Antibody-drug conjugates (ADCs) are at the forefront of next-generation targeted cancer therapies, owing to their high specificity and potent cytotoxicity. The linker within ADCs plays a critical role in balancing efficacy and safety. Cleavable peptide linkers, dominating clinical-stage ADC design due to their capacity for selective drug release, nonetheless face challenges such as structural homogeneity, limited mouse plasma stability, and insufficient hydrophobicity improvement. Consequently, developing novel peptide linkers with enhanced stability, selectivity, and physicochemical properties is a key research focus. Here, by highlighting the cleavable peptide linkers used in clinical-stage ADCs and summarizing novel strategies in next-generation linker designs, we provide a timely overview of advances in peptide linkers, covering new peptide or peptidomimetic sequences, exolinker strategies, dual-cascade triggering mechanisms, and hydrophilic modifications. This review aims to offer a theoretical foundation and research insights for innovative linker design, thereby advancing next-generation ADCs to meet the growing demand for precision therapies.
Li et al. (2025) studied this question.