Cell系列综述：北京协和医学院李宁/王书航总结ADC药物在精准癌症治疗中的挑战与创新解决方案

Core Viewpoint - The article discusses the challenges and innovative solutions related to Antibody-drug conjugates (ADCs) in precision cancer therapy, highlighting their potential and limitations in clinical applications [4][22]. Group 1: ADC Overview - ADCs combine the specificity of antibodies with the potency of cytotoxic drugs, aiming to improve cancer treatment by targeting tumor cells while minimizing damage to healthy cells [6][7]. - As of 2024, 15 ADCs have been approved globally, with 12 receiving FDA approval, and over 1000 ADCs are under research, including 268 in clinical trials [8]. Group 2: Mechanism of Action - ADCs specifically bind to tumor-associated antigens on cancer cells, leading to internalization and release of cytotoxic payloads that induce cell death [12]. - The modular structure of ADCs includes an antibody for targeting, a linker for payload delivery, and a cytotoxic agent [10]. Group 3: Challenges in ADC Efficacy - Key challenges affecting ADC efficacy include: - Antibody "streaming" effect, where antibodies bind to normal tissues, reducing drug availability at tumor sites [14]. - Binding site barrier effect, limiting drug penetration into tumors due to high affinity binding near blood vessels [14]. - Tumor heterogeneity, leading to inconsistent antigen expression and variable ADC uptake [14]. - Downregulation of target antigens by tumor cells, affecting binding and internalization [14]. Group 4: Optimization Strategies - Strategies to enhance ADC specificity and reduce off-target toxicity include: - Improving linker stability and reducing toxicity through various responsive linkers [16]. - Utilizing tumor microenvironment (TME) triggers for controlled release of the drug [16]. - Implementing emerging payload strategies like immune-stimulating ADCs (ISAC) and degradation-inducing ADCs (DAC) [18][22]. Group 5: Future Directions - The article emphasizes the need for a deeper understanding of tumor delivery barriers and bridging the gap between preclinical and clinical studies to fully realize the potential of ADCs in precision oncology [22].