Tumor-associated macrophages (TAMs) constitute 50–80% of stromal cells in most solid tumors with high mortality and poor prognosis. Tumor-infiltrating dendritic cells (TIDCs) and TAMs are key components mediating immune responses within the tumor microenvironment (TME). Considering their refractory properties, simultaneous remodeling of TAMs and TIDCs is a potential strategy of boosting tumor immunity and restoring immunosurveillance. In this study, mannose-decorated poly(lactic--glycolic acid) nanoparticles loading with R848 (Man-pD-PLGA-NP@R848) were prepared to dually target TAMs and TIDCs for efficient tumor immunotherapy. The three-dimensional (3D) cell culture model can simulate tumor growth as influenced by the TME and its 3D structural arrangement. Consequently, cancer spheroids enriched with tumor-associated macrophages (TAMs) were fabricated to assess the therapeutic effectiveness of Man-pD-PLGA-NP@R848. In the TME, Man-pD-PLGA-NP@R848 targeted both TAMs and TIDCs in a mannose receptor-mediated manner. Subsequently, Man-pD-PLGA-NP@R848 released R848 to activate Toll-like receptors 7 and 8, following dual-reprograming of TIDCs and TAMs. Man-pD-PLGA-NP@R848 could uniquely reprogram TAMs into antitumoral phenotypes, decrease angiogenesis, reprogram the immunosuppressive TME from “cold tumor” into “hot tumor”, with high CD4+ and CD8+ T cell infiltration, and consequently hinder tumor development in B16F10 tumor-bearing mice. Therefore, dual-reprograming of TIDCs and TAMs with the Man-pD-PLGA-NP@R848 is a promising cancer immunotherapy strategy.

中文翻译：

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使用甘露糖化纳米疗法靶向肿瘤相关巨噬细胞，提供 TLR7/8 激动剂，增强癌症免疫治疗


肿瘤相关巨噬细胞（TAM）占大多数实体瘤基质细胞的 50-80%，死亡率高，预后差。肿瘤浸润树突状细胞 (TIDC) 和 TAM 是介导肿瘤微环境 (TME) 内免疫反应的关键成分。考虑到它们的难治特性，TAM 和 TIDC 的同时重塑是增强肿瘤免疫和恢复免疫监视的潜在策略。在本研究中，制备了负载R848的甘露糖修饰的聚乳酸-乙醇酸纳米颗粒（Man-pD-PLGA-NP@R848），以双重靶向TAM和TIDC，以实现有效的肿瘤免疫治疗。三维 (3D) 细胞培养模型可以模拟受 TME 及其 3D 结构排列影响的肿瘤生长。因此，制备了富含肿瘤相关巨噬细胞 (TAM) 的癌症球体，以评估 Man-pD-PLGA-NP@R848 的治疗效果。在 TME 中，Man-pD-PLGA-NP@R848 以甘露糖受体介导的方式同时靶向 TAM 和 TIDC。随后，在对 TIDC 和 TAM 进行双重重编程后，Man-pD-PLGA-NP@R848 释放 R848 来激活 Toll 样受体 7 和 8。 Man-pD-PLGA-NP@R848可以独特地将TAM重编程为抗肿瘤表型，减少血管生成，将免疫抑制TME从“冷肿瘤”重编程为“热肿瘤”，具有高CD4+和CD8+ T细胞浸润，从而阻碍肿瘤的发展B16F10 荷瘤小鼠。因此，使用 Man-pD-PLGA-NP@R848 对 TIDC 和 TAM 进行双重重编程是一种有前景的癌症免疫治疗策略。