Tumor-Associated Immune-Cell-Mediated Tumor-Targeting Mechanism with NIR-II Fluorescence Imaging.

The strategy of structure-inherent tumor targeting (SITT) with cyanine-based fluorophores is receiving more attention because no chemical conjugation of targeting moieties is required. However, the targeting mechanism behind SITT has not yet been well explained. Here, it is demonstrated that heptamethine-cyanine-based fluorophores possess not only targetability of tumor microenvironments without the need for additional targeting ligands but also second near-infrared spectral window (NIR-II) imaging capabilities, i.e., minimum scattering and ultralow autofluorescence. The new SITT mechanism suggests that bone-marrow-derived and/or tissue-resident/tumor-associated immune cells can be a principal target for cancer detection due to their abundance in tumoral tissues. Among the tested, SH1 provides ubiquitous tumor targetability and a high tumor-to-background ratio (TBR) ranging from 9.5 to 47 in pancreatic, breast, and lung cancer mouse models upon a single bolus intravenous injection. Furthermore, SH1 can be used to detect small cancerous tissues smaller than 2 mm in diameter in orthotopic lung cancer models. Thus, SH1 could be a promising cancer-targeting agent and have a bright future for intraoperative optical imaging and image-guided cancer surgery.