Antibody–Drug Conjugates Emerge as Immune Modulators, Not Just Targeted Chemotherapy

Antibody–drug conjugates, once regarded simply as guided missiles that ferry potent chemotherapy to tumour cells, are being reinterpreted as far more versatile agents. A comprehensive review published in Nature Reviews Clinical Oncology by Paola Zagami, Giuseppe Curigliano and colleagues argues that the clinical activity of these drugs extends well beyond direct cytotoxicity, encompassing a coordinated spectrum of immunomodulatory effects. According to the authors, these effects arise from the interplay between antibody-driven Fc-mediated functions and payload-induced cellular stress, and they collectively reshape the tumour microenvironment in ways that can be exploited therapeutically. The reframing matters because it changes how clinicians and drug developers think about combination strategies, biomarker selection and the design of next-generation molecules.

The structural logic of an antibody–drug conjugate explains why its immunological reach is broad. Each molecule combines a monoclonal antibody that recognises a tumour-associated antigen, a cleavable or non-cleavable linker and a cytotoxic payload, typically a tubulin-disrupting agent or a DNA-damaging topoisomerase I inhibitor. When the conjugate binds its target and is internalised, the payload is released inside the cancer cell. But the story does not end there. Many payloads, particularly those with membrane-permeable chemistry, diffuse out of the killed cell and kill neighbouring tumour cells regardless of antigen expression, a phenomenon known as bystander killing. That same permeability allows released drug to affect stromal and immune cells within the tumour, setting the stage for immune consequences that were largely unappreciated in the earliest clinical studies.

Central to the new paradigm is the concept of immunogenic cell death. Unlike silent apoptosis, immunogenic cell death releases damage-associated molecular patterns and tumour-associated antigens in a context that alerts the immune system. Preclinical work summarised in the review shows that maytansine-bearing conjugates induce hallmarks of immunogenic cell death selectively in antigen-positive cells, that brentuximab vedotin-driven microtubule disruption triggers endoplasmic reticulum stress leading to immunogenic cell death, and that trastuzumab deruxtecan activates the cGAS-STING pathway in gastric cancer models, upregulating HLA class I molecules and the chemokines CXCL9, CXCL10 and CXCL11. Datopotamab deruxtecan has likewise been shown to induce hallmarks of immunogenic cell death. The released antigens can then be taken up by dendritic cells, which mature and cross-present them to T cells, seeding a sustained adaptive antitumour response.

The antibody component contributes its own immunological layer. Fc-mediated functions such as antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis recruit natural killer cells and macrophages to destroy antibody-coated tumour cells. Tumour-associated macrophages can, in fact, contribute to antitumour activity through Fcγ receptor-mediated processing of antibody–drug conjugates, effectively acting as payload-delivery and antigen-release amplifiers. The choice of IgG subclass, glycosylation pattern and Fc engineering therefore has functional consequences: afucosylated antibodies augment CD16-mediated serial killing and interferon-γ secretion by natural killer cells, while Fc-silencing platforms can be used when effector engagement is undesirable. These design decisions determine whether a given conjugate behaves as a silent cytotoxic or as an active recruiter of innate immunity.

This biological foundation underpins the explosive clinical interest in combining antibody–drug conjugates with immune checkpoint inhibitors. The rationale is complementary: the conjugate converts an immunologically cold tumour into an inflamed one by releasing antigens and provoking dendritic cell activation, while checkpoint blockade removes the brakes on the T cells that are thereby primed. The most striking validation has come in urothelial cancer, where the combination of enfortumab vedotin with pembrolizumab produced practice-changing survival benefits in previously untreated metastatic disease, reshaping first-line standards of care. Perioperative studies of the same pairing have now reported positive results in bladder cancer, extending the strategy into earlier disease settings.

However, the review is careful to note that efficacy is not universal. In HER2-positive breast cancer, the phase 2 KATE2 trial of trastuzumab emtansine with atezolizumab did not meet its primary endpoint, and the phase 3 ASTEFANIA adjuvant trial of the same combination has not established the pairing in residual disease. By contrast, datopotamab deruxtecan plus durvalumab has shown encouraging activity in triple-negative breast cancer in the BEGONIA platform trial, including in first-line disease, and sacituzumab govitecan plus pembrolizumab outperformed chemotherapy plus pembrolizumab in PD-L1-positive metastatic triple-negative breast cancer in the randomised phase 3 ASCENT-04 study. Biomarker analyses from ASCENT-04 are now being used to understand which patients benefit, and the authors emphasise that biomarker-informed development will probably be required to avoid empiric, one-size-fits-all combination strategies.

Lung, gastric and other tumour types are also being tested. Trastuzumab deruxtecan has been combined with nivolumab and with pembrolizumab in phase 1b studies of HER2-expressing breast and urothelial cancers, and datopotamab deruxtecan plus pembrolizumab with or without platinum chemotherapy has been evaluated in first-line non-small cell lung cancer in the TROPION-Lung02 trial. In gastric and gastroesophageal cancers, DESTINY-Gastric03 is exploring trastuzumab deruxtecan-based doublets and triplets including pembrolizumab. Disitamab vedotin plus toripalimab has produced positive phase 3 results in HER2-expressing urothelial cancer, and tisotumab vedotin combinations are under study in cervical cancer. The breadth of these programmes reflects a shared hypothesis: that payload-driven immune priming can convert checkpoint-refractory or checkpoint-naive tumours into responsive ones.

The next generation of conjugate design is shifting explicitly towards immune-oriented engineering. Bispecific constructs that bind two antigens, such as the EGFR–HER3 bispecific antibody–drug conjugate BL-B01D1 and izalontamab brengitecan, have shown clinical activity and, in some settings, phase 3 superiority over chemotherapy. Dual-targeting designs can also improve lysosomal trafficking and payload delivery, as demonstrated by conjugates targeting HER2 together with CD63. Immune-stimulating antibody conjugates represent another frontier: molecules such as BDC-1001, which couples a HER2-directed antibody to TLR7/8 agonists, and XMT-2056, a STING-agonist conjugate, are designed to deliver innate immune activation directly to the tumour. Probody technology, in which the antibody is masked until cleaved by tumour proteases, aims to widen the therapeutic window, and high-avidity, low-affinity antibody engineering can auto-tune delivery across heterogeneous antigen expression.

Targeting the tumour microenvironment itself is emerging as a complementary strategy. Conjugates directed at fibroblast activation protein can deplete cancer-associated fibroblasts that maintain an immunosuppressive stroma, while agents targeting B7-H3, B7-H4 and even PD-L1 itself repurpose immune checkpoint molecules as delivery portals, potentially killing checkpoint-ligand-expressing cells and simultaneously relieving immunosuppression. Novel payload classes are also in play, including splicing modulators with intrinsic immune-stimulatory properties and immunosuppressive payloads that could theoretically be used to dampen harmful inflammation. The review also highlights TCR-mimic antibody–drug conjugates capable of targeting intracellular oncoproteins such as WT1 and MART-1 through peptide–MHC complexes, dramatically expanding the pool of druggable targets beyond surface antigens.

Safety considerations temper the enthusiasm. The same immune mechanisms that enhance efficacy can contribute to toxicity, and the interstitial pneumonitis associated with trastuzumab deruxtecan has been linked in preclinical work to perivascular niche–resident alveolar macrophages, suggesting an immune-mediated component. Fcγ receptor-dependent internalisation of conjugate aggregates can drive off-target cytotoxicity, and immune complex clearance mechanisms help explain some adverse events. A companion review in the same journal addresses the clinical toxicity of antibody–drug conjugates and their combinations with checkpoint inhibitors. The overall message from the Milan-based and Chapel Hill-based team is that antibody–drug conjugates should no longer be viewed merely as targeted cytotoxics but as modulators of tumour–immune interactions, a repositioning that will shape monotherapy use, combination regimens and drug design for years to come.

Subject of Research: Immunological mechanisms of action of antibody–drug conjugates and their combination with immune checkpoint inhibitors in cancer therapy

Article Title: Exploring the immunological effects of antibody–drug conjugates

Article References: Zagami, P., Trapani, D., Marra, A., Carey, L. A., & Curigliano, G. (2026). Exploring the immunological effects of antibody–drug conjugates. Nature Reviews Clinical Oncology. https://doi.org/10.1038/s41571-026-01209-z

Image Credits: AI Generated

DOI: 10.1038/s41571-026-01209-z

Keywords: antibody–drug conjugates, immunogenic cell death, immune checkpoint inhibitors, tumour microenvironment, dendritic cells, antibody-dependent cellular cytotoxicity, trastuzumab deruxtecan, enfortumab vedotin, bispecific antibodies, cGAS-STING pathway, breast cancer, urothelial cancer