Antibody-drug conjugates and tumor immunity in breast cancer

Antibody-drug conjugates (ADCs) combine antigen-directed delivery with cytotoxic or immunostimulatory payloads. Their antitumor activity can involve direct tumor-cell killing, but the extent to which conventional ADCs remodel human breast-cancer immunity remains incompletely defined. This review critically separates established cytotoxic mechanisms from immune-mediated effects and incorporates emerging STING agonist ADCs, neonatal Fc receptor (FcRn) trafficking, and quantitative antigen measurement. A focused narrative synthesis of mechanistic, translational, and clinical literature was performed, emphasizing primary studies of HER2-, TROP2-, and HER3-directed ADCs and tumor-targeted STING agonist conjugates. Peer-reviewed studies were prioritized; congress abstracts and non-peer-reviewed sources were used only when specifically requested or when no full report was available. Evidence was classified as preclinical, translational, or clinical, and causal claims were restricted accordingly. Conventional ADCs first produce antigen-dependent internalization, intracellular payload release, and direct cytotoxicity. Bystander killing can extend cytotoxic exposure beyond antigen-high cells. In selected preclinical systems, payload-induced stress or DNA damage can generate immunogenic-cell-death signals, engage cGAS-STING signaling, preserve Fcγ receptor-dependent effector functions, and support antigen presentation. These effects are platform- and context-dependent and are not uniformly demonstrated in patients. By contrast, STING agonist ADCs and immune-stimulating antibody conjugates are designed to deliver an innate agonist to antigen-bearing tumors and can activate STING in tumor and myeloid compartments in mouse models; their clinical value in breast cancer remains investigational. FcRn primarily rescues pinocytosed IgG in acidic endosomes and governs exposure and tissue disposition; wild-type IgG uptake at neutral pH is predominantly fluid-phase, whereas residual neutral-pH FcRn binding in engineered variants may increase uptake when FcRn is abundant. Current HER2 and TROP2 immunohistochemistry does not quantify accessible membrane antigen, internalization, or immune contribution with sufficient precision. Quantitative continuous scoring and membrane-localization metrics are promising but require prospective, breast-cancer-specific validation. ADC efficacy should not be interpreted as proof of immune activation. A rigorous framework must measure antigen abundance and localization, ADC delivery and trafficking, payload pharmacology, and serial immune changes, while separately evaluating target-independent toxicity. Mechanism-linked sampling and prospective validation are required before immune biomarkers, FcRn-related variables, or quantitative antigen metrics can guide routine ADC selection.