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.

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Near-infrared (NIR) cyanine dyes showed enhanced properties for biomedical imaging. A systematic modification within the cyanine skeleton has been made through a facile design and synthetic route for optimal bioimaging. Herein, we report the synthesis of 11 NIR cyanine fluorophores and an investigation of their physicochemical properties, optical characteristics, photostability, and in vivo performance. All synthesized fluorophores absorb and emit within 610–817 nm in various solvents. These dyes also showed high molar extinction coefficients ranging from 27,000 to 270,000 cm–1 M–1, quantum yields 0.01 to 0.33, and molecular brightness 208–79,664 cm–1 M–1 in the tested solvents. Photostability data demonstrate that all tested fluorophores 28, 18, 20, 19, 25, and 24 are more photostable than the FDA-approved indocyanine green. In the biodistribution study, most compounds showed tissue-specific targeting to selectively accumulate in the adrenal glands, lymph nodes, or gallbladder while excreted to the hepatobiliary clearance route. Among the tested, compound 23 showed the best targetability to the bone marrow and lymph nodes. Since the safety of cyanine fluorophores is well established, rationally designed cyanine fluorophores established in the current study will expand an inventory of contrast agents for NIR imaging of not only normal tissues but also cancerous regions originating from these organs/tissues.