Clinical toxicity of ADCs and ICI-ADC combinations: mechanisms, patterns and management

Antibody-drug conjugates (ADCs) and immune checkpoint inhibitors (ICIs) have reshaped cancer therapy both as monotherapy and in combination. However, these drug classes have toxicity profiles that, despite arising from different biological mechanisms, often converge on the same organs. Given that ICI-ADC combinations are moving into earlier lines of treatment, including curative-intent settings, clinicians increasingly face overlapping pulmonary, hepatic, gastrointestinal and cutaneous adverse events with uncertain attribution, and the management of toxicities during the acute event and subsequent treatment resumption and the management of rechallenge after toxicity resolution remain variable. In this Review, we propose a unified, mechanism-informed framework that links three interacting layers: immune activation, payload cytotoxicity and payload-independent effects (from target, platform and host-related determinants). We compare organ-level patterns across major payload classes, highlight consistent organ signatures and provide practical algorithms for evaluation, initial management and treatment resumption in patients receiving ADC monotherapy or ICI-ADC combinations. Finally, we propose minimum reporting standards to harmonize toxicity phenotyping and enable cross-trial comparisons, biomarker discovery and the development of safer regimens.