Researchers from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology published a review on June 24 that synthesizes current knowledge on resistance to antibody-drug conjugates (ADCs) and outlines potential solutions. The review appears in Cancer Biology & Medicine and systematically analyzes mechanisms by which cancer cells evade ADC therapies.
The team examined how tumors can resist ADCs at multiple stages, including shedding target antigens, altering internalization pathways, impairing lysosomal processing, or using efflux pumps to remove cytotoxic payloads. Tumor heterogeneity further complicates treatment as antigen-negative subclones may survive therapy and repopulate the tumor.
The review identifies seven interconnected categories of resistance: antigen downregulation and mutation; deficits in internalization involving proteins such as caveolin-1; trafficking dysfunction linked to Rab GTPase alterations; impaired lysosomal acidification; payload-related efflux via adenosine triphosphate-binding cassette transporters; barriers created by the tumor microenvironment; and modulation of apoptotic pathways. The authors said, "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," they added, "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."
To counteract these challenges, the researchers evaluated approaches such as bispecific antibody-drug conjugates targeting two antigens simultaneously, dual-payload designs with complementary cytotoxic effects, immunostimulatory antibody conjugates intended to enhance immune response within the tumor microenvironment, and rational combination regimens with chemotherapy or targeted agents. The review highlights findings from clinical trials like EV-302 where enfortumab vedotin combined with pembrolizumab nearly doubled progression-free survival compared to chemotherapy alone for urothelial carcinoma.
The authors state their findings have immediate implications for both clinical practice and drug development. For oncologists, they recommend biomarker-driven patient selection based on target antigen levels and other indicators. For researchers developing new therapies, they emphasize incorporating features such as payload diversification and bispecific targeting into next-generation ADCs. They also caution against assuming similar payload classes are interchangeable due to evidence suggesting cross-resistance among topoisomerase I inhibitor-based ADCs.
