肿瘤细胞治疗研究
英文原题：PD-L1-targeted OMV priming licenses myeloid co-stimulation and chemokine circuits to potentiate CAR-T therapy in advanced-stage solid tumors.
PD-L1-targeted OMV priming licenses myeloid co-stimulation and chemokine circuits to potentiate CAR-T therapy in advanced-stage solid tumors.
靶向 PD-L1 的 OMV 预激提供了一种模块化、全身性的策略，通过激活髓系细胞区室并增强瘤内共刺激来重编程实体瘤免疫生态系统，从而支持改善 CAR-T 的招募和功能。
**背景：**CAR-T（CAR-T）细胞疗法在血液系统恶性肿瘤中取得显著成功，但实体瘤中的免疫抑制性肿瘤微环境（TME）常限制其迁移、持续性和效应功能。靶向预处理策略若能重塑髓系细胞群并增强肿瘤内共刺激，可能有助于克服这些障碍。**方法：**我们构建了表面展示靶向 PD-L1 单链可变片段的细菌外膜囊泡（OMV PD-L1 scFv），并在体外评估其肿瘤靶向及免疫调节功能，包括 DC 成熟、共刺激能力、巨噬细胞极化和吞噬作用。在同系模型中评估其抗肿瘤疗效及 TME 重塑，特别考察其与降低剂量 CAR-T 治疗的协同作用。进一步通过单细胞 RNA 测序（scRNA-seq）阐明 OMV 预处理相关的早期免疫重编程机制和细胞间通讯程序。**结果：**全身给药后，OMV PD-L1 scFv 在肿瘤中的蓄积增加，并通过提高 DC 成熟度和共刺激能力，以及使巨噬细胞转向促炎、吞噬肿瘤的程序，促进髓系细胞功能许可。体内，OMV PD-L1 scFv 重塑 TME，改善 CAR-T 活化、肿瘤迁移和抗肿瘤疗效；即使在晚期实体瘤中使用降低剂量的 CAR-T，也能实现强效肿瘤控制。scRNA-seq 显示淋巴系和髓系细胞协调重塑，其特征包括 T 细胞功能状态改善相关表达谱富集、可能与 Xcl1 介导 DC 募集有关的转录特征、增强的 DC-T 共刺激 CD28 轴，以及预测由 Ccl3/4/5-Ccr5 参与的趋化因子驱动髓系-淋巴系通讯增强。**结论：**靶向 PD-L1 的 OMV 预处理提供了一种模块化全身策略，可通过赋能髓系细胞群并增强肿瘤内共刺激，重编程实体瘤免疫生态系统，从而改善 CAR-T 募集和功能。这些发现确立了工程化 OMV 作为具有机制依据的预处理平台，可与 CAR 设计互补，用于实体瘤免疫治疗。
BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable success in hematologic malignancies, yet its efficacy in solid tumors is frequently limited by an immunosuppressive tumor microenvironment (TME) that restrains trafficking, persistence, and effector function. Targeted priming strategies that remodel myeloid compartments and reinforce intratumoral co-stimulation may help overcome these barriers. METHODS: We engineered bacterial outer membrane vesicles displaying PD-L1-targeting single-chain variable fragment (OMV PD-L1 scFv ). Their tumor-targeting and immunomodulatory functions, including DC maturation, co-stimulatory capacity, macrophage polarization, and phagocytosis, were evaluated in vitro. The potent antitumor efficacy and TME remodeling were examined in syngeneic models, specifically highlighting its synergy with dose-de-escalated CAR-T therapy. Single-cell RNA sequencing (scRNA-seq) further elucidated the mechanisms of early immune rewiring and intercellular communication programs associated with OMV priming. RESULTS: OMV PD-L1 scFv demonstrated enhanced tumor accumulation following systemic administration and promoted myeloid licensing by increasing DC maturation and co-stimulatory competence while repolarizing macrophages toward pro-inflammatory, tumor-phagocytic program. In vivo, OMV PD-L1 scFv remodeled the TME and improved CAR-T activation, tumor trafficking, and antitumor efficacy, achieving robust tumor control even at reduced CAR-T dosages in advanced solid tumors. scRNA-seq analyses highlighted transcriptomic signatures consistent with coordinated lymphoid and myeloid remodeling, characterized by enriched profiles of improved T-cell functional states, a potential transcriptomic basis for Xcl1-mediated DC recruitment, strengthened DC-to-T co-stimulatory CD28 axis, and predicted enrichment of chemokine-driven myeloid-lymphoid communication involving Ccl3/4/5-Ccr5. CONCLUSIONS: PD-L1-directed OMV priming provides a modular, systemic strategy to reprogram the solid-tumor immune ecosystem by licensing myeloid compartments and reinforcing intratumoral co-stimulation, thereby supporting improved CAR-T recruitment and function. These findings establish engineered OMVs as a mechanistically grounded priming platform to complement CAR design for solid tumor immunotherapy.
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