Antibody–drug conjugates and tumor immunity in breast cancer

A focused narrative review of antibody–drug conjugates (ADCs) concludes that their ability to reshape human breast-cancer immunity remains incompletely defined, even though their direct cytotoxic activity is well established. The synthesis emphasizes primary studies involving HER2-, TROP2- and HER3-directed ADCs, as well as tumor-targeted STING agonist conjugates, while separating preclinical, translational and clinical evidence. Conventional ADCs generally bind a tumor antigen, enter the cell, release a cytotoxic or immunostimulatory payload and directly damage antigen-bearing cells.

A response to an ADC therefore cannot by itself be treated as proof that tumor immunity has been activated. The most clearly established mechanism is antigen-dependent delivery. After binding its target, an ADC is internalized and trafficked intracellularly, where processing enables payload release.

Released cytotoxic agents can kill directly targeted cells, while bystander killing can extend exposure to neighboring tumor cells that may have lower antigen expression. This effect broadens cytotoxic activity, but it does not distinguish the contribution of direct damage from that of systemic or local immune responses. The review also finds that payload-induced stress or DNA damage can generate immunogenic-cell-death signals in selected preclinical systems, engage the cGAS–STING pathway, preserve Fcγ receptor-dependent effector functions and support antigen presentation.

These observations remain platform- and context-dependent and have not been uniformly demonstrated in patients. STING agonist ADCs represent a different design. Rather than relying only on a payload that kills tumor cells, these agents are intended to deliver an innate immune agonist to antigen-bearing tumors.

In mouse models, tumor-targeted STING conjugates activated STING signaling in tumor and myeloid compartments, showing that localized innate immune stimulation is possible. Their clinical value in breast cancer, however, remains investigational. Evidence for immune remodeling is strongest as a mechanistic or model-based observation, not as a demonstrated explanation for human treatment responses.

Antibody trafficking adds another layer of complexity. The neonatal Fc receptor, FcRn, rescues IgG that is pinocytosed into acidic endosomes and consequently influences antibody exposure and tissue disposition. Wild-type IgG uptake at neutral pH is predominantly fluid-phase, while engineered variants with residual neutral-pH FcRn binding may increase uptake in environments where FcRn is abundant.

For ADC biology, uptake, intracellular routing and delivery to the appropriate compartment are integral to payload action. The review treats FcRn-related variables as potentially informative, but not yet established as determinants of routine ADC selection. Current biomarker practice also leaves important questions unresolved.

HER2 and TROP2 immunohistochemistry can document the presence of a target, but it does not quantify accessible membrane antigen with enough precision to establish receptor abundance, internalization, ADC delivery or the immune contribution to efficacy. Quantitative continuous scoring and membrane-localization measurements are described as promising, but they require prospective, breast-cancer-specific validation. A rigorous assessment must separately characterize antigen abundance and localization, ADC delivery and trafficking, payload pharmacology and serial immune changes, while also evaluating target-independent toxicity.

Until mechanism-linked sampling and prospective studies establish these relationships, ADC efficacy should not be interpreted as evidence of immune activation, and neither FcRn variables nor quantitative antigen metrics are sufficiently validated to guide routine ADC selection.

Subject of Research: Mechanisms and immune effects of antibody–drug conjugates in breast cancer

Article Title: Antibody–drug conjugates and tumor immunity in breast cancer

Article References: Kashiwagi, S. (2026). Antibody–drug conjugates and tumor immunity in breast cancer. Medical Oncology, 43(11), Article 345. https://doi.org/10.1007/s12032-026-03458-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03458-5

Keywords: antibody–drug conjugates, breast cancer, tumor immunity, HER2, TROP2, HER3, STING signaling, FcRn, immunogenic cell death, ADC biomarkers, Antibody, drug