Nature子刊：谭蔚泓院士团队开发in vivo CAR-M细胞疗法，增强癌症免疫治疗

Core Viewpoint - The article discusses the significant clinical challenge of peritoneal metastasis in solid tumors and highlights the potential of CAR macrophage (CAR-M) therapy as a promising immunotherapy approach to address this unmet clinical need [2][7]. Group 1: Clinical Challenges and Current Treatments - Peritoneal metastasis from solid tumors poses a major clinical challenge, with current treatments like cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) only benefiting a small subset of patients with very low tumor burden [2]. - Immunotherapy is seen as a promising frontier for treating peritoneal metastasis, but many patients develop escape mechanisms against the immune system, leading to disease progression and poor prognosis [2]. Group 2: CAR-M Therapy Development - The research led by Chinese Academy of Sciences explores 36 different CAR combinations targeting macrophages, utilizing an mRNA lipid nanoparticle (LNP) system for efficient in vivo construction of CAR-M cells necessary for tumor immunotherapy [3][7]. - The study demonstrates that intraperitoneal programming of CAR-M cells can induce robust adaptive immune system activation and significantly enhance the efficacy of standard PD-1/PD-L1 immune checkpoint blockade therapies in resistant models [4][7]. Group 3: Mechanisms and Findings - Customized CAR-M cells with CD3ζ and TLR4 transmembrane domains can trigger strong adaptive immune activation and significantly synergize with PD-1/PD-L1 therapies [7]. - Single-cell RNA sequencing (scRNA-seq) reveals that CAR-M cells reshape the immunosuppressive tumor microenvironment (TME) and promote the formation of TCF1+ PD-1+ exhausted CD8+ T cell populations [4][7]. - Mechanistically, CAR-M cells maintain a pro-inflammatory phenotype while upregulating MHC-I and PD-L1 through interference with the NF-κB pathway [4][7]. Group 4: Conclusion and Future Directions - The study develops an mRNA-LNP delivery system for targeted in vivo programming of CAR-M cells, deepening the understanding of the regulatory and feedback mechanisms of CAR-M therapy in treating solid tumors [10].