Skip to main content

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.

  • Article
  • Published:

A novel FAP-targeting antibody-exatecan conjugate improves immune checkpoint blockade by reversing immunosuppressive microenvironment in pancreatic cancer

Oncogene volume 44, pages 4114–4129 (2025)Cite this article

Subjects

Abstract

Pancreatic cancer is a highly aggressive malignancy with a dismal prognosis, characterized by a complex tumor microenvironment that promotes immunosuppression and limits the efficacy of immune checkpoint blockade (ICB) therapy. Fibroblast activation protein (FAP) is overexpressed in the tumor stroma and represents a promising target for therapeutic intervention. Here, we developed a novel antibody-drug conjugate (ADC) targeting FAP, and investigated its anti-tumor activity and ability to enhance ICB efficacy in pancreatic cancer. We conjugated a humanized anti-FAP antibody with the potent topoisomerase I inhibitor exatecan to generate a novel FAP-targeting ADC (FAP-ADC) with a drug-to-antibody ratio of eight. The cytotoxicity and internalization of FAP-ADC were evaluated in vitro using FAP-expressing cell lines, and its anti-tumor activity was assessed in vivo using cell-derived xenograft models. Mechanistic studies revealed that FAP-ADC synergistically improved the efficacy of anti-PD-L1 antibody in vivo by leading to an increased level of M1-polarized macrophages and reduced abundance of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. Furthermore, FAP-ADC treatment enhanced the infiltration of CD8+ T cells into the tumor and upregulated the expression of pro-inflammatory cytokines. Combination therapy with FAP-ADC and anti-PD-L1 antibodies resulted in superior anti-tumor efficacy compared to either monotherapy. Collectively, our novel FAP-targeting ADC exerts potent anti-tumor activity in pancreatic cancer by selectively depleting FAP-expressing cells and reversing the immunosuppressive tumor microenvironment. The combination of FAP-ADC with ICB therapy represents a promising therapeutic strategy to improve the treatment outcomes for patients with this fatal cancer.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: Generation and characterization of FAP-ADC.
Fig. 2: The FAP-ADC exhibits potent and specific dose-dependent cytotoxic activity both in vivo and in vitro.
Fig. 3: Anti-tumor activity of FAP-ADC in multiple models of pancreatic cancer.
Fig. 4: FAP-ADC exerts anti-tumor activity by reshaping the tumor immune microenvironment.
Fig. 5: FAP-ADC-induced antitumor immunity is primarily dependent on elimination of FAP-positive CAFs.
Fig. 6: FAP-ADC enhances the efficacy of immunotherapy in vivo.
Fig. 7: FAP-ADC combined with anti-PD-L1 antibodies activates anti-tumor immunity by reducing Tregs and MDSCs.
Fig. 8: The antitumor response of combined FAP-ADC and anti-PD-L1 is dependent on CD8+ T cells and macrophages.

Similar content being viewed by others

Data availability

Data will be made available on request.

References

  1. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet. 2020;395:2008–20.

    Article  CAS  PubMed  Google Scholar 

  2. Naimi A, Mohammed RN, Raji A, Chupradit S, Yumashev AV, Suksatan W, et al. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell Commun Signal. 2022;20:44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Henriksen A, Dyhl-Polk A, Chen I, Nielsen D. Checkpoint inhibitors in pancreatic cancer. Cancer Treat Rev. 2019;78:17–30.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang X, Lao M, Yang H, Sun K, Dong Y, He L, et al. Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance. Autophagy. 2024;20:1314–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Duan Y, Zhang X, Ying H, Xu J, Yang H, Sun K, et al. Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix. Oncogene. 2023;42:2061–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang T, Ren Y, Yang P, Wang J, Zhou H. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cell Death Dis. 2022;13:897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shahvali S, Rahiman N, Jaafari MR, Arabi L. Targeting fibroblast activation protein (FAP): advances in CAR-T cell, antibody, and vaccine in cancer immunotherapy. Drug Deliv Transl Res. 2023;13:2041–56.

    Article  CAS  PubMed  Google Scholar 

  8. Fitzgerald AA, Weiner LM. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev. 2020;39:783–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cohen SJ, Alpaugh RK, Palazzo I, Meropol NJ, Rogatko A, Xu Z, et al. Fibroblast Activation Protein and Its Relationship to Clinical Outcome in Pancreatic Adenocarcinoma. Pancreas. 2008;37:154–8.

    Article  CAS  PubMed  Google Scholar 

  10. MacNeil T, Vathiotis IA, Shafi S, Aung TN, Zugazagoitia J, Gruver AM, et al. Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes, Cancer-Associated Fibroblasts, and CD200 in Pancreatic Cancer. Cancers (Basel). 2021;13:5501.

    Article  CAS  PubMed  Google Scholar 

  11. Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W, et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 2003;9:1639–47.

    CAS  PubMed  Google Scholar 

  12. Adams S, Miller GT, Jesson MI, Watanabe T, Jones B, Wallner BP. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004;64:5471–80.

    Article  CAS  PubMed  Google Scholar 

  13. Privé BM, Boussihmad MA, Timmermans B, van Gemert WA, Peters SMB, Derks YHW, et al. Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies. Eur J Nucl Med Mol Imaging. 2023;50:1906–18.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Petrausch U, Schuberth PC, Hagedorn C, Soltermann A, Tomaszek S, Stahel R, et al. Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1). BMC Cancer. 2012;12:615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gottschalk S, Yu F, Ji M, Kakarla S, Song XT. A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading. PLoS One. 2013;8:e82658.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lee J, Fassnacht M, Nair S, Boczkowski D, Gilboa E. Tumor Immunotherapy Targeting Fibroblast Activation Protein, a Product Expressed in Tumor-Associated Fibroblasts. Cancer Res. 2005;65:11156–63.

    Article  CAS  PubMed  Google Scholar 

  17. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11:69.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee CC, Restifo NP, et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med. 2013;210:1125–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li X, Wang Y, Zhao Y, Yang H, Tong A, Zhao C, et al. Immunotherapy of tumor with vaccine based on basic fibroblast growth factor-activated fibroblasts. J Cancer Res Clin Oncol. 2014;140:271–80.

    Article  CAS  PubMed  Google Scholar 

  20. Fabre M, Ferrer C, Domínguez-Hormaetxe S, Bockorny B, Murias L, Seifert O, et al. OMTX705, a Novel FAP-Targeting ADC Demonstrates Activity in Chemotherapy and Pembrolizumab-Resistant Solid Tumor Models. Clinical Cancer Res. 2020;26:3420–30.

    Article  CAS  Google Scholar 

  21. Gogia P, Ashraf HA-O, Bhasin S, Xu Y. Antibody-Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence. Cancers (Basel). 2023;15:3886.

    Article  CAS  PubMed  Google Scholar 

  22. Weng W, Meng T, Zhao Q, Shen Y, Fu G, Shi J, et al. Antibody–Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer. Cancer Discov. 2023;13:950–73.

    Article  PubMed  Google Scholar 

  23. Peng H, Wu X, Liu S, He M, Xie C, Zhong R, et al. Multiplex immunofluorescence and single-cell transcriptomic profiling reveal the spatial cell interaction networks in the non-small cell lung cancer microenvironment. Clin Transl Med. 2023;13:e1155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330:827–30.

    Article  CAS  PubMed  Google Scholar 

  25. Galbo PM Jr, Zang X, Zheng D. Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance. Clin Cancer Res. 2021;27:2636–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fiori ME, Di Franco S, Villanova L, Bianca P, Stassi G, De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol Cancer. 2019;18:70.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lo A, Li C-P, Buza EL, Blomberg R, Govindaraju P, Avery D, et al. Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma. JCI Insight. 2017;2:e92232.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Santos AM, Jung J, Aziz N, Kissil JL, Puré E. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. Journal Clin Investig. 2009;119:3613–25.

    Article  CAS  Google Scholar 

  29. Baah S, Laws M, Rahman KM. Antibody-Drug Conjugates-A Tutorial Review. Molecules. 2021;26:2943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA. 2013;110:20212–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lin Y, Li B, Yang X, Cai Q, Liu W, Tian M, et al. Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment. Neoplasia. 2019;21:1133–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. O’Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, Sun W, et al. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019;5:1431–8.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bear AS, Vonderheide RH, O’Hara MH. Challenges and Opportunities for Pancreatic Cancer Immunotherapy. Cancer Cell. 2020;38:788–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Key Research & Development Program (No. 2020YFA0804300/2020YFA0804301), the National Natural Science Foundation of China (Nos. 82273338, 32321002, and 82188102), The Major Research Plan of the National Natural Science Foundation of China (No. 92474301), Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0525100/2024ZD0525104) and Major Project Jointly Constructed by Science and Education Department of National Administration of Traditional Chinese Medicine and Zhejiang Provincial Administration of Traditional Chinese Medicine (GZY-ZJ-KJ-23025).

Author information

Author notes

  1. These authors contributed equally: Xiaobao Wei, Jiangchao Wu.

Authors and Affiliations

  1. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Xiaobao Wei, Jiangchao Wu, Wanyue Cao, Qitai Chen, Chengyang Hu, Yize Zhang, Tingbo Liang & Qi Zhang

  2. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Xiaobao Wei, Jiangchao Wu, Wanyue Cao, Qitai Chen, Chengyang Hu, Yize Zhang, Tingbo Liang & Qi Zhang

  3. MOE Joint International Research Laboratory of Pancreatic Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Xiaobao Wei, Jiangchao Wu, Wanyue Cao, Qitai Chen, Chengyang Hu, Yize Zhang, Tingbo Liang & Qi Zhang

  4. Zhejiang University Cancer Center, Zhejiang University, Hangzhou, China

    Xiaobao Wei, Jiangchao Wu, Wanyue Cao, Qitai Chen, Zhenduo Shao, Chengyang Hu, Yize Zhang, Tingbo Liang & Qi Zhang

  5. Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China

    Zhenduo Shao

  6. Multitude Therapeutics, Xuhui District, Shanghai, China

    Weining Weng & Xun Meng

  7. Abmart Inc, Xuhui District, Shanghai, China

    Weining Weng & Xun Meng

  8. MabCare Therapeutics, Shanghai, China

    Tao Meng

  9. HySlink Therapeutics, Shanghai, China

    Tao Meng

  10. Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China

    Tingbo Liang & Qi Zhang

  11. The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China

    Tingbo Liang & Qi Zhang

Authors
  1. Xiaobao Wei
    View author publications

    Search author on:PubMed Google Scholar

  2. Jiangchao Wu
    View author publications

    Search author on:PubMed Google Scholar

  3. Wanyue Cao
    View author publications

    Search author on:PubMed Google Scholar

  4. Qitai Chen
    View author publications

    Search author on:PubMed Google Scholar

  5. Zhenduo Shao
    View author publications

    Search author on:PubMed Google Scholar

  6. Chengyang Hu
    View author publications

    Search author on:PubMed Google Scholar

  7. Yize Zhang
    View author publications

    Search author on:PubMed Google Scholar

  8. Weining Weng
    View author publications

    Search author on:PubMed Google Scholar

  9. Tao Meng
    View author publications

    Search author on:PubMed Google Scholar

  10. Xun Meng
    View author publications

    Search author on:PubMed Google Scholar

  11. Tingbo Liang
    View author publications

    Search author on:PubMed Google Scholar

  12. Qi Zhang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Xiaobao Wei: Methodology, Animal studies, Formal analysis, Investigation, Validation, Writing – original draft, Writing review and Editing. Jiangchao Wu: Methodology, Animal studies, Formal analysis, Investigation, Validation, Writing – original draft, Writing review and Editing. Wanyue Cao: Methodology, Writing–review and Editing. Qitai Chen: Investigation, Animal studies and Writing–review and Editing. Zhenduo Shao: Investigation, Animal studies and Writing–review and Editing. Chengyang Hu: Investigation, Animal studies and Writing–review and Editing. Yize Zhang: Investigation, Animal studies and Writing–review and Editing. Weining Weng: Investigation, Writing–review and Editing. Tao Meng: Investigation, Writing–review and Editing. Xun Meng: Conceptualization, investigation, Methodology, Project administration, Preparation and characterization of materials, Writing–review and Editing. Qi Zhang: Methodology, Conceptualization, Writing–original draft, Project administration, Writing–review and Editing, Funding acquisition. Tingbo Liang: Methodology, Conceptualization, Writing–original draft, Project administration, Writing–review and Editing, Funding acquisition.

Corresponding authors

Correspondence to Xun Meng, Tingbo Liang or Qi Zhang.

Ethics declarations

Competing interests

Dr. Xun Meng and Weining Weng work in and holds share of Multitude Therapeutics and Abmart Inc. Tao Meng works in MabCare Therapeutics and HySlink Therapeutics. The other authors declare no conflict of interest.

Ethics approval and consent to participate

All experimental procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the First Affiliated Hospital, School of medicine, Zhejiang University (Approval No. 2024-1177). A copy of the ethics committee’s approval letter is available as online supplementary material. Human pancreatic ductal adenocarcinoma (PDAC) specimens were surgically obtained from the Hepatobiliary and Pancreatic Surgery Department. This study protocol received ethical clearance from the Institutional Review Board (IRB) of the First Affiliated Hospital, School of Medicine, Zhejiang University (Approval No. IIT20240569). Written informed consent was acquired from all participating subjects prior to tissue collection. All methods were performed in accordance with the relevant guidelines and regulations.

Additional information

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

Supplementary information

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

Wei, X., Wu, J., Cao, W. et al. A novel FAP-targeting antibody-exatecan conjugate improves immune checkpoint blockade by reversing immunosuppressive microenvironment in pancreatic cancer. Oncogene 44, 4114–4129 (2025). https://doi.org/10.1038/s41388-025-03567-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-025-03567-x

Search

Advanced search

Quick links