Radiotherapy-Conditioned Antibody–Drug Conjugate Activity: Molecular Mechanisms, Therapeutic Windows and Organ-Specific Toxicity

Antibody–drug conjugate (ADC) activity depends on accessible targets, tissue distribution, payload release, cellular susceptibility, and host immunity. Radiotherapy (RT) can modify these determinants, creating a time- and tissue-dependent radiation-conditioned ADC state. This critical narrative review integrates mechanistic and clinical evidence, distinguishing intact ADC–RT experiments from studies of isolated components, ADCs without RT, and engineered platforms. Direct preclinical studies support selected target-conditioning, payload, and immune interactions, but do not establish a class-wide effect. We organize the evidence into four overlapping, potentially competing biological windows: targeting, radiosensitization, immune priming, and normal-tissue injury. The framework links mechanisms to schedule comparisons, measurements, and organ-specific constraints. Delivery-mediated interactions require altered exposure; response-mediated effects may occur at comparable exposure. Clinical evidence is predominantly observational and heterogeneous in the drug, irradiated site, fractionation, overlap, and follow-up. Feasibility reports involving trastuzumab deruxtecan and the association between trastuzumab emtansine and radionecrosis after stereotactic radiosurgery require a separate interpretation. Biological susceptibility also differs from later injury detection. Prospective studies should compare durable tumor control, treatment continuity, and acute and delayed toxicity, using selected mechanistic substudies. The framework is hypothesis-generating and does not establish a universal treatment sequence.