Antibody–drug conjugates (ADCs) were conceived to deliver cytotoxic payloads selectively to tumour cells, but emerging evidence indicates their antitumour activity also involves coordinated immunomodulatory effects. These effects arise from two principal components: antibody-mediated functions (including Fc-driven effector mechanisms such as antibody-dependent cell-mediated cytotoxicity) and payload-induced cellular stress that can be immunogenic. The interplay of these processes can increase tumour-antigen release, promote dendritic cell activation and facilitate the priming and maintenance of antitumour T cell responses within the tumour microenvironment.
Preclinical and translational studies summarized in the review describe mechanisms such as immunogenic cell death, whereby dying tumour cells release damage-associated molecular patterns and tumour-associated antigens that recruit and activate antigen-presenting cells. This antigen release can bridge innate and adaptive immunity, converting local cytotoxic effects into broader immune recognition of tumour cells. Additionally, antibody Fc functions can recruit innate immune effectors that contribute directly to tumour cell clearance and to shaping subsequent adaptive responses.
The review includes a figure that schematizes these immunological mechanisms, highlighting both direct and indirect paths through which ADCs influence tumour–immune interactions.
On the biological basis that ADCs can induce antigen release and immune activation, combination strategies pairing ADCs with immune checkpoint inhibitors (ICIs) have been pursued. ADC–ICI combinations aim to potentiate checkpoint blockade by increasing tumour immunogenicity or by remodelling the tumour microenvironment to favour immune infiltration and effector function.
The authors note that ADC–ICI combinations have demonstrated substantial clinical benefit in selected settings and that ongoing trials are exploring these combinations broadly. However, benefit is not universal across tumour types or clinical contexts, and the review emphasises that patient selection and biomarker development will be important to maximise the therapeutic index of these combinations.
The review collates preclinical, translational and emerging clinical data that support an immunological component to ADC activity. Translational analyses from clinical programmes and dedicated biomarker studies have explored features such as antigen shedding, immune cell infiltration, dendritic cell activation and T cell responses after ADC treatment. Some referenced clinical developments (for example, trials and biomarker analyses involving agents such as trastuzumab deruxtecan) are cited to illustrate the evolving understanding of mechanisms of action and resistance.
Although the article highlights examples and references clinical abstracts and trials, the preview is subscription-restricted; therefore, full methodological and outcome details from specific clinical studies are presented in the full article and referenced sources rather than in the preview text.
A central theme of the review is the transition of ADC development from a sole focus on targeted cytotoxicity to deliberate immune-oriented engineering. Strategies described include antibody engineering to modulate Fc interactions, design of bispecific antibodies to engage multiple targets or immune cells, targeting of components of the tumour microenvironment rather than tumour-cell intrinsic antigens, and the incorporation of novel or dual payloads that possess immunostimulatory properties.
The review also discusses conceptual approaches such as using payloads that induce immunogenic stress, designing linkers and conjugation chemistries to improve antigen presentation, and combining ADCs with other immune-stimulating agents beyond ICIs. A figure in the article summarizes these innovative strategies to enhance immune modulation by ADCs.
Despite promising biological rationale and selective clinical successes, the review highlights persistent challenges. Efficacy of ADC–ICI combinations is heterogeneous and not guaranteed across indications. The authors underscore the likely need for biomarker-informed development to identify patients and tumour contexts most likely to benefit from ADC-driven immunomodulation. Other challenges include understanding mechanisms of acquired resistance to ADCs, optimising tumour penetration and selectivity, and balancing enhanced immune activation with tolerability.
Future directions emphasised in the review include continued translational study to define immune correlates of response, clinical trials testing next-generation immune-oriented ADCs and rational combination strategies, and iterative design advances to amplify immune activation while preserving therapeutic selectivity.
This Review reframes ADCs as agents with dual roles: targeted cytotoxic delivery and modulators of tumour–immune interactions. The accumulated preclinical, translational and emerging clinical evidence supports combinations of ADCs with ICIs and other immunotherapies, and motivates next-generation ADC designs that intentionally harness immune mechanisms. For comprehensive experimental and clinical detail, the full article and cited references should be consulted, as the preview contains summary material and selected references.