Skip to main content
See More

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Unveiling the molecular and immunological drivers of antibody–drug conjugates in cancer treatment

Nature Reviews Cancer (2025)Cite this article

Subjects

Abstract

After decades of investment, antibody–drug conjugates (ADCs) are finally demonstrating their potential, marked by a growing number of clinical approvals, applications in earlier lines of treatment and integration into drug combinations, including immunotherapies. This progress has spurred investment in developing new ADCs and expanding the use of approved ADCs in clinical practice. The design of ADCs is complex, involving multiple molecular components that interact with both tumour and host tissue microenvironments. In this Review, we explore the molecular and immunological factors influencing ADC efficacy and toxicity. We describe how the molecular components of ADCs determine their systemic, tissue and cellular distribution, which ultimately dictates therapeutic efficacy. These interactions also determine the toxicity profile and set limitations on maximum dosing. Finally, we discuss the impact of ADC treatment on immune cells, emphasizing the distinct but interconnected roles of immunogenic cell death, activation of immune cells such as dendritic cells and antibody–Fc interactions. These mechanisms are crucial for increasing efficacy beyond the direct cytotoxic effects of the payload. By providing insights into the intricate interactions of ADCs, this Review aims to inform the rational design of combination therapies and guide the development of the next generation of clinically effective ADCs.

Key points

  • Antibody–drug conjugates (ADCs) are complex therapeutics with multiple molecular interactions that determine their distribution, efficacy and toxicity including specific target (Fab) and receptor (Fc) binding and non-specific (for example, lipophilic payload) interactions.

  • Targeted delivery of ADCs is the primary driver of success by concentrating the payload within the tumour (and often subcellular) location provided sufficient tumour tissue penetration is achieved.

  • Although tumour concentrations are higher, the majority of the total administered ADC does not reach the tumour and is diffusely metabolized elsewhere in the body, releasing the payload and driving toxicity.

  • The mechanisms of healthy tissue uptake are varied such that reduction in some (for example, release of the payload in plasma) can increase others (for example, receptor-mediated uptake of intact ADC).

  • ADCs interact directly and indirectly with the immune system through immunogenic cell death, Fc-effector functions, Fc-mediated payload uptake, and bystander payload uptake that either kills or stimulates immune cells.

  • The multiple mechanisms of action of ADC payloads and antibodies make them ideal candidates for pairing with immunotherapeutics by controlling cancer cell versus immune cell delivery and stimulation.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Anatomy of an antibody–drug conjugate.
Fig. 2: Systemic antibody–drug conjugate pharmacokinetics.
Fig. 3: Tissue and cellular antibody–drug conjugate pharmacokinetics.
Fig. 4: Mechanisms contributing to antibody–drug conjugate toxicity.
Fig. 5: Immune interactions of antibody–drug conjugates in the tumour microenvironment.

Similar content being viewed by others

References

  1. Colombo, R., Tarantino, P., Rich, J. R., LoRusso, P. M. & de Vries, E. G. E. The journey of antibody–drug conjugates: lessons learned from 40 years of development. Cancer Discov. 14, 2089–2108 (2024).

    Article  CAS  PubMed  Google Scholar 

  2. Dumontet, C., Reichert, J. M., Senter, P. D., Lambert, J. M. & Beck, A. Antibody–drug conjugates come of age in oncology. Nat. Rev. Drug Discov. 22, 641–661 (2023).

    Article  CAS  PubMed  Google Scholar 

  3. Meric-Bernstam, F. et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J. Clin. Oncol. 42, 47–58 (2024).

    Article  CAS  PubMed  Google Scholar 

  4. Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610–621 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Powles, T. et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N. Engl. J. Med. 390, 875–888 (2024).

    Article  CAS  PubMed  Google Scholar 

  6. Mathe, G., Tran Ba, L. O. & Bernard, J. Effect on mouse leukemia 1210 of a combination by diazo-reaction of amethopterin and γ-globulins from hamsters inoculated with such leukemia by heterografts [French]. C. R. Hebd. Seances Acad. Sci. 246, 1626–1628 (1958).

    CAS  PubMed  Google Scholar 

  7. Ghose, T. et al. Immunochemotherapy of cancer with chlorambucil-carrying antibody. Br. Med. J. 3, 495–499 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ford, C. H. et al. Localisation and toxicity study of a vindesine–anti-CEA conjugate in patients with advanced cancer. Br. J. Cancer 47, 35–42 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Trail, P. A. et al. Cure of xenografted human carcinomas by BR96–doxorubicin immunoconjugates. Science 261, 212–215 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Maecker, H., Jonnalagadda, V., Bhakta, S., Jammalamadaka, V. & Junutula, J. R. Exploration of the antibody–drug conjugate clinical landscape. MAbs 15, 2229101 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rubahamya, B., Dong, S. & Thurber, G. M. Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data. Sci. Adv. 10, eadk1894 (2024). This study compares the preclinical versus clinical efficacy of approved ADCs versus discontinued agents alongside a mechanistic explanation. Notably, the approved agents are all able to shrink tumours when administered to mice at the same milligram per kilogram dose level, whereas only 19% of discontinued agents meet this threshold.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hurvitz, S. A. et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open 9, 102924 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Balinda, H. U. et al. Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial. Nat. Commun. 15, 6707 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dannehl, D. et al. The efficacy of sacituzumab govitecan and trastuzumab deruxtecan on stable and active brain metastases in metastatic breast cancer patients—a multicenter real-world analysis. ESMO Open. 9, 102995 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hamblett, K. J. et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin. Cancer Res. 10, 7063–7070 (2004). This foundational study on the impact of drug loading has had a major impact on the field, leading to the initial predominance of ADCs with a DAR of 4 while also motivating advances in conjugation strategies and linker design to enable a wide range of DAR values with suitable pharmacokinetic properties.

    Article  CAS  PubMed  Google Scholar 

  16. Simmons, J. K., Burke, P. J., Cochran, J. H., Pittman, P. G. & Lyon, R. P. Reducing the antigen-independent toxicity of antibody-drug conjugates by minimizing their non-specific clearance through PEGylation. Toxicol. Appl. Pharmacol. 392, 114932 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. Goldenberg, D. M., Cardillo, T. M., Govindan, S. V., Rossi, E. A. & Sharkey, R. M. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody–drug conjugate (ADC). Oncotarget 6, 22496–22512 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Damelang, T. et al. Impact of structural modifications of IgG antibodies on effector functions. Front. Immunol. 14, 1304365 (2023).

    Article  CAS  PubMed  Google Scholar 

  19. Junutula, J. R. et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat. Biotechnol. 26, 925–932 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Ohri, R. et al. High-throughput cysteine scanning to identify stable antibody conjugation sites for maleimide- and disulfide-based linkers. Bioconjug. Chem. 29, 473–485 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Shen, B. Q. et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody–drug conjugates. Nat. Biotechnol. 30, 184–189 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Clardy, S. M. et al. Site-specific dolasynthen antibody–drug conjugates exhibit consistent pharmacokinetic profiles across a wide range of drug-to-antibody ratios. Mol. Cancer Ther. 23, 84–91 (2024).

    Article  CAS  PubMed  Google Scholar 

  23. Liu, J., Barfield, R. M. & Rabuka, D. Site-specific bioconjugation using SMARTag® technology: a practical and effective chemoenzymatic approach to generate antibody–drug conjugates. Methods Mol. Biol. 2033, 131–147 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Rabuka, D., Rush, J. S., deHart, G. W., Wu, P. & Bertozzi, C. R. Site-specific chemical protein conjugation using genetically encoded aldehyde tags. Nat. Protoc. 7, 1052–1067 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van Geel, R. et al. Chemoenzymatic conjugation of toxic payloads to the globally conserved N-glycan of native mAbs provides homogeneous and highly efficacious antibody–drug conjugates. Bioconjug. Chem. 26, 2233–2242 (2015).

    Article  PubMed  Google Scholar 

  26. de Bever, L. et al. Generation of DAR1 antibody–drug conjugates for ultrapotent payloads using tailored GlycoConnect technology. Bioconjug. Chem. 34, 538–548 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Matsuda, Y. et al. AJICAP-M: traceless affinity peptide mediated conjugation technology for site-selective antibody–drug conjugate synthesis. Org. Lett. 26, 5597–5601 (2024).

    Article  CAS  PubMed  Google Scholar 

  28. Burke, P. J. et al. Optimization of a PEGylated glucuronide–monomethylauristatin E linker for antibody–drug conjugates. Mol. Cancer Ther. 16, 116–123 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Okamoto, H. et al. Pharmacokinetics of trastuzumab deruxtecan (T-DXd), a novel anti-HER2 antibody–drug conjugate, in HER2-positive tumour-bearing mice. Xenobiotica 50, 1242–1250 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Chang, H. P., Cheung, Y. K. & Shah, D. K. Whole-body pharmacokinetics and physiologically based pharmacokinetic model for monomethyl auristatin E (MMAE). J. Clin. Med. 10, 1332 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Girish, S. et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother. Pharmacol. 69, 1229–1240 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Montoyo, H. P. et al. Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice. Proc. Natl Acad. Sci. USA 106, 2788–2793 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mellman, I., Plutner, H. & Ukkonen, P. Internalization and rapid recycling of macrophage Fc receptors tagged with monovalent antireceptor antibody: possible role of a prelysosomal compartment. J. Cell Biol. 98, 1163–1169 (1984).

    Article  CAS  PubMed  Google Scholar 

  34. Challa, D. K., Velmurugan, R., Ober, R. J. & Ward, E. S. in Fc Receptors. Current Topics in Microbiology and Immunology Vol. 382 (eds Daeron, M. & Nimmerjahn, F.) 249–272 (Springer, 2014).

  35. Cetinbas, N. M. et al. Tumor cell-directed STING agonist antibody–drug conjugates induce type III interferons and anti-tumor innate immune responses. Nat. Commun. 15, 5842 (2024). This study highlights the development of tumour-targeted antibody–STING agonist conjugates that enhance antitumour immunity with reduced systemic toxicity, uncovering a critical role for type III interferons and providing a strong foundation for their clinical advancement in cancer immunotherapy.

    Article  Google Scholar 

  36. Ravetch, J. V. & Kinet, J. P. Fc receptors. Annu. Rev. Immunol. 9, 457–492 (1991).

    Article  CAS  PubMed  Google Scholar 

  37. Lu, J. et al. FcγRI FG-loop functions as a pH sensitive switch for IgG binding and release. Front. Immunol. 14, 1100499 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Thibault, G. et al. Association of IgG1 antibody clearance with FcγRIIA polymorphism and platelet count in infliximab-treated patients. Int. J. Mol. Sci. 22, 6051 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sharma, S. K. et al. Fc-mediated anomalous biodistribution of therapeutic antibodies in immunodeficient mouse models. Cancer Res. 78, 1820–1832 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, F. et al. Mouse strains influence clearance and efficacy of antibody and antibody–drug conjugate via Fc–FcγR interaction. Mol. Cancer Ther. 18, 780–787 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Bruhns, P. & Jonsson, F. Mouse and human FcR effector functions. Immunol. Rev. 268, 25–51 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Vorsatz, C., Friedrich, N., Nimmerjahn, F. & Biburger, M. There is strength in numbers: quantitation of Fcγ receptors on murine tissue-resident macrophages. Int. J. Mol. Sci. 22, 12172 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu, R., Oldham, R. J., Teal, E., Beers, S. A. & Cragg, M. S. Fc-engineering for modulated effector functions—improving antibodies for cancer treatment. Antibodies 9, 64 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Saunders, K. O. Conceptual approaches to modulating antibody effector functions and circulation half-life. Front. Immunol. 10, 1296 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jin, H. et al. Avelumab internalization by human circulating immune cells is mediated by both Fcγ receptor and PD-L1 binding. Oncoimmunology 10, 1958590 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Thurber, G. M., Schmidt, M. M. & Wittrup, K. D. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv. Drug Deliv. Rev. 60, 1421–1434 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Thurber, G. M. & Wittrup, K. D. A mechanistic compartmental model for total antibody uptake in tumors. J. Theor. Biol. 314, 57–68 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Adams, G. et al. High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules. Cancer Res. 61, 4750–4755 (2001).

    CAS  PubMed  Google Scholar 

  49. Fujimori, K., Covell, D. G., Fletcher, J. E. & Weinstein, J. N. A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J. Nucl. Med. 31, 1191–1198 (1990).

    CAS  PubMed  Google Scholar 

  50. Lu, G. et al. Co-administered antibody improves penetration of antibody–dye conjugate into human cancers with implications for antibody–drug conjugates. Nat. Commun. 11, 5667 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lu, G. et al. Predicting therapeutic antibody delivery into human head and neck cancers. Clin. Cancer Res. 26, 2582–2594 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, B. et al. Targeting FAK improves the tumor uptake of antibody–drug conjugates to strengthen the anti-cancer responses. iScience 28, 111536 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Blumenthal, R. D. et al. The effect of antibody protein dose on the uniformity of tumor distribution of radioantibodies—an autoradiographic study. Cancer Immunol. Immunother. 33, 351–358 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Graff, C. P. & Wittrup, K. D. Theoretical analysis of antibody targeting of tumor spheroids: importance of dosage for penetration, and affinity for retention. Cancer Res. 63, 1288–1296 (2003).

    CAS  PubMed  Google Scholar 

  55. Catenacci, D. V. T. et al. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b–2 trial. Lancet Oncol. 21, 1066–1076 (2020).

    Article  CAS  PubMed  Google Scholar 

  56. Stroh, M. et al. Clinical pharmacokinetics and pharmacodynamics of atezolizumab in metastatic urothelial carcinoma. Clin. Pharmacol. Ther. 102, 305–312 (2017).

    Article  CAS  PubMed  Google Scholar 

  57. Katz, U., Achiron, A., Sherer, Y. & Shoenfeld, Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun. Rev. 6, 257–259 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Colombo, R. & Rich, J. R. The therapeutic window of antibody drug conjugates: a dogma in need of revision. Cancer Cell 40, 1255–1263 (2022). This perspective analyses the maximum tolerated doses of small molecule drugs versus ADC payloads across different classes of chemotherapeutics. Interestingly, the retrospective study finds that once the molecular weight of the antibody is taken into account, a similar total dose of the molecule is tolerated with or without antibody conjugation.

    Article  CAS  PubMed  Google Scholar 

  59. Saber, H. & Leighton, J. K. An FDA oncology analysis of antibody–drug conjugates. Regul. Toxicol. Pharmacol. 71, 444–452 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Donaghy, H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody–drug conjugates. MAbs 8, 659–671 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kopp, A. et al. Antibody–drug conjugate sacituzumab govitecan drives efficient tissue penetration and rapid intracellular drug release. Mol. Cancer Ther. 22, 102–111 (2023).

    Article  CAS  PubMed  Google Scholar 

  62. Ponte, J. F. et al. Antibody co-administration can improve systemic and local distribution of antibody–drug conjugates to increase in vivo efficacy. Mol. Cancer Ther. 20, 203–212 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Cilliers, C., Menezes, B., Nessler, I., Linderman, J. & Thurber, G. M. Improved tumor penetration and single-cell targeting of antibody–drug conjugates increases anticancer efficacy and host survival. Cancer Res. 78, 758–768 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Wei, Q. et al. Spatiotemporal quantification of HER2-targeting antibody–drug conjugate bystander activity and enhancement of solid tumor penetration. Clin. Cancer Res. 30, 984–997 (2024).

    Article  CAS  PubMed  Google Scholar 

  65. Cilliers, C., Guo, H., Liao, J., Christodolu, N. & Thurber, G. M. Multiscale modeling of antibody–drug conjugates: connecting tissue and cellular distribution to whole animal pharmacokinetics and potential implications for efficacy. AAPS J. 18, 1117–1130 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Hamadani, M. et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood 137, 2634–2645 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hamblett, K. J. et al. SLC46A3 is required to transport catabolites of noncleavable antibody maytansine conjugates from the lysosome to the cytoplasm. Cancer Res. 75, 5329–5340 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Tsui, C. K. et al. CRISPR–Cas9 screens identify regulators of antibody–drug conjugate toxicity. Nat. Chem. Biol. 15, 949–958 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Erickson, H. K. et al. Antibody–maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 66, 4426–4433 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Erickson, H. K. et al. Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody–maytansinoid conjugates. Bioconjug. Chem. 21, 84–92 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Mattes, M. J. et al. Processing of antibody–radioisotope conjugates after binding to the surface of tumor cells. Cancer 73, 787–793 (1994).

    Article  CAS  PubMed  Google Scholar 

  72. Rudnick, S. I. et al. Influence of affinity and antigen internalization on the uptake and penetration of anti-HER2 antibodies in solid tumors. Cancer Res. 71, 2250–2259 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Thurber, G. M. & Wittrup, K. D. Quantitative spatiotemporal analysis of antibody fragment diffusion and endocytic consumption in tumor spheroids. Cancer Res. 68, 3334–3341 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dennis, M. S. et al. Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent. Cancer Res. 67, 254–261 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Cazzamalli, S., Dal Corso, A., Widmayer, F. & Neri, D. Chemically defined antibody– and small molecule–drug conjugates for in vivo tumor targeting applications: a comparative analysis. J. Am. Chem. Soc. 140, 1617–1621 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bordeau, B. M., Yang, Y. & Balthasar, J. P. Transient competitive inhibition bypasses the binding site barrier to improve tumor penetration of trastuzumab and enhance T-DM1 efficacy. Cancer Res. 81, 4145–4154 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tsao, L. C. et al. Effective extracellular payload release and immunomodulatory interactions govern the therapeutic effect of trastuzumab deruxtecan (T-DXd). Nat. Commun. 16, 3167 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bocci, M. et al. In vivo activation of FAP-cleavable small molecule–drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment. J. Control. Rel. 367, 779–790 (2024).

    Article  CAS  Google Scholar 

  79. Szot, C. et al. Tumor stroma-targeted antibody–drug conjugate triggers localized anticancer drug release. J. Clin. Invest. 128, 2927–2943 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Khera, E. et al. Cellular-resolution imaging of bystander payload tissue penetration from antibody–drug conjugates. Mol. Cancer Ther. 21, 310–321 (2022).

    Article  CAS  PubMed  Google Scholar 

  81. Ackerman, M. E. et al. A33 antigen displays persistent surface expression. Cancer Immunol. Immunother. 57, 1017–1027 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schmidt, M. M., Thurber, G. M. & Wittrup, K. D. Kinetics of anti-carcinoembryonic antigen antibody internalization: effects of affinity, bivalency, and stability. Cancer Immunol. Immunother. 57, 1879–1890 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Austin, C. D. et al. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol. Biol. Cell 15, 5268–5282 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sunada, H., Magun, B. E., Mendelsohn, J. & MacLeod, C. L. Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc. Natl Acad. Sci. USA 83, 3825–3829 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, J. Y. et al. A biparatopic HER2-targeting antibody–drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29, 117–129 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. Nessler, I. et al. Increased tumor penetration of single-domain antibody drug conjugates improves in vivo efficacy in prostate cancer models. Cancer Res. 80, 1268–1278 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ahn, G. et al. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat. Chem. Biol. 17, 937–946 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. DeVay, R. M. et al. Improved lysosomal trafficking can modulate the potency of antibody drug conjugates. Bioconjug. Chem. 28, 1102–1114 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. Mayor, S., Presley, J. & Maxfield, F. Sorting of membrane components from endosomes and subsequent recycling to the cell surface occurs by a bulk flow process. J. Cell Biol. 121, 1257–1269 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. Menezes, B. et al. Pharmacokinetics and pharmacodynamics of TAK-164 antibody drug conjugate coadministered with unconjugated antibody. AAPS J. 24, 107 (2022).

    Article  CAS  PubMed  Google Scholar 

  91. Li, Q. et al. HER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial. Nat. Commun. 15, 5158 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Song, Y. et al. Safety and efficacy in patients with advanced lymphomas from a global phase 1a/1b, first-in-human study of CS5001, a novel anti-ROR1 ADC. Blood 144, 1739 (2024).

    Article  Google Scholar 

  93. Tranoy-Opalinski, I. et al. β-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: an update. Eur. J. Med. Chem. 74, 302–313 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Zhao, H. et al. A potential mechanism for ADC-induced neutropenia: role of neutrophils in their own demise. Mol. Cancer Ther. 16, 1866–1876 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Ogitani, Y., Hagihara, K., Oitate, M., Naito, H. & Agatsuma, T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody–drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 107, 1039–1046 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Li, F. et al. Intracellular released payload influences potency and bystander-killing effects of antibody–drug conjugates in preclinical models. Cancer Res. 76, 2710–2719 (2016). This study highlights the importance of intracellular delivery across ADCs with differing expression levels of antigens and internalization rates. The study also shows the importance of bystander effects in tumours with heterogeneous expression of antigens.

    Article  CAS  PubMed  Google Scholar 

  97. Nguyen, T. D., Bordeau, B. M. & Balthasar, J. P. Mechanisms of ADC toxicity and strategies to increase ADC tolerability. Cancers 15, 713 (2023). This review describes the different mechanisms driving ADC toxicity, including non-specific uptake of intact ADCs followed by payload release; and systemic payload release from circulating ADCs followed by systemic uptake of free payload.

    Article  Google Scholar 

  98. Zhang, X., Shedden, K. & Rosania, G. R. A cell-based molecular transport simulator for pharmacokinetic prediction and cheminformatic exploration. Mol. Pharm. 3, 704–716 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Khera, E., Cilliers, C., Bhatnagar, S. & Thurber, G. Computational transport analysis of antibody–drug conjugate bystander effects and payload tumoral distribution: implications for therapy. Mol. Syst. Des. Eng. 3, 73–88 (2018).

    Article  CAS  Google Scholar 

  100. Li, F. et al. Tumor-associated macrophages can contribute to antitumor activity through FcγR-mediated processing of antibody–drug conjugates. Mol. Cancer Ther. 16, 1347–1354 (2017). This study highlights the multiple roles of FcγR binding. Aside from Fc-effector function, FcγR binding can change the intratumour distribution and payload release profile even without target binding.

    Article  CAS  PubMed  Google Scholar 

  101. Khera, E. et al. Quantifying ADC bystander payload penetration with cellular resolution using pharmacodynamic mapping. Neoplasia 23, 210–221 (2021).

    Article  CAS  PubMed  Google Scholar 

  102. Wittrup, K. D. Antitumor antibodies can drive therapeutic T cell responses. Trends Cancer 3, 615–620 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Demetri, G. D. et al. First-in-human phase 1 study of ABBV-085, an antibody–drug conjugate (ADC) targeting LRRC15, in sarcomas and other advanced solid tumors. J. Clin. Oncol. 37, 3004–3004 (2019).

    Article  Google Scholar 

  104. Kinder, M., Greenplate, A. R., Strohl, W. R., Jordan, R. E. & Brezski, R. J. An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions. MAbs 7, 494–504 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Oflazoglu, E. et al. Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30. Blood 110, 4370–4372 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Montes de Oca, R. et al. Belantamab mafodotin (GSK2857916) drives immunogenic cell death and immune-mediated antitumor responses in vivo. Mol. Cancer Ther. 20, 1941–1955 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Park, S. et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18, 160–170 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Taylor, C. et al. Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin. Cancer Res. 13, 5133–5143 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Ingram, J. R. et al. Anti-CTLA-4 therapy requires an Fc domain for efficacy. Proc. Natl Acad. Sci. USA 115, 3912–3917 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Moquist, P. N. et al. Reversible chemical modification of antibody effector function mitigates unwanted systemic immune activation. Bioconjug. Chem. 35, 855–866 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Elter, A. et al. Protease-activation of Fc-masked therapeutic antibodies to alleviate off-tumor cytotoxicity. Front. Immunol. 12, 715719 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tvedt, T. H. A., Vo, A. K., Bruserud, Ø & Reikvam, H. Cytokine release syndrome in the immunotherapy of hematological malignancies: the biology behind and possible clinical consequences. J. Clin. Med. 10, 5190 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Doessegger, L. & Banholzer, M. L. Clinical development methodology for infusion-related reactions with monoclonal antibodies. Clin. Transl. Immunol. 4, e39 (2015).

    Article  Google Scholar 

  114. Taylor, R. P. & Lindorfer, M. A. Antibody drug conjugate adverse effects can be understood and addressed based on immune complex clearance mechanisms. Blood 144, 137–144 (2024). In this perspective, the authors highlight the potential negative effects of FcγR binding that could contribute to ADC toxicity. These effects must be balanced against potential contributions of FcγR binding to efficacy.

    Article  CAS  PubMed  Google Scholar 

  115. Baker, M. P., Reynolds, H. M., Lumicisi, B. & Bryson, C. J. Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self Nonself 1, 314–322 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Casi, G. & Neri, D. Antibody–drug conjugates and small molecule–drug conjugates: opportunities and challenges for the development of selective anticancer cytotoxic agents. J. Med. Chem. 58, 8751–8761 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Sharkey, R. M. et al. Enhanced delivery of SN-38 to human tumor xenografts with an anti-trop-2-SN-38 antibody conjugate (Sacituzumab Govitecan). Clin. Cancer Res. 21, 5131–5138 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Huang, Q., Ravindra Pilvankar, M., Dixit, R. & Yu, H. Approaches to improve the translation of safety, pharmacokinetics and therapeutic index of ADCs. Xenobiotica 54, 533–542 (2024).

    Article  CAS  PubMed  Google Scholar 

  119. Drago, J. Z., Modi, S. & Chandarlapaty, S. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat. Rev. Clin. Oncol. 18, 327–344 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Vasista, A. et al. Survival and cardiac toxicity in patients with HER2-positive, metastatic breast cancer treated with trastuzumab in routine clinical practice. Asia Pac. J. Clin. Oncol. 16, 34–38 (2020).

    Article  PubMed  Google Scholar 

  121. Nowsheen, S. et al. Incidence, diagnosis, and treatment of cardiac toxicity from trastuzumab in patients with breast cancer. Curr. Breast Cancer Rep. 9, 173–182 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. FDA. US prescribing information: enfortumab vedotin. FDA.gov https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761137s018.pdf (2023).

  123. Challita-Eid, P. M. et al. Enfortumab vedotin antibody–drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 76, 3003–3013 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Maric, G., Rose, A. A., Annis, M. G. & Siegel, P. M. Glycoprotein non-metastatic B (GPNMB): a metastatic mediator and emerging therapeutic target in cancer. Onco Targets Ther. 6, 839–852 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Ott, P. A. et al. Phase I/II study of the antibody–drug conjugate glembatumumab vedotin in patients with advanced melanoma. J. Clin. Oncol. 32, 3659–3666 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. FDA. US prescribing information: brentuximab vedotin. FDA.gov https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125388s100lbl.pdf (2019).

  127. FDA. US prescribing information: polatuzumab vedotin. FDA.gov https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761121s000lbl.pdf (2019).

  128. FDA. US prescribing information tisotumab vedotin. FDA.gov https://seagendocs.com/Tivdak_Full_Ltr_Master.pdf (2021).

  129. Strop, P. et al. RN927C, a site-specific trop-2 antibody–drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol. Cancer Ther. 15, 2698–2708 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Tsuchikama, K., Anami, Y., Ha, S. Y. & Yamazaki, C. M. Exploring the next generation of antibody–drug conjugates. Nat. Rev. Clin. Oncol. 21, 203–223 (2024).

    Article  CAS  PubMed  Google Scholar 

  131. Masters, J. C., Nickens, D. J., Xuan, D., Shazer, R. L. & Amantea, M. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest. N. Drugs 36, 121–135 (2018).

    Article  CAS  Google Scholar 

  132. Saber, H., Simpson, N., Ricks, T. K. & Leighton, J. K. An FDA oncology analysis of toxicities associated with PBD-containing antibody–drug conjugates. Regul. Toxicol. Pharmacol. 107, 104429 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. Zhu, Y., Liu, K., Wang, K. & Zhu, H. Treatment-related adverse events of antibody–drug conjugates in clinical trials: a systematic review and meta-analysis. Cancer 129, 283–295 (2023).

    Article  CAS  PubMed  Google Scholar 

  134. Mahalingaiah, P. K. et al. Potential mechanisms of target-independent uptake and toxicity of antibody–drug conjugates. Pharmacol. Ther. 200, 110–125 (2019).

    Article  CAS  PubMed  Google Scholar 

  135. Bryniarski, M. A. et al. Utility of cellular measurements of non-specific endocytosis to assess the target-independent clearance of monoclonal antibodies. J. Pharm. Sci. 113, 3100–3111 (2024).

    Article  CAS  PubMed  Google Scholar 

  136. Sun, X. et al. Effects of drug–antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody–maytansinoid conjugates. Bioconjug. Chem. 28, 1371–1381 (2017).

    Article  CAS  PubMed  Google Scholar 

  137. Boswell, C. A. et al. Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjug. Chem. 21, 2153–2163 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Zhao, H. et al. Modulation of macropinocytosis-mediated internalization decreases ocular toxicity of antibody–drug conjugates. Cancer Res. 78, 2115–2126 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. Bruggeman, C. W. et al. Tissue-specific expression of IgG receptors by human macrophages ex vivo. PLoS ONE 14, e0223264 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hackshaw, M. D. et al. Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer. Breast Cancer Res. Treat. 183, 23–39 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kumagai, K. et al. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab–drug conjugate, in monkeys. Cancer Sci. 111, 4636–4645 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Berger, M. et al. Tissue-specific Fcγ and complement receptor expression by alveolar macrophages determines relative importance of IgG and complement in promoting phagocytosis of Pseudomonas aeruginosa. Pediatr. Res. 35, 68–77 (1994).

    Article  CAS  PubMed  Google Scholar 

  143. Conte, P. et al. Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment. ESMO Open. 7, 100404 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Uppal, H. et al. Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1). Clin. Cancer Res. 21, 123–133 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Zhao, H. et al. Inhibition of megakaryocyte differentiation by antibody–drug conjugates (ADCs) is mediated by macropinocytosis: implications for ADC-induced thrombocytopenia. Mol. Cancer Ther. 16, 1877–1886 (2017).

    Article  CAS  PubMed  Google Scholar 

  146. Yang, Q. & Liu, Y. Technical, preclinical, and clinical developments of Fc-glycan-specific antibody–drug conjugates. RSC Med. Chem. 16, 50–62 (2025).

    Article  CAS  PubMed  Google Scholar 

  147. Liu, Y., Lee, A. G., Nguyen, A. W. & Maynard, J. A. An antibody Fc engineered for conditional antibody-dependent cellular cytotoxicity at the low tumor microenvironment pH. J. Biol. Chem. 298, 101798 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gorovits, B. & Krinos-Fiorotti, C. Proposed mechanism of off-target toxicity for antibody–drug conjugates driven by mannose receptor uptake. Cancer Immunol. Immunother. 62, 217–223 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Goetze, A. M. et al. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology 21, 949–959 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. Wolska-Washer, A. & Robak, T. Safety and tolerability of antibody–drug conjugates in cancer. Drug Saf. 42, 295–314 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Tsuchikama, K. & An, Z. Antibody–drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell 9, 33–46 (2018).

    Article  CAS  PubMed  Google Scholar 

  152. Lu, J., Jiang, F., Lu, A. & Zhang, G. Linkers having a crucial role in antibody–drug conjugates. Int. J. Mol. Sci. 17, 561 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Bargh, J. D., Isidro-Llobet, A., Parker, J. S. & Spring, D. R. Cleavable linkers in antibody–drug conjugates. Chem. Soc. Rev. 48, 4361–4374 (2019).

    Article  CAS  PubMed  Google Scholar 

  154. Bordeau, B. M., Nguyen, T. D., Polli, J. R., Chen, P. & Balthasar, J. P. Payload-binding fab fragments increase the therapeutic index of MMAE antibody–drug conjugates. Mol. Cancer Ther. 22, 459–470 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nguyen, T. D., Bordeau, B. M. & Balthasar, J. P. Use of payload binding selectivity enhancers to improve therapeutic index of maytansinoid–antibody–drug conjugates. Mol. Cancer Ther. 22, 1332–1342 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Journeaux, T. & Bernardes, G. J. L. Homogeneous multi-payload antibody–drug conjugates. Nat. Chem. 16, 854–870 (2024).

    Article  CAS  PubMed  Google Scholar 

  157. Heist, R. et al. MYTX-011, a cMET-targeting antibody–drug conjugate (ADC), in patients with previously treated, advanced NSCLC: updated dose escalation results in the phase 1 KisMET-01 study. J. Clin. Oncol. 43, 8613 (2025).

    Article  Google Scholar 

  158. Camidge, D. R. et al. Phase I study of 2- or 3-week dosing of telisotuzumab vedotin, an antibody–drug conjugate targeting c-Met, monotherapy in patients with advanced non-small cell lung carcinoma. Clin. Cancer Res. 27, 5781–5792 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Conilh, L., Sadilkova, L., Viricel, W. & Dumontet, C. Payload diversification: a key step in the development of antibody–drug conjugates. J. Hematol. Oncol. 16, 3 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. O’Donnell, J. S., Teng, M. W. L. & Smyth, M. J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 16, 151–167 (2019).

    Article  PubMed  Google Scholar 

  161. Finn, O. J. A believer’s overview of cancer immunosurveillance and immunotherapy. J. Immunol. 200, 385–391 (2018).

    Article  CAS  PubMed  Google Scholar 

  162. Pittet, M. J., Di Pilato, M., Garris, C. & Mempel, T. R. Dendritic cells as shepherds of T cell immunity in cancer. Immunity 56, 2218–2230 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Rios-Doria, J. et al. Antibody–drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads are immunomodulatory and synergize with multiple immunotherapies. Cancer Res. 77, 2686–2698 (2017). This study demonstrates that ADCs with PBD or tubulysin payloads induce ICD, stimulate immunological memory and synergize with immunotherapies, highlighting their potential in potent combinatorial cancer treatments with reduced toxicity.

    Article  CAS  PubMed  Google Scholar 

  164. Bauzon, M. et al. Maytansine-bearing antibody–drug conjugates induce in vitro hallmarks of immunogenic cell death selectively in antigen-positive target cells. Oncoimmunology 8, e1565859 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Müller, P. et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci. Transl. Med. 7, 315ra188 (2015).

    Article  PubMed  Google Scholar 

  166. D’Amico, L. et al. A novel anti-HER2 anthracycline-based antibody–drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer. J. Immunother. Cancer 7, 1–15 (2019).

    Article  Google Scholar 

  167. Müller, P. et al. Microtubule-depolymerizing agents used in antibody–drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol. Res. 2, 741–755 (2014).

    Article  PubMed  Google Scholar 

  168. Wei, Q. et al. The promise and challenges of combination therapies with antibody–drug conjugates in solid tumors. J. Hematol. Oncol. 17, 1 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Kroemer, G., Galassi, C., Zitvogel, L. & Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 23, 487–500 (2022).

    Article  CAS  PubMed  Google Scholar 

  170. Heiser, R. A. et al. Brentuximab vedotin-driven microtubule disruption results in endoplasmic reticulum stress leading to immunogenic cell death and antitumor immunity. Mol. Cancer Ther. 23, 68–83 (2024).

    Article  CAS  PubMed  Google Scholar 

  171. Boshuizen, J. et al. Cooperative targeting of immunotherapy-resistant melanoma and lung cancer by an AXL-targeting antibody–drug conjugate and immune checkpoint blockade. Cancer Res. 81, 1775–1787 (2021).

    Article  CAS  PubMed  Google Scholar 

  172. Martin, K. et al. The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity. Cancer Immunol. Immunother. 63, 925–938 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Mizumoto, N. et al. Discovery of novel immunostimulants by dendritic-cell-based functional screening. Blood 106, 3082–3089 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tanaka, H., Matsushima, H., Mizumoto, N. & Takashima, A. Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res. 69, 6978–6986 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Müller, P., Martin, K., Theurich, S., von Bergwelt-Baildon, M. & Zippelius, A. Cancer chemotherapy agents target intratumoral dendritic cells to potentiate antitumor immunity. Oncoimmunology 3, e954460 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Kashyap, A. S. et al. GEF-H1 signaling upon microtubule destabilization is required for dendritic cell activation and specific anti-tumor responses. Cell Rep. 28, 3367–3380 (2019). This study uncovers a novel GEF-H1-dependent signalling axis in DCs triggered by microtubule destabilization, highlighting its critical role in promoting antitumour immunity and its potential as a prognostic marker for improved survival of patients with cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer 4, 253–265 (2004).

    Article  CAS  PubMed  Google Scholar 

  178. Iwata, T. N. et al. A HER2-targeting antibody–drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol. Cancer Ther. 17, 1494–1503 (2018).

    Article  CAS  PubMed  Google Scholar 

  179. Galvez-Cancino, F. et al. Fcγ receptors and immunomodulatory antibodies in cancer. Nat. Rev. Cancer 24, 51–71 (2024).

    Article  CAS  PubMed  Google Scholar 

  180. Vidarsson, G., Dekkers, G. & Rispens, T. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 5, 520 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Bakalar, M. H. et al. Size-dependent segregation controls macrophage phagocytosis of antibody-opsonized targets. Cell 174, 131–142.e13 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Karampatzakis, A. et al. Antibody afucosylation augments CD16-mediated serial killing and IFNγ secretion by human natural killer cells. Front. Immunol. 12, 641521 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Ogitani, Y. et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin. Cancer Res. 22, 5097–5108 (2016).

    Article  CAS  PubMed  Google Scholar 

  184. Junttila, T. T., Li, G., Parsons, K., Phillips, G. L. & Sliwkowski, M. X. Trastuzumab–DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res. Treat. 128, 347–356 (2011).

    Article  CAS  PubMed  Google Scholar 

  185. Tai, Y.-T. et al. Novel anti-B-cell maturation antigen antibody–drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 123, 3128–3138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Hoffmann, R. M. et al. Antibody structure and engineering considerations for the design and function of antibody drug conjugates (ADCs). Oncoimmunology 7, e1395127 (2018).

    Article  PubMed  Google Scholar 

  187. Pittet, M. J., Michielin, O. & Migliorini, D. Clinical relevance of tumour-associated macrophages. Nat. Rev. Clin. Oncol. 19, 402–421 (2022).

    Article  PubMed  Google Scholar 

  188. Fu, C. et al. When will the immune-stimulating antibody conjugates (ISACs) be transferred from bench to bedside. Pharmacol. Res. 203, 107160 (2024).

    Article  CAS  PubMed  Google Scholar 

  189. Urban-Wojciuk, Z. et al. The role of TLRs in anti-cancer immunity and tumor rejection. Front. Immunol. 10, 2388 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Ackerman, S. E. et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat. Cancer 2, 18–33 (2021). This study demonstrates the development of ISACs that safely harness TLR7 and TLR8 activation for tumour-targeted immune responses, achieving localized tumour clearance, durable immunological memory and a compelling rationale for their clinical application.

    Article  CAS  PubMed  Google Scholar 

  191. Li, B. T. et al. A phase 1/2 study of a first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients with advanced HER2-expressing solid tumors. J. Clin. Oncol. 41, 2538–2538 (2023).

    Article  Google Scholar 

  192. Bolt Biotherapeutics. News Release Q1 2024. BoltBio.com https://investors.boltbio.com/news-releases/news-release-details/bolt-biotherapeutics-reports-first-quarter-2024-results/ (2024).

  193. Perez, C. et al. 743 INCLINE-101: preliminary safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of TAC-001 (TLR9 agonist conjugated to a CD22 mAb) in patients with advanced or metastatic solid tumors. J. Immunother. Cancer 11, A838 (2023).

    Google Scholar 

  194. Amouzegar, A., Chelvanambi, M., Filderman, J. N., Storkus, W. J. & Luke, J. J. STING agonists as cancer therapeutics. Cancers 13, 2695 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Chelvanambi, M., Fecek, R. J., Taylor, J. L. & Storkus, W. J. STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment. J. Immunother. Cancer 9, e001906 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Najem, H. et al. STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma. J. Clin. Invest. 134, e175033 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Wu, Y. T. et al. Tumor-targeted delivery of a STING agonist improves cancer immunotherapy. Proc. Natl Acad. Sci. USA 119, e2214278119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Duvall, J. R. et al. XMT-2056, a HER2-targeted immunosynthen STING-agonist antibody–drug conjugate, binds a novel epitope of HER2 and shows increased anti-tumor activity in combination with trastuzumab and pertuzumab. Cancer Res. 82, 3503–3503 (2022).

    Article  Google Scholar 

  199. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05514717 (2025).

  200. Korman, A. J., Garrett-Thomson, S. C. & Lonberg, N. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat. Rev. Drug Discov. 21, 509–528 (2022).

    Article  CAS  PubMed  Google Scholar 

  201. Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).

    Article  PubMed  Google Scholar 

  202. Okajima, D. et al. Abstract 2932: datopotamab deruxtecan (Dato-DXd) enhances antitumor response to PD-1/PD-L1 inhibitors in TROP2-expressing tumors in mice. Cancer Res. 83, 2932 (2023).

    Article  Google Scholar 

  203. Olson, D. et al. 1187 Enfortumab vedotin induces immunogenic cell death, elicits antitumor immune memory, and shows enhanced preclinical activity in combination with immune checkpoint inhibitors. J. Immunother. Cancer 10, A1231 (2022).

    Google Scholar 

  204. Iwai, T. et al. Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies. Oncotarget 9, 31411–31421 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).

    Article  CAS  PubMed  Google Scholar 

  206. Fultang, L. et al. MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers. EBioMedicine 47, 235–246 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Nicolò, E. et al. Combining antibody–drug conjugates with immunotherapy in solid tumors: current landscape and future perspectives. Cancer Treat. Rev. 106, 102395 (2022).

    Article  PubMed  Google Scholar 

  208. Mosele, F. et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat. Med. 29, 2110–2120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Mosele, M. F. et al. 343MO Unraveling the mechanisms of action and resistance to trastuzumab deruxtecan (T-DXd): supplementary biomarker analyses from DAISY trial. Ann. Oncol. 35, S359 (2024).

    Article  Google Scholar 

  210. Pistilli, B. et al. 340O Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase II study of patritumab deruxtecan (HER3-DXd) in patients (pts) with HR+/HER2– advanced breast cancer (ABC). Ann. Oncol. 35, S357 (2024).

    Article  Google Scholar 

  211. Oliveira, M. et al. Patritumab deruxtecan in untreated hormone receptor-positive/HER2-negative early breast cancer: final results from part A of the window-of-opportunity SOLTI TOT-HER3 pre-operative study. Ann. Oncol. 34, 670–680 (2023).

    Article  CAS  PubMed  Google Scholar 

  212. O’Donnell, P. H. et al. Enfortumab vedotin with or without pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial cancer. J. Clin. Oncol. 41, 4107–4117 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Tolaney, S. M. et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J. Clin. Oncol. 43, LBA109–LBA109 (2025).

    Article  Google Scholar 

  214. Emens, L. A. et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 21, 1283–1295 (2020).

    Article  CAS  PubMed  Google Scholar 

  215. Garrido-Castro, A. C. et al. SACI-IO HR+: a randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer. J. Clin. Oncol. 42, LBA1004 (2024).

    Article  Google Scholar 

  216. Schmid, P. et al. PD11-08 Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR−), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study. Cancer Res. 83 (Suppl. 5), abstr. PD11-08 (2023).

    Article  Google Scholar 

  217. Patel, J. D. et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) in first-line (1L) metastatic non-small cell lung cancer (mNSCLC) with PD-L1 ≥ 50%: Cohort A of EVOKE-02. J. Clin. Oncol. 42, 8592 (2024).

    Article  Google Scholar 

  218. Levy, B. P. et al. Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC): subgroup analysis from TROPION-Lung02. J. Clin. Oncol. 42, 8617 (2024).

    Article  Google Scholar 

  219. Lee, H. J. et al. Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced-stage classical Hodgkin lymphoma. Blood 145, 290–299 (2025).

    Article  CAS  PubMed  Google Scholar 

  220. Oliva, M. et al. 607O Interim results of a phase I study of SGN-PDL1V (PF-08046054) in patients with PDL1-expressing solid tumors. Ann. Oncol. 35 (Suppl. 2), S486 (2024).

    Article  Google Scholar 

  221. Sun, Q. et al. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal. Transduct. Target. Ther. 8, 320 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Xiong, A. et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet 405, 839–849 (2025).

    Article  CAS  PubMed  Google Scholar 

  223. Wu, L. et al. Efficacy and safety of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with solid tumors: clinical data from advanced cervical cancer and platinum-resistant recurrent ovarian cancer cohorts. J. Clin. Oncol. 42, 5524 (2024).

    Article  Google Scholar 

  224. Guo, Y. et al. Phase Ib/IIa safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced solid tumors. J. Clin. Oncol. 41, 2536 (2023).

    Article  Google Scholar 

  225. Sheng, X. et al. 1692P A phase Ib/IIa trial to evaluate the safety and efficacy of PM8002/ BNT327, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced renal cell carcinoma. Ann. Oncol. 35, S1014 (2024).

    Article  Google Scholar 

  226. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT06793332 (2025).

  227. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT06957561 (2025).

  228. Klein, C., Brinkmann, U., Reichert, J. M. & Kontermann, R. E. The present and future of bispecific antibodies for cancer therapy. Nat. Rev. Drug Discov. 23, 301–319 (2024).

    Article  CAS  PubMed  Google Scholar 

  229. Kang, M. S., Kong, T. W. S., Khoo, J. Y. X. & Loh, T. P. Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibody–drug conjugates. Chem. Sci. 12, 13613–13647 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Doi, T. et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 18, 1512–1522 (2017).

    Article  CAS  PubMed  Google Scholar 

  231. Leyland-Jones, B. et al. Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated. J. Clin. Oncol. 28, 960–966 (2010).

    Article  CAS  PubMed  Google Scholar 

  232. Dijkers, E. C. et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin. Pharmacol. Ther. 87, 586–592 (2010).

    Article  CAS  PubMed  Google Scholar 

  233. Davies, A. J. Radioimmunotherapy for B-cell lymphoma: Y-90 ibritumomab tiuxetan and I-131 tositumomab. Oncogene 26, 3614–3628 (2007).

    Article  CAS  PubMed  Google Scholar 

  234. Jain, R. K. Transport of molecules, particles, and cells in solid tumors. Annu. Rev. Biomed. Eng. 1, 241–263 (1999).

    Article  CAS  PubMed  Google Scholar 

  235. Mager, D. E. Target-mediated drug disposition and dynamics. Biochem. Pharmacol. 72, 1–10 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank K. Schäuble for valuable feedback and discussion.

Author information

Authors and Affiliations

  1. Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland

    Alfred Zippelius

  2. Medical Oncology, University Hospital Basel, Basel, Switzerland

    Alfred Zippelius

  3. Division of Breast Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Sara M. Tolaney & Paolo Tarantino

  4. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Paolo Tarantino

  5. Department of Pharmaceutical Sciences and Center for Protein Therapeutics, State University of New York at Buffalo, Buffalo, NY, USA

    Joseph P. Balthasar

  6. Department of Chemical Engineering and Biomedical Engineering, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Greg M. Thurber

Authors
  1. Alfred Zippelius
    View author publications

    Search author on:PubMed Google Scholar

  2. Sara M. Tolaney
    View author publications

    Search author on:PubMed Google Scholar

  3. Paolo Tarantino
    View author publications

    Search author on:PubMed Google Scholar

  4. Joseph P. Balthasar
    View author publications

    Search author on:PubMed Google Scholar

  5. Greg M. Thurber
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Greg M. Thurber.

Ethics declarations

Competing interests

A.Z. received consulting/adviser fees from Bristol Myers Squibb, Merck Sharp & Dohme, Hoffmann–La Roche, NBE Therapeutics and Engimmune; and maintains further non-commercial research agreements with Hoffmann–La Roche, T3 Pharma, Bright Peak Therapeutics, AstraZeneca and Memo Therapeutics. S.M.T receives institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, OncoPep, Daiichi Sankyo and Menarini/Stemline; has served as an adviser/consultant for Novartis, Pfizer (SeaGen), Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp., Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, Johnson&Johnson/Ambrx, Launch Therapeutics, Zuellig Pharma and Bicycle Therapeutics; and receives travel support from Eli Lilly, Sanofi, Gilead, Jazz Pharmaceuticals, Pfizer and Arvinas. P.T. received institutional research funding from AstraZeneca; and has served as an adviser/consultant for AstraZeneca, Daiichi Sankyo, Gilead, Roche/Genentech, Eli Lilly, Menarini/Stemline, Merck and Novartis. J.P.B. serves as Director of the University at Buffalo Center for Protein Therapeutics; has a portion of his research funded by the Center, which is supported by AbbVie, Amgen, AstraZeneca, CSL-Behring, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Merck, Roche, Sanofi and Seagen; has portions of his research supported by grants from the National Cancer Institute of the National Institutes of Health (NIH) (CA246785, CA256928, CA275967) and through a sponsored research agreement with Abceutics, Inc., a subsidiary of Merck; has received consulting fees from AbbVie, Amgen, AstraZeneca, GlaxoSmithKline, Genentech, Janssen, Merck, Roche and Sanofi; and also holds financial interests in specific compositions and in platform technologies (that is, anti-idiotypic distribution enhancers, payload-binding selectivity enhancers) that are under development for increasing the safety and efficacy of antibody–drug conjugates (ADCs). G.M.T receives institutional research funding, consulting/advising fees and/or travel support/honoraria from Abbvie, AstraZeneca/Medimmune, Advanced Proteome Therapeutics, Bristol Myers Squibb, Catalent, Crescendo Biologics, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Gilead Sciences, Iksuda Pharmaceuticals, Immunogen, Immunomedics, Incyte Corp., InVicro, Janssen Pharmaceuticals, Lumicell, Merck & Co., Merck KGaA, Mersana, Neoleukin, Nodus Therapeutics, Novartis, Pfizer, Roche/Genentech, Seattle Genetics, Synaffix/Lonza and Takeda Pharmaceuticals.

Peer review

Peer review information

Nature Reviews Cancer thanks Charles Dumontet, Gail Lewis and Barbara Pistilli for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Afucosylation

A glyco-engineering technique using the removal of fucose from N-linked glycans in Fc regions to increase natural killer cell-mediated antibody-dependent cellular cytotoxicity.

Antibody-dependent cellular cytotoxicity

(ADCC). A cell-to-cell cytolysis mechanism carried out by Fcγ receptor IIIA (FcγRIIIA)-expressing immune cells, such as natural killer cells, against cells coated in antibodies.

Antibody-dependent cellular phagocytosis

(ADCP). A cellular programme driven by Fcγ receptor I (FcγRI) and FcγRIIA primarily on macrophages to engulf cells coated with antibodies.

Antigen-presenting cells

(APCs). Immune cells that can internalize proteins, often facilitated by antibody Fc receptors, to process and display antigens (for example, cancer neoantigens) bound by major histocompatibility complex (MHC) proteins on their surface.

Dysgeusia

A condition where a person’s perception of taste is altered.

Fcγ receptor

(FcγR). A family of receptors on immune cells including the high-affinity FcγRI (also known as CD64) (cytokine release, antibody-dependent cellular phagocytosis (ADCP)) and low-affinity FcγRIIa (also known as CD32A) (ADCP), FcγRIIb (also known as CD32B) (inhibition) and FcγRIII (also known as CD16) (antibody-dependent cellular cytotoxicity).

Mannosylation

A type of glycosylation marked by the addition of mannose sugar residues to a protein, such as the glycosylation sites in the Fc domain of an antibody.

Maytansinoid

A payload drug class based on derivatives of the microtubule inhibitor maytansine.

Multivalency

The ability to bind to more than one site on a target cell including the bivalent (two binding sites) of an IgG protein and higher-order binding of novel constructs (such as tetravalent antibodies).

Neonatal Fc receptor

(FcRn). Originally described for antibody transmission from mother to young, this pH-sensitive receptor has a critical role in antibody and albumin metabolism and transcytosis.

On-rates

The bindings per time of an antibody (or other protein) to the target protein, often normalized to the concentration of the antibody, so the units are per molar per second.

Paratope

The surface of an antibody, typically the amino acid residues in the complementarity determining region, that directly interacts with the surface of the target protein, which is known as the epitope.

Pattern recognition receptors

(PRRs). Evolutionarily conserved proteins expressed by innate immune cells that trigger pro-inflammatory immune responses upon detection of pathogen-associated molecular patterns and damage-associated molecular patterns.

Pharmacodynamic response

The physiological changes induced by a drug, such as the antibody and/or the small-molecule payload, including for example the induction of apoptosis for a cytotoxic drug; often simply described as ‘the impact of the drug on the body’.

Pharmacokinetics

The time-varying concentration of drug and metabolites at different locations within the body including absorption, distribution, metabolism and excretion; often simply described as ‘the impact of the body on the drug’.

pKa

The negative log of the acid–base association constant describing the protonated state of a drug molecule at different pH values.

Protein degraders

Small-molecule drugs that can bind to a target protein and ubiquitin ligase to catalytically degrade the target protein, enabling the destruction of proteins without the need to inhibit their enzymatic activity.

Reticuloendothelial system

A network of phagocytic cells including macrophages, monocytes and Kupffer cells responsible for the removal of foreign particles including antibody complexes.

Self-immolating segments

A section of the linker that undergoes a spontaneous chemical reaction that cleaves all remaining linker atoms from the payload.

Target-mediated drug disposition

The altered pharmacokinetics of a drug due to substantial binding to its target in the body, often seen with antibodies at low doses against targets expressed at high concentrations in healthy tissue, thereby speeding up clearance.

Thrombocytopenia

Low platelet counts in the blood; a common type of antibody–drug conjugate toxicity.

Type III interferons

(Also known as interferon-λs). Antimicrobial cytokines initially recognized for their key roles in immune host defence at endothelial and epithelial barriers.

Vascular leak syndrome

A symptom wherein fluid leaks from capillaries in the tissue, leading to swelling and organ damage.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zippelius, A., Tolaney, S.M., Tarantino, P. et al. Unveiling the molecular and immunological drivers of antibody–drug conjugates in cancer treatment. Nat Rev Cancer (2025). https://doi.org/10.1038/s41568-025-00869-w

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41568-025-00869-w

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer