Bridging innate and adaptive immunity: A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance
4 affiliations
- 1School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China
- 2Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China
- 3Department of Research and Development, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- 4Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Abstract
Macrophage-directed immunotherapy, exemplified by blocking the CD47-signal regulatory protein α (SIRPα) axis, can eliminate tumors by unleashing phagocytosis. However, such approaches often fail to generate durable antitumor immunity, revealing a disconnect between innate activation and effective T cell responses. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as an adaptive resistance factor induced by macrophage checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of major histocompatibility complex class I (MHC-I) in macrophages, impairing antigen cross-presentation and CD8+ T cell priming—thus showing how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this, we engineer bispecific fusion proteins co-targeting the CD47-SIRPα checkpoint and the PCSK9-MHC-I axis, among which SIRPαD1-αPCSK9 is optimal. Dual targeting synergistically enhances phagocytosis, preserves antigen cross-presentation, and reprograms tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 activates innate and adaptive antitumor immunity, achieving potent tumor control with improved safety. These findings uncover a resistance mechanism to macrophage-centered cancer immunotherapy and establish a dual-targeting strategy bridging phagocytosis and T cell activation.
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BibTeX
@article{xu2026bridging,
title = {{Bridging innate and adaptive immunity: A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance}},
author = {Caili Xu and Kaicheng Zhou and Xiaozhi Hu and Yanyang Nan and Yun Sun and Zihan Dou and Rui Zhou and Wenjing Xue and Qinchao Hu and Xiting Huang and Xianxin Hua and Dianwen Ju and Xuyao Zhang},
journal = {Cell Reports Medicine},
year = {2026},
month = oct,
doi = {10.1016/j.xcrm.2026.103087},
url = {https://doi.org/10.1016/j.xcrm.2026.103087},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Bridging innate and adaptive immunity: A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance
AU - Caili Xu
AU - Kaicheng Zhou
AU - Xiaozhi Hu
AU - Yanyang Nan
AU - Yun Sun
AU - Zihan Dou
AU - Rui Zhou
AU - Wenjing Xue
AU - Qinchao Hu
AU - Xiting Huang
AU - Xianxin Hua
AU - Dianwen Ju
AU - Xuyao Zhang
PY - 2026
DA - 2026/10/05
JO - Cell Reports Medicine
DO - 10.1016/j.xcrm.2026.103087
UR - https://doi.org/10.1016/j.xcrm.2026.103087
AB - Macrophage-directed immunotherapy, exemplified by blocking the CD47-signal regulatory protein α (SIRPα) axis, can eliminate tumors by unleashing phagocytosis. However, such approaches often fail to generate durable antitumor immunity, revealing a disconnect between innate activation and effective T cell responses. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as an adaptive resistance factor induced by macrophage checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of major histocompatibility complex class I (MHC-I) in macrophages, impairing antigen cross-presentation and CD8+ T cell priming—thus showing how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this, we engineer bispecific fusion proteins co-targeting the CD47-SIRPα checkpoint and the PCSK9-MHC-I axis, among which SIRPαD1-αPCSK9 is optimal. Dual targeting synergistically enhances phagocytosis, preserves antigen cross-presentation, and reprograms tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 activates innate and adaptive antitumor immunity, achieving potent tumor control with improved safety. These findings uncover a resistance mechanism to macrophage-centered cancer immunotherapy and establish a dual-targeting strategy bridging phagocytosis and T cell activation.
SN - 2666-3791
ER -