Tong Qi-Song, Huang Hua, Yu Hui-Han, Liu Rong, Shen Song, Du Jin-Zhi
Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China; School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, China.
School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 511442, China.
Biomaterials. 2025 Apr;315:122910. doi: 10.1016/j.biomaterials.2024.122910. Epub 2024 Oct 22.
Remodeling the immunosuppressive tumor microenvironment (TME) by immunomodulators has been well studied in the past years. However, strategies that enable concurrent modulation of both the immunosuppressive TME and tumor-draining lymph nodes (TDLNs) are still in the infancy. Here, we report a pH-sensitive size-switchable nanocluster, SPN-R848, to achieve simultaneous accumulation in tumor and TDLNs for immune activation. SPN-R848 with original size around 150 nm was formed by self-assembly of resiquimod (R848)-conjugated polyamidoamine (PAMAM) derivative, which could disintegrate into its small constituents (～ 8 nm) upon exposure to tumor acidity. The size reduction not only enhanced their accumulation and perfusion in the primary tumor, but promoted their transport and distribution in TDLNs. Accordingly, SPN-R848 remarkably remodeled the immunosuppressive TME by polarizing M2 to M1 macrophages and activated dendritic cells (DCs) in TDLNs, which synergistically facilitated the production and stimulation of cytotoxic T cells, and inhibited tumor growth in breast cancer and melanoma mouse models. Our study suggests that co-activation of immune microenvironments in both tumor and TDLNs may represent a promising direction to elicit strong antitumor immunity.
在过去几年中，通过免疫调节剂重塑免疫抑制性肿瘤微环境（TME）已得到充分研究。然而，能够同时调节免疫抑制性TME和肿瘤引流淋巴结（TDLN）的策略仍处于起步阶段。在此，我们报告一种pH敏感的尺寸可切换纳米簇SPN-R848，以实现其在肿瘤和TDLN中的同时积累，从而激活免疫。原始尺寸约为150纳米的SPN-R848由瑞喹莫德（R848）缀合的聚酰胺胺（PAMAM）衍生物自组装而成，在暴露于肿瘤酸性环境时可分解成其小的组成部分（约8纳米）。尺寸减小不仅增强了它们在原发性肿瘤中的积累和灌注，还促进了它们在TDLN中的转运和分布。因此，SPN-R848通过将M2巨噬细胞极化为M1巨噬细胞，显著重塑了免疫抑制性TME，并激活了TDLN中的树突状细胞（DC），协同促进了细胞毒性T细胞的产生和刺激，并在乳腺癌和黑色素瘤小鼠模型中抑制了肿瘤生长。我们的研究表明，同时激活肿瘤和TDLN中的免疫微环境可能是引发强大抗肿瘤免疫的一个有前景的方向。
