Exploring the immunological effects of antibody-drug conjugates

Antibody-drug conjugates (ADCs) have profoundly reshaped the therapeutic landscape across multiple malignancies, establishing a new paradigm of targeted cytotoxic delivery. Emerging evidence indicates that the activity of ADCs extends beyond direct cytotoxicity to encompass a coordinated spectrum of immunomodulatory effects, arising from both antibody-mediated functions and payload-induced cellular stress. These mechanisms include immunogenic cell death and subsequent tumour-associated antigen release, antibody-dependent cell-mediated cytotoxicity, dendritic cell activation and tumour microenvironment reprogramming. On the basis of this biological foundation, ADCs have been increasingly explored in combination with immune checkpoint inhibitors and also with other immune-stimulating agents. Furthermore, novel ADC designs with enhanced immunological activity are emerging. In this Review, we examine the direct and indirect immunological effects underpinning the clinical activity of ADCs, appraise the clinical evidence supporting the combination of ADCs with immune checkpoint inhibitors and highlight innovative strategies to further optimize the immunogenic potential of ADCs, including antibody engineering, targeting of the tumour microenvironment, novel combinations and the use of immunostimulant payloads or bispecific antibodies. This evolving paradigm positions ADCs not merely as targeted cytotoxic agents, but rather as modulators of tumour-immune interactions, with implications for the activity of both monotherapy and combination regimens.