Review outlines key strategies to overcome antibody drug conjugate resistance

The first Antibody-drug conjugate (ADC) was approved overa quarter-century ago, and today more than 20 have reached the clinic. Yet resistance remains the Achilles' heel of this otherwise transformative approach. Cancer cells can shed target antigens, reroute internalization pathways, disable lysosomal processing, or pump out cytotoxic payloads before they can act. Tumor heterogeneity further complicates the picture, allowing antigen-negative subclones to survive and repopulate. Based on these challenges, the research team conducted an in-depth analysis of resistance mechanisms and emerging solutions to guide the next generation of ADC development.

Now publishing (DOI: 10.20892/j.issn.2095-3941.2025.0707) in Cancer Biology & Medicine , investigators from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, have synthesized current knowledge on ADC resistance and strategies to overcome it. Their review systematically examines resistance at every stage of ADC action—from antibody-antigen binding to payload delivery and cytotoxicity—and evaluates cutting-edge approaches including bispecific ADCs, dual-payload designs, and rational combination regimens.

The review identifies resistance mechanisms spanning seven interconnected categories: antigen downregulation and mutation, internalization deficits involving proteins such as *caveolin-1*, trafficking dysfunction driven by Rab GTPase alterations, impaired lysosomal acidification, payload-related efflux via adenosine triphosphate-binding cassette (ABC) transporters, tumor microenvironment-mediated barriers, and apoptotic pathway modulation. Notably, the team highlights that resistance rarely arises from a single defect—tumors often deploy multiple strategies simultaneously. To counter this, they explore bispecific antibody-drug conjugates (BsADCs) that target two antigens at once, dual-payload ADCs that combine complementary cytotoxic mechanisms, and immunostimulatory antibody conjugates (ISACs) that reprogram the tumor microenvironment to enhance immune attack. The review also examines combination approaches with chemotherapy, targeted agents, anti-angiogenic drugs, and immune checkpoint inhibitors, noting that the EV-302 trial of enfortumab vedotin plus pembrolizumab nearly doubled progression-free survival compared to chemotherapy alone in urothelial carcinoma.

"We are seeing that resistance to ADCs is not a single problem but a network of adaptive responses that cancer cells can activate at multiple points along the therapeutic pathway," the authors said. "The encouraging news is that we now have a much clearer picture of these mechanisms, which allows us to design smarter ADCs—whether through bispecific antibodies that overcome antigen heterogeneity, novel payloads that bypass efflux pumps, or combination strategies that strike tumors from multiple angles at once."

The findings carry immediate implications for clinical practice and drug development. For oncologists, the review underscores the importance of biomarker-driven patient selection—measuring target antigen levels, efflux pump activity, and lysosomal function could help predict which patients are most likely to respond. For researchers, it points toward next-generation ADCs that incorporate payload diversification, bispecific targeting, and immune-stimulating components. The authors also caution against assuming that ADCs sharing similar payload classes can be used interchangeably, as emerging data suggest cross-resistance among topoisomerase I inhibitor-based ADCs. Ultimately, the review argues that overcoming ADC resistance will require moving beyond single-agent thinking toward rationally designed combination regimens and multi-mechanistic ADCs that address both tumor cell intrinsic defenses and the protective tumor microenvironment.