Click chemistry-driven tumor theranostics: recent advances, challenges, and future perspectives

Tumor theranostics, which integrates accurate diagnosis and precise therapy, has emerged as a pivotal approach in modern oncology for improving treatment efficacy and reducing off-target toxicity. Click chemistry, which is characterized by high efficiency, selectivity, biocompatibility, and modularity, has become an indispensable tool for constructing versatile theranostic systems. This review systematically summarizes the recent progress in click chemistry-based tumor theranostic systems, starting with an overview of core click reactions and the unique features in biomedical applications. We then focus on the application of click chemistry within a diagnosis-therapy-theranostics framework to three key aspects of tumor theranostics: (ⅰ) tumor diagnosis (molecular imaging probes and circulating tumor cell detection); (ⅱ) tumor therapy (chemotherapy, phototherapy, immunotherapy, and gene therapy); and (ⅲ) integrated theranostics (multimodal imaging-guided combinatorial therapy). Furthermore, the current challenges, such as the biocompatibility of catalysts and in vivo reaction efficiency, are critically discussed. Finally, we highlight promising directions, including stimuli-responsive click reactions, AI-assisted probe design, and personalized theranostic systems. This review not only serves as a comprehensive reference for researchers but also highlights how click chemistry uniquely bridges molecular design with clinical functionality, distinguishing click chemistry from conventional conjugation or labeling methods by enabling spatiotemporal control, modular integration, and bioorthogonal precision in complex biological settings.