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<p>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.</p>

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Intraperitoneal programming of tailored CAR macrophages via mRNA lipid nanoparticle to boost cancer immunotherapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月24日

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  • Kedan Gu,
  • Ting Liang,
  • Luting Hu,
  • Yifan Zhao,
  • Weiyang Ying,
  • Mengke Zhang,
  • Yashuang Chen,
  • Benmeng Liang,
  • Xinrui Lin,
  • Yanqi Zhang,
  • Hongyu Wu,
  • Meng Wang,
  • Yuping Zhu,
  • Wenxi Wang,
  • Yu Zhang,
  • Chao Zuo,
  • Zhen Du,
  • Penghui Zhang,
  • Jia Song,
  • Liwen Li,
  • Xiangsheng Liu,
  • Sitao Xie,
  • Weihong Tan

摘要

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+PD-1+ progenitor-exhausted CD8+ 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.