Antibody-drug conjugates: unpacking toxicity profiles and optimized designs for enhanced safety and antitumor efficacy

Antibody-drug conjugates (ADCs) have expanded treatment options across multiple malignancies, but their clinical benefit remains constrained by heterogeneous and sometimes serious toxicities. These toxicities rarely arise from a single component; instead, they reflect the association between target biology, molecular architecture, systemic exposure, and tissue susceptibility. We first examine the structural basis of ADC toxicity by discussing the distinct contributions of the antibody-target axis, linker, payload, drug loading, and conjugation strategy to systemic exposure and tissue toxicity. We distinguish organ-selective "on-target, off-tumor" injury from target-independent toxicity and further characterize two major off-target routes: context-dependent uptake of intact ADCs through Fcγ receptor-mediated or pinocytosis-dominant pathways, and spatially distinct exposure to released payload arising from premature systemic release or localized bystander diffusion. Furthermore, we summarize a multidisciplinary management framework, ranging from prophylactic measures to graded interventions across complex scenarios such as treatment rechallenge and combination therapy. Finally, we discuss strategies to widen the therapeutic window through exposure-response-guided dosing, next-generation molecular engineering, and emerging conjugate platforms. Artificial intelligence and computational approaches may further extend safety optimization from drug design to patient stratification and real-world surveillance. By linking molecular design, spatial exposure, and clinical management, this review provides an integrated framework to improve ADC safety while preserving antitumor efficacy.