Recent advances in functional activatable probes for oncological surgery: Illuminating precision or hindering clinical translation?

Fluorescence-guided surgery has advanced significantly by developing activatable probes that selectively illuminate tumors by responding to microenvironmental biomarkers, minimizing background noise, and improving tumor-to-normal ratios. Unlike conventional “Always-on” probes, activatable designs leverage tumor-specific triggers—such as enzymatic activity, acidic pH, hypoxia, or redox imbalances—to achieve precise fluorescence unmasking. Recent innovations include single-stimuli probes with rapid activation kinetics for real-time intraoperative imaging and multi-stimuli systems to enhance specificity. Targeted strategies for integrating ligands for folate receptors, integrins, or PSMA further improve tumor accumulation. Despite preclinical success, clinical translation remains limited. The field now prioritizes interdisciplinary collaboration to address probe stability, safety, and reproducibility challenges, aiming to bridge the gap between molecular innovation and surgical practicality. By harmonizing probe design with clinical needs, activatable fluorescence imaging promises to redefine precision in oncological surgery, though scalability demands concerted efforts in probe rational design and technology integration.