PSGL-1 is a phagocytosis checkpoint that enables tumor escape from macrophage clearance
Cancer immunotherapies exhibit impressive efficacy in some cancers but show only limited benefits for refractory hematological malignancies. The complex immune escape mechanisms of hematological cancers remain unclear. Here, we found that P-selectin glycoprotein ligand 1 (PSGL-1) was highly expressed by hematological cancers and negatively correlated with cancer prognosis. PSGL-1 deficiency in tumors suppressed the progression of multiple mouse models of hematological cancer by promoting infiltration of macrophages and their phagocytic activity. Tumor PSGL-1 inhibited the interaction between tumor ICAM-1 and CD11a/CD18 integrin (LFA-1) in macrophages, thereby suppressing prophagocytic signaling downstream of LFA-1. A humanized antibody targeting human PSGL-1 (αhPSGL-1) efficiently triggered macrophage phagocytosis of human hematological malignancies in vitro and slowed cancer progression in vivo. Additionally, PSGL-1 blockade potentiated the efficacy of doxorubicin chemotherapy and anti-CD47 and anti-CD38 antibody therapy. Therefore, PSGL-1 is a previously undescribed phagocytosis checkpoint, and targeting PSGL-1 could be a promising immunotherapy strategy for treating hematological malignancies.
Authors
- Chunliu Huang
- Cheng Zhong (ORCID: https://orcid.org/0000-0002-5815-5668)
- Yiyi Li (ORCID: https://orcid.org/0009-0000-8711-2723)
- Jing Liao (ORCID: https://orcid.org/0000-0001-6613-2696)
- Yue Sheng (ORCID: https://orcid.org/0000-0002-9424-123X)
- Yingyi He (ORCID: https://orcid.org/0000-0001-5479-2099)
- Zijin Xia
- Lixiang Wang
- Congzhou Luo (ORCID: https://orcid.org/0000-0002-3426-6806)
- Xianmiao Wang
- Chen-Yang Liao (ORCID: https://orcid.org/0000-0002-2898-7607)
- Hui Zhang (ORCID: https://orcid.org/0000-0001-8791-5753)
- Xinyu Wang
- Yi Wei (ORCID: https://orcid.org/0000-0003-0943-7244)
- Xiumei Wang (ORCID: https://orcid.org/0000-0001-8979-0747)
- Hongrui Song
- Chengzhou Mao (ORCID: https://orcid.org/0009-0007-1423-6929)
- Yongyi Feng
- Xiaolei Wei (ORCID: https://orcid.org/0000-0002-4271-9588)
- Jun Chen (ORCID: https://orcid.org/0000-0001-8051-5503)
- Yujia Liu (ORCID: https://orcid.org/0009-0001-1923-4611)
- W.F. Mai (ORCID: https://orcid.org/0000-0001-6859-0156)
- Yao Zhang
- Hong Yuan
Institutions
- Central South University (CN)
- Sun Yat-sen University (CN)
- Shenzhen University (CN)
- Wuhan University (CN)
- Shanghai Children's Medical Center (CN)
- Nanfang Hospital (CN)
- Guangzhou Women and Children Medical Center (CN)
- Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN)
- Fifth Affiliated Hospital of Sun Yat-sen University (CN)
- Second Xiangya Hospital of Central South University (CN)
- Hangzhou Cancer Hospital (CN)
- Southern Medical University (CN)
- Zhejiang University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-06-13
- DOI
- https://doi.org/10.1126/sciimmunol.adn4302
- Citations
- 13
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 10.37