The evolution of “magic bullets”: precision guidance, clinical challenges, and efficacy enhancement of antibody-drug conjugates in solid tumors

Abstract Antibody-drug conjugates (ADCs) are targeted therapeutic agents formed by covalently linking monoclonal antibodies to potent cytotoxic drugs via chemical linkers. They achieve targeted delivery of cytotoxic drugs through the antibody’s specific recognition of tumor surface antigens, enhancing antitumor activity while significantly reducing systemic toxicity. They are hailed as “biological missiles.” In recent years, with the advancement of ADCs, they have demonstrated remarkable efficacy in multiple clinical studies for solid tumors such as breast cancer, lung cancer, and urothelial carcinoma. They are progressively becoming an integral part of standard treatment regimens for various advanced cancers. However, the clinical application of ADCs still faces numerous challenges, including therapeutic variability due to heterogeneous expression of target antigens, the gradual emergence of resistance mechanisms (such as target downregulation, lysosomal dysfunction, and activation of drug efflux pumps), and unique toxicity profiles (such as ocular toxicity and hematologic toxicity). Furthermore, the therapeutic window for ADCs remains relatively narrow, and significant inter-individual pharmacokinetic variability further limits their widespread adoption. This review systematically elucidates the mechanisms of action and structural basis of ADCs, summarizes their clinical practice and evolving indications in solid tumors, analyzes the mechanisms and management strategies for common and specific adverse events, and thoroughly explores the molecular pathways underlying resistance development and corresponding countermeasures. This review further focuses on the technological development directions of the new generation of ADCs, including targeted conjugation strategies, the development of novel linker-payload systems, the construction of bispecific ADCs, and advances in combination therapies involving ADCs with immunotherapy and targeted drugs in order to provide new insights for overcoming existing clinical bottlenecks.