Intraperitoneal programming of tailored CAR macrophages via mRNA lipid nanoparticle to boost cancer immunotherapy
Therapeutic strategies for peritoneal metastasis in solid tumors are urgently needed. Programming chimeric antigen receptor macrophages (CAR-Ms) in situ offers opportunities for an unmet demand. However, potential intracellular domains (ICDs) for CAR design and their antitumor mechanisms for macrophage empowerment remain to be explored systematically. By developing a macrophage-targeted mRNA lipid nanoparticle (mRNA-LNP) system, we evaluate 36 CAR formats in CAR-Ms. Tailored CAR-Ms with CD3ζ TLR4 ICDs elicit robust adaptive immune activation and significantly synergize with PD-1/L1 therapy. Single-cell RNA sequencing (scRNA-seq) reveals that CAR-Ms reshape the immunosuppressive tumor microenvironment (TME) and boost the TCF1<sup>+</sup>PD-1<sup>+</sup> progenitor-exhausted CD8<sup>+</sup> T cells (Tpex) population. Mechanistically, CAR-Ms maintain a proinflammatory phenotype and simultaneously upregulate MHC-I and PD-L1 by perturbing NF-κB pathways. Collectively, this approach enables intraperitoneal programming of tailored CAR-Ms and broadens understanding of both regulatory and feedback mechanisms for CAR-M therapies against solid tumors.
Authors
- Kedan Gu
- Sitao Xie (ORCID: https://orcid.org/0000-0002-4976-4840)
- Zhen Du (ORCID: https://orcid.org/0000-0001-7145-186X)
- Y. Zhang
- Juan Song (ORCID: https://orcid.org/0000-0001-7350-9578)
- Benmeng Liang
- Chao Zuo (ORCID: https://orcid.org/0000-0002-8419-6527)
- Yuping Zhu
- Hongyu Wu (ORCID: https://orcid.org/0000-0003-1278-4183)
- Liwen Li (ORCID: https://orcid.org/0000-0002-1777-2854)
- Wenxi Wang (ORCID: https://orcid.org/0000-0002-7088-0539)
- Penghui Zhang (ORCID: https://orcid.org/0000-0002-6512-1511)
- Yanqi Zhang (ORCID: https://orcid.org/0000-0001-6896-8657)
- Xinrui Lin (ORCID: https://orcid.org/0000-0003-3632-5563)
- Luting Hu
- Ting Liang
- Yashuang Chen
- Meng Wang
- Xiangsheng Liu
- Weihong Tan
- Mengke Zhang
- Yifan Zhao
- Weiyang Ying
Institutions
- Hunan University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Renji Hospital (CN)
- Zhejiang Cancer Hospital (CN)
- Zhejiang Center for Disease Control and Prevention (CN)
- Institute for Advanced Study (DE)
- University of Chinese Academy of Sciences (CN)
- Hangzhou Cancer Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-24
- DOI
- https://doi.org/10.1038/s41467-025-67674-9
- Citations
- 2
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- National Key Research and Development Program of China