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Antibody-drug conjugates (ADCs), which couple monoclonal antibodies to cytotoxic drugs via covalent linkers, have emerged as powerful targeted cancer therapies, with over a dozen ADCs clinically approved globally and hundreds more in development. Nevertheless, ADCs face intrinsic limitations that constrain their broader therapeutic potential. Because ADC 'payloads' (the therapeutic compounds) are directly attached to the side chains of the monoclonal antibody via short linkers, the types of payload and linker strongly influence ADC physical properties, which has many downstream consequences. For example, the drug-to-antibody ratio (DAR, the number of drug molecules per antibody) is typically capped at ≤8 to preserve stability, solubility and pharmacokinetics. This restriction necessitates the use of very potent cytotoxic payloads (with a half-maximal inhibitory concentration (IC, the concentration required to inhibit a biological activity by 50%) of < ~10 nM), with limited mechanisms of action. These narrow payload options contribute to dose-limiting toxicities, acquired resistance and limited flexibility to explore more-selective or synergistic therapeutic modalities.