Antibody–drug conjugates amplify cancer immunotherapy in selected solid tumors

Antibody–drug conjugates combined with immune checkpoint inhibitors have produced significant clinical gains in several solid tumors, according to a review of basic, translational and clinical evidence published in Frontiers in Oncology. The combination is not uniformly effective, however: results vary with cancer type, molecular subtype, treatment setting, antigen target, cytotoxic payload and prior therapy. Randomized phase III trials have shown prolonged progression-free and overall survival in advanced urothelial carcinoma, while smaller or more recent studies have produced mixed results in breast, lung, gastric, head and neck and uterine cancers. The review concludes that the approach has moved beyond an experimental concept, but its optimal use requires sharper patient selection, safer combinations and more consistent dosing.

An antibody–drug conjugate, or ADC, has three functional components: a monoclonal antibody that recognizes a target on tumor cells, a linker and a cytotoxic payload. After binding and internalization, the linker releases the payload, which kills the target cell. Cleavable linkers can also generate a bystander effect, allowing some released drug to diffuse from antigen-positive tumor cells into neighboring cells with low or absent target expression. This can help address antigen heterogeneity, but freely diffused payload may also damage immune cells and normal tissue. ADCs have demonstrated antitumor activity as single agents, yet antigen loss, antigen downregulation and acquired resistance can limit sustained disease control.

The central rationale for pairing ADCs with immunotherapy lies in a bidirectional relationship between the drugs and the tumor microenvironment. Certain payloads trigger immunogenic cell death, an orderly process that exposes and releases damage-associated molecular patterns. Calreticulin, protein disulfide isomerase A3 and heat-shock proteins move to the tumor-cell surface and facilitate antigen capture by dendritic cells. Released ATP recruits monocyte and macrophage precursors through P2RY2 and activates the NLRP3 inflammasome in dendritic cells through P2RX7, promoting interleukin-1β maturation. Later, high-mobility group box 1 and annexin A1 are released as membrane integrity is lost. These signals can improve dendritic-cell maturation, antigen cross-presentation and activation of CD4+ and CD8+ T cells, creating an in situ vaccine effect. The pathway varies with the payload: microtubule-targeting agents can promote endoplasmic-reticulum stress, whereas DNA-damaging payloads may additionally activate a type I interferon response through cytoplasmic DNA sensing.

ADCs can also recruit innate immune mechanisms through the retained Fc domain of many IgG antibodies. Binding of Fcγ receptor IIIa on natural killer cells can initiate antibody-dependent cellular cytotoxicity, with perforin and granzyme B contributing to tumor-cell lysis. Fc receptors on macrophages and dendritic cells can promote antibody-dependent cellular phagocytosis, while interaction with serum C1q can initiate complement-dependent cytotoxicity. These actions may accelerate clearance of dying cells and presentation of tumor antigens, although the contribution of Fc-mediated activity to clinical benefit remains uncertain. The review notes that bicycle drug conjugates without an Fc domain have shown clinical activity comparable to conventional ADCs carrying the same payload, suggesting that direct cytotoxicity and immunogenic cell death may be more important than antibody-dependent killing alone.

At the same time, ADCs can alter suppressive cellular and molecular pathways. If a target is expressed on regulatory T cells, an ADC may deplete some of them and reduce interleukin-10 and transforming growth factor beta. Other studies have reported inhibition of myeloid-derived suppressor cells, repolarization of tumor-associated macrophages from an M2 toward an M1 phenotype, and recruitment of cytotoxic T cells, natural killer cells and mature dendritic cells. Activation of the cGAS–STING pathway can produce type I interferon and increase PD-L1 expression through JAK–STAT signaling, creating a target for checkpoint blockade. The tumor can also impede the ADC itself. Dense collagen, cancer-associated fibroblasts and elevated interstitial pressure restrict delivery of large molecules, while Fcγ receptors on M2-polarized macrophages can capture conjugates and lower the effective local concentration. Suppressive cytokines may blunt antibody-dependent cytotoxicity and interferon-associated antigen presentation without necessarily preventing the payload from directly killing exposed cells.

The strongest clinical evidence comes from urothelial carcinoma. In the phase III EV-302 trial, 886 previously untreated patients with locally advanced or metastatic disease received enfortumab vedotin plus pembrolizumab or platinum chemotherapy. Median progression-free survival was 12.5 months with the combination and 6.3 months with chemotherapy, while median overall survival was 31.5 and 16.1 months, respectively. Objective response was 67.7% versus 44.4%, and grade 3 or higher treatment-related adverse events occurred in 55.9% and 69.5%. A separate phase III trial in 484 patients with HER2-positive urothelial carcinoma reported median progression-free survival of 13.1 months for disitamab vedotin plus toripalimab, compared with 6.5 months for chemotherapy, and median overall survival of 31.5 versus 16.9 months. Toxicity varies by regimen: sacituzumab govitecan plus avelumab produced median progression-free survival of 11.17 months versus 3.75 months for avelumab alone in a phase II maintenance trial, yet grade 3 or higher treatment-related adverse events reached 69.9% and neutropenia was dose-limiting.

Breast cancer illustrates why combination results cannot be generalized across tumor biology. In a phase III trial of 443 patients with PD-L1-positive, locally advanced unresectable or metastatic triple-negative breast cancer, sacituzumab govitecan plus pembrolizumab produced median progression-free survival of 11.2 months, compared with 7.8 months for pembrolizumab plus platinum chemotherapy; median duration of response was 16.5 versus 9.2 months, while overall-survival data were immature. Because the trial lacked ADC-only and checkpoint-inhibitor-only arms, it could not separate synergy from additive or ADC-driven effects. In hormone receptor-positive, HER2-negative disease, a phase II trial of 104 patients did not meet its overall progression-free survival endpoint, although exploratory benefit was observed in the PD-L1-positive subgroup. For HER2-low breast cancer, durvalumab plus trastuzumab deruxtecan produced a confirmed response rate of 62.1%, below the prespecified threshold, with median progression-free and overall survival of 12.6 and 30.3 months; drug-related interstitial lung disease or pneumonitis occurred in 20.7%.

Recent lung-cancer data include a phase III trial in 413 patients with PD-L1-positive, driver-gene-negative advanced non-small cell lung cancer. Sacituzumab tirumotecan plus pembrolizumab yielded a response rate of 70%, compared with 42% for pembrolizumab alone, and a 12-month progression-free survival rate of 62% versus 29%. Median progression-free survival was not reached in the combination arm and was 5.7 months in the monotherapy arm, although overall-survival data remained immature and grade 3 or higher adverse events were more frequent with the combination. In a separate phase II trial involving patients whose advanced disease had progressed after PD-1 inhibition, brentuximab vedotin plus pembrolizumab produced modest response rates of 8% in primary resistance and 14% in acquired resistance. Exploratory analyses suggested possible depletion of CD30-positive regulatory T cells. In gastric cancer, a phase I study of disitamab vedotin plus toripalimab reported a 43% response rate among 28 evaluable patients, with four cases of treatment-related pneumonitis. Smaller basket and single-arm studies in head and neck squamous cell carcinoma and uterine serous carcinoma remain preliminary.

Beyond conventional ADC–checkpoint inhibitor combinations, several experimental strategies are being tested in cell and animal models. Combining ADCs with OX40, GITR or CD40 agonists can increase CD8+ T-cell infiltration, reduce regulatory T cells or favor M1-like macrophages, sometimes allowing tumor regression at lower ADC doses. Dual-payload ADCs place a cytotoxic drug and an immune stimulant on the same antibody: a HER2-targeted construct carrying a topoisomerase I inhibitor and a Toll-like receptor 7 agonist produced stronger activity than either single-payload component in a trastuzumab-resistant breast-cancer model, while a CD276-targeted conjugate combining a microtubule-disrupting payload with a TLR7/8 agonist increased CD8+ T-cell and natural-killer-cell infiltration in triple-negative breast cancer. ADC–CAR-T combinations are also being explored in pancreatic-cancer models, using the ADC to kill cells and release antigens before engineered T cells eliminate residual disease. These findings remain preclinical and do not establish clinical benefit.

Translation is constrained by tumor heterogeneity, overlapping toxicity, weak biomarkers and inconsistent trial design. Antigen expression and PD-L1 status do not capture the spatial complexity of the immune microenvironment, and no validated dynamic biomarker yet predicts resistance early enough to guide treatment. Combining ADCs with immunotherapy can also double up on pulmonary risk because ADC-associated interstitial lung disease and immune-mediated pneumonitis have overlapping symptoms, while bone marrow suppression, neuropathy and immune-related dermatitis, pneumonitis and neurotoxicity may accumulate. Clinical studies currently vary widely in drug choice, dose, interval and sequencing. The review identifies more rigorous, multicenter trials, standardized dose-modification rules, spatial and circulating-biopsy biomarkers, and individualized sequencing as priorities. It also notes that broad adoption of “synergy” as a description of improved combination outcomes would be premature unless future studies include monotherapy controls capable of separating each component’s contribution.

Subject of Research: Clinical and mechanistic evaluation of antibody–drug conjugates combined with immunotherapy for solid tumors

Article Title: Combination of antibody–drug conjugates with immunotherapy: a new paradigm in cancer treatment

Article References: Lai, Y., Qin, R., & Liu, Z. (2026). Combination of antibody–drug conjugates with immunotherapy: a new paradigm in cancer treatment. Frontiers in Oncology, 16, Article 1945452. https://doi.org/10.3389/fonc.2026.1945452

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1945452

Keywords: antibody–drug conjugates, immune checkpoint inhibitors, cancer immunotherapy, tumor microenvironment, urothelial carcinoma, breast cancer, non-small cell lung cancer, gastric cancer, immunogenic cell death, drug resistance, Combination, antibody