Harnessing biosynthetic logic for next-generation ADC payloads.

Antibody-drug conjugates (ADCs) have revolutionized oncology by linking the precise targeting of monoclonal antibodies with the ultrapotent activity of small-molecule payloads. Despite rapid advances in antibody and linker engineering, the field continues to rely on a narrow set of natural product-derived payloads, which limits mechanistic diversity and may contribute to cross-resistance and restricted tumor coverage. Recent breakthroughs in genome mining and synthetic biology are now reshaping this landscape by revealing the biosynthetic gene clusters and enzymatic logic underlying clinically used payloads, thereby offering new avenues for innovation. This review summarizes recent advances in the discovery, biosynthesis, and manufacturing of clinical payloads, with a focus on their biogenetic origins, enzymatic assembly, and strategies for scalable production. We further consider harnessing biosynthetic knowledge to expand the accessible chemical space of payloads and discuss emerging non-toxin modalities that may complement conventional cytotoxins. These insights provide a roadmap for diversifying and optimizing ADC payloads toward safer, more effective, and mechanistically sophisticated therapies.