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

Authors

Xiaobao Wei, Jiangchao Wu, Wanyue Cao, Qitai Chen, Zhenduo Shao, Chengyang Hu, Yize Zhang, Weining Weng, Tao Meng, Xun Meng, Tingbo Liang, Qi Zhang

Published in

Oncogene. Sep 10, 2025. Epub Sep 10, 2025.

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.

PMID:
40931050
Bibliographic data and abstract were imported from PubMed on 11 Sep 2025.

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