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

Abstract

Immunotherapy, which activates the host immune system to recognize and eliminate tumor cells, has become an important modality in cancer treatments. However, tumor heterogeneity and the immunosuppressive tumor microenvironment often drive resistance to single-agent immunotherapy, thereby limiting its clinical efficacy. Antibody–drug conjugates (ADCs) are a class of targeted anticancer agents composed of a monoclonal antibody, a linker, and a cytotoxic payload. In addition to direct tumor cell killing, ADCs can remodel the tumor microenvironment through multiple mechanisms, thereby contributing to the reversal of immune resistance. Consequently, combination strategies integrating ADCs with immunotherapy have attracted increasing attention. Clinical studies have demonstrated encouraging benefits of ADC–immune checkpoint inhibitor combinations across multiple tumor types, and several emerging regimens have shown promising therapeutic potential. Nevertheless, significant challenges remain in clinical translation. This review summarizes the synergistic mechanisms and recent advances in ADC–immunotherapy combinations, discusses current limitations, and outlines future directions, with the aim of guiding the precise and standardized development of these combination strategies.