The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, China; Shenzhen Bay Laboratory, Shenzhen 518132, China; School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, China.
Shenzhen Bay Laboratory, Shenzhen 518132, China.
Acta Biomater. 2024 Sep 15;186:369-382. doi: 10.1016/j.actbio.2024.07.042. Epub 2024 Aug 2.
Immunotherapy, as a promising treatment strategy for cancer, has been widely employed in clinics, while its efficiency is limited by the immunosuppression of tumor microenvironment (TME). Tumor-associate macrophages (TAMs) are the most abundant immune cells infiltrating the TME and play a crucial role in immune regulation. Herein, a M0-type macrophage-mediated drug delivery system (PR-M) was designed for carrying Toll-like receptors (TLRs) agonist-loaded nanoparticles. When TLR agonist R848 was released by responding to the TME, the PR-Ms were polarized from M0-type to M1-type and TAMs were also stimulated from M2-type to M1-type, which eventually reversed the immunosuppressive states of TME. By synergizing with the released R848 agonists, the PR-M significantly activated CD4 and CD8 T cells in the TME and turned the 'cold' tumor into 'hot' tumor by regulating the secretion of cytokines including IFN-γ, TNF-α, IL-10, and IL-12, thus ultimately promoting the activation of antitumor immunity. In a colorectal cancer mouse model, the PR-M treatment effectively accumulated at the tumor site, with a 5.47-fold increase in M1-type and a 65.08 % decrease in M2-type, resulting in an 85.25 % inhibition of tumor growth and a 87.55 % reduction of tumor volume compared with the non-treatment group. Our work suggests that immune cell-mediated drug delivery systems can effectively increase drug accumulation at the tumor site and reduce toxic side effects, resulting in a strong immune system for tumor immunotherapy. STATEMENT OF SIGNIFICANCE: The formation of TME and the activation of TAMs create an immunosuppressive network that allows tumor to escape the immune system and promotes its growth and spread. In this study, we designed an M0-type macrophage-mediated drug delivery system (PR-M). It leverages the synergistic effect of macrophages and agonists to improve the tumor immunosuppressive micro-environment by increasing M1-type macrophages and decreasing M2-type macrophages. As part of the treatment, the drug-loaded macrophages endowed the system with excellent tumor targeting. Furthermore, loading R848 into TME-responsive nanoparticles could protect macrophages and reduce the potential toxicity of agonists. Further investigations demonstrated that the designed PR-M could be a feasible strategy with high efficacy in tumor targeting, drug loading, autoimmunity activation, and lower side effects.
免疫疗法作为一种有前途的癌症治疗策略，已在临床上广泛应用，但其疗效受到肿瘤微环境（TME）免疫抑制的限制。肿瘤相关巨噬细胞（TAMs）是浸润 TME 的最丰富的免疫细胞，在免疫调节中发挥着关键作用。在此，设计了一种 M0 型巨噬细胞介导的药物传递系统（PR-M），用于携带 Toll 样受体（TLR）激动剂负载的纳米颗粒。当 TLR 激动剂 R848 响应 TME 释放时，PR-M 从 M0 型极化为 M1 型，TAMs 也从 M2 型极化为 M1 型，从而最终逆转 TME 的免疫抑制状态。通过与释放的 R848 激动剂协同作用，PR-M 显著激活了 TME 中的 CD4 和 CD8 T 细胞，并通过调节 IFN-γ、TNF-α、IL-10 和 IL-12 等细胞因子的分泌，将“冷”肿瘤转化为“热”肿瘤，从而最终促进抗肿瘤免疫的激活。在结直肠癌小鼠模型中，PR-M 治疗有效地在肿瘤部位聚集，M1 型增加了 5.47 倍，M2 型减少了 65.08%，与未治疗组相比，肿瘤生长抑制了 85.25%，肿瘤体积减少了 87.55%。我们的工作表明，免疫细胞介导的药物传递系统可以有效地增加肿瘤部位的药物积累，减少毒副作用，从而为肿瘤免疫治疗提供强大的免疫系统。
