Antibody-Drug Conjugates in Breast Cancer: Therapeutic-Window Engineering, Tumor Heterogeneity, and Immunotherapy Combinations

Abstract

Abstract Antibody–drug conjugates (ADCs) have become a major therapeutic class in breast cancer, but their clinical performance cannot be predicted by antigen expression alone. This review uses therapeutic-window engineering as a unifying framework to connect ADC molecular architecture with tumor heterogeneity, clinical positioning, resistance, immune effects, and toxicity. We examine how target selection, antibody properties, linker stability, payload mechanism and membrane permeability, drug-to-antibody ratio (DAR), conjugation homogeneity, and intratumoral delivery jointly determine efficacy and safety. We then distinguish established clinical uses from investigational strategies across HER2-positive, HER2-low/ultralow, hormone receptor-positive/HER2-negative, and triple-negative breast cancer, reflecting the rapid movement of ADCs into earlier treatment lines and selected early-stage settings. Rather than treating ADCs as a homogeneous class, we critically assess how payload class, linker behavior, bystander killing, Fc-mediated activity, and baseline immune context may favor or limit combinations with immune checkpoint inhibitors. We also map resistance along the delivery-to-kill cascade and integrate practical safety considerations, including interstitial lung disease/pneumonitis, hematologic toxicity, ocular events, and overlapping toxicities in combination regimens. Three principles emerge: ADC efficacy is a systems property; strategies that broaden tumor coverage may also increase normal-tissue exposure; and successful combinations require platform-specific rather than class-wide rationale. Future progress will depend on biomarker-guided sequencing, rational platform selection, and safety-adapted optimization of the therapeutic window.