The ADC-driven development paradigm and evolution into XDC: Current landscape and future trends

Conventional antibody–drug conjugates (ADCs) serve as promising targeted delivery systems that harnesses monoclonal antibodies to selectively deliver potent cytotoxic agents to tumor cells. However, clinical translation remains hindered by key challenges, including tumor heterogeneity, drug resistance, on-target off-tumor toxicity, and manufacturing complexity. To address these limitations, the field has evolved beyond classical ADC designs toward a diverse array of novel conjugates (XDCs). On the targeting side, extensive exploration of various carrier moieties (X) and bispecific strategies aims to overcome tumor heterogeneity and reduce off-tumor toxicity. On the payload side, beyond cytotoxic agents with distinct mechanisms, alternative payload formats, such as degraders, immune stimulators, and oligonucleotides, are being increasingly applied to further lower dose-limiting toxicities. These advances have given rise to platforms including bispecific ADCs, dual-payload ADCs, immune-stimulating antibody conjugates, degrader-antibody conjugates, antibody–oligonucleotide conjugates, peptide–drug conjugates, aptamer–drug conjugates, small molecule–drug conjugates, cell–drug conjugates, and virus-like drug conjugates. Leveraging their unique features, these architectures hold promise for improved therapeutic efficacy. This review highlights recent progress in XDCs design strategies and offers perspectives on future directions for next-generation targeted cancer therapies.