肿瘤相关巨噬细胞（TAM）——肿瘤微环境（TME）中的代表性免疫抑制细胞——已知可促进肿瘤进展和转移，因此被认为是癌症治疗的一个有吸引力的靶点。然而，目前的 TAM 靶向策略不足以产生强大的抗肿瘤功效。在这里，我们报告了一种封装免疫刺激性 CpG 寡脱氧核苷酸（SLNP@CpG）的小脂质纳米颗粒，作为一种新的免疫治疗方式，可以重新编程 TAM 并进一步桥接先天免疫和适应性免疫。我们发现 SLNP@CpG 治疗增强了巨噬细胞介导的癌细胞吞噬作用和肿瘤抗原交叉呈递，并在体外扭曲了巨噬细胞的极化状态。将 SLNP@CpG 瘤内注射到已建立的小鼠 E.G7-OVA 肿瘤模型中，可显着抑制肿瘤生长并显着延长生存期，完全根除 83.3% 小鼠的肿瘤。此外，无肿瘤小鼠通过诱导免疫记忆和长期抗肿瘤免疫来抵抗 E.G7-OVA 癌细胞的再次攻击。 SLNP@CpG 甚至通过将 TME 重塑为免疫刺激和肿瘤消除，在侵袭性 B16-F10 黑色素瘤模型中发挥抗肿瘤功效。这些发现表明，通过调节 TAM 的功能并重塑免疫抑制性 TME，这里开发的 SLNP@CpG 纳米药物可能成为适用于多种肿瘤的有前途的免疫治疗选择。本文受版权保护。保留所有权利。本文受版权保护。版权所有。

Tumor-associated macrophages (TAMs)-representative immune-suppressive cells in the tumor microenvironment (TME)-are known to promote tumor progression and metastasis, and thus have been considered an attractive target for cancer therapy. However, current TAM-targeting strategies are insufficient to result in robust antitumor efficacy. Here, we report a small lipid nanoparticle encapsulating immunostimulatory CpG oligodeoxynucleotides (SLNP@CpG) as a new immunotherapeutic modality that can reprogram TAMs and further bridge innate-to-adaptive immunity. We found that SLNP@CpG treatment enhanced macrophage-mediated phagocytosis of cancer cells and tumor antigen cross-presentation and skewed the polarization state of macrophages in vitro. Intratumoral injection of SLNP@CpG into an established murine E.G7-OVA tumor model significantly suppressed tumor growth and considerably prolonged survival, completely eradicating tumors in 83.3% of mice. Furthermore, tumor-free mice resisted rechallenge with E.G7-OVA cancer cells through induction of immunological memory and long-term antitumor immunity. SLNP@CpG even exerted antitumor efficacy in an aggressive B16-F10 melanoma model by remodeling TME towards immune stimulation and tumor elimination. These findings suggest that, by modulating the function of TAMs and reshaping an immunosuppressive TME, the SLNP@CpG nanomedicine developed here may become a promising immunotherapeutic option applicable to a variety of tumors. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.