Antibody-drug conjugates in oncology: A spotlight on overcoming resistance.

Antibody-drug conjugates (ADCs), which combine precise monoclonal antibodies with cytotoxic payloads, represent a transformative class of anticancer therapeutics. Despite their clinical success, resistance mechanisms significantly limit their therapeutic utility. This review systematically summarizes the multifaceted mechanisms underlying ADC resistance, including antibody-related factors, aberrant intracellular trafficking, payload-related factors, and dysregulated survival signaling. We further evaluated strategies to overcome resistance, including third-generation ADCs, novel payloads, and multimodal combination therapies. By integrating preclinical insights and clinical advancements, this review provides a theoretical framework for optimizing ADC efficacy and overcoming therapeutic resistance in oncology.