“…Fluorescence imaging-guided surgery (FGS) provides a new solution for precise resection of solid tumors due to its advantages of immediacy, high resolution, high specificity, and low cost compared with traditional clinical imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasonography (US), etc. − Fluorescent probes are mainly categorized into targeted imaging probes and activated imaging probes . For targeted imaging probes, the basis of their design cannot be separated from the markers that are highly expressed in the lesion, such as integrins, epidermal growth factor receptor, vascular endothelial growth factor receptor, folate receptor, and so on. − Activatable imaging probes, also known as “turn-on” probes, can be activated by chemical reactions with enzymes highly expressed in the tumor microenvironment or other conditions that turn on fluorescence and contrast with normal tissue, − such as CB enzyme, MMP-2 enzyme, and other things. − All of these targeted imaging probes and activated imaging probes have achieved good results in FGS, and a number of probes have even entered clinical trials, but their use is subject to certain prerequisites; i.e., the tumor needs to be highly expressive of a specific protein or enzyme. − However, many proteins or enzymes are not fully highly expressed in pan-cancer; for example, integrins are only 50% expressed in breast cancer, and the expression of folate receptor α in endometrial cancers is 20–50%, which means that there is currently no specific protein or enzyme that can be employed as a universal biomarker of fluorescent probes for pan-cancer surgical navigation. In short, the heterogeneity of pan-cancer hinders the clinical application of fluorescent probes, which forebodes that developing a universal fluorescent probe remains a challenge.…”