nodules during curative resection.</p>

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Fibroblast activation protein-targeted near-infrared labeling of cancer-associated fibroblasts in a non-small-cell lung cancer tumor microenvironment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月12日

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  • Feredun Azari,
  • Gregory T. Kennedy,
  • Ian Folkert,
  • Gregory Jones,
  • Ashley Chang,
  • Bilal Nadeem,
  • Austin B. Chang,
  • Andrew Conner,
  • Neil T. Sullivan,
  • Sunil Singhal

摘要

Intraoperative molecular imaging (IMI) has emerged as a valuable tool for the surgical management of non-small cell lung cancer (NSCLC), enabling detection of otherwise imperceptible pulmonary nodules. However, current IMI tracers target tumor-specific receptors that are heterogeneously expressed across different NSCLC subtypes, limiting their universal applicability. This study investigated fibroblast activation protein (FAP), selectively expressed by cancer-associated fibroblasts (CAFs) in the tumor microenvironment but absent in normal lung parenchyma, as a potential universal target for fluorescence-guided surgery in NSCLC patients. We demonstrated that a FAP-targeted near-infrared fluorophore (FAPL-S0456) specifically bound to FAP-expressing fibroblasts in vitro with high affinity (Kd ~ 12.1 × 10⁻⁷ M). In heterotopic flank xenograft models combining NSCLC cells with FAP+ fibroblasts, FAPL-S0456 selectively labeled tumors containing FAP-expressing CAFs with excellent signal-to-background ratios (up to 12.67 ± 4.5), while showing no uptake in tumors with FAP-negative fibroblasts or cancer cells alone. These findings were replicated in orthotopic pulmonary xenograft models, where FAPL-S0456 precisely identified FAP+/αSMA+ regions within tumors. Biodistribution studies confirmed no fluorescence in normal lung tissue, with renal clearance as the primary excretion pathway. FAPL-S0456 demonstrates high specificity for FAP-expressing CAFs within the NSCLC tumor microenvironment, with negligible binding to normal tissues. This approach offers a potential universal strategy for fluorescence-guided surgery in NSCLC patients, regardless of tumor histological subtype, by targeting the stromal component rather than heterogeneously expressed tumor cell receptors. The ability to visualize CAF-rich regions may enhance complete surgical resection and potentially improve outcomes for NSCLC patients. FAP targeted labeling of CAFs during intraoperative molecular imaging allows for accurate localization and resection of lung nodules during curative resection.