RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
特洛伊木马 NK 细胞在三阴性乳腺癌中增强靶向药物递送并提升记忆 T 细胞介导的免疫应答
英文原题：Trojan horse natural killer cells enhance targeted drug delivery and boost memory T cell-mediated immune responses in triple-negative breast cancer.
查看英文原题
Trojan horse natural killer cells enhance targeted drug delivery and boost memory T cell-mediated immune responses in triple-negative breast cancer.
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中文摘要
自然杀伤（NK）细胞癌症治疗是免疫治疗领域的一项关键创新。然而，目前关于NK“死亡细胞”介导的药物递送系统（DDSs）的研究仍然有限。为此，我们开发了一种创新方法，利用快速玻璃化冷冻和缓慢程序化复苏获得死亡NK细胞作为药物载体。冻融NK细胞（FTKs）通过上调C-X-C基序趋化因子受体3和整合素β2的表达，显示出增强的肿瘤靶向能力。
因此，FTKs作为类似特洛伊木马的载体，能够高效递送毒性化疗药物。此外，FTKs还被发现可通过释放危险相关分子模式刺激树突状细胞（DCs）的成熟。与化疗联合使用时，该策略可协同利用化疗药物的免疫调节特性，增加免疫原性细胞死亡，缓解肿瘤微环境中的免疫抑制，并减缓三阴性乳腺癌（TNBC）的进展。在转移性TNBC小鼠模型中，该策略通过重新激活细胞毒性T淋巴细胞并促进记忆T细胞应答的重新获得，增强了程序性细胞死亡蛋白1抑制剂的免疫效应。
因此，我们提出了一种基于NK“死亡细胞”的增强靶向递送系统，该系统可快速制备用于临床，从而为创新性免疫治疗药物递送策略提供了新见解。意义声明：三阴性乳腺癌是乳腺癌中高度侵袭性的亚型，化疗是其主要的治疗方式。
然而，传统化疗常因靶向特异性不足而受到限制，导致全身毒性。在本研究中，我们开发了一种基于自然杀伤（NK）细胞的药物递送平台。通过快速玻璃化冷冻和缓慢程序化解冻处理细胞，我们获得了冻融 NK 细胞（FTKs），其特征是膜结构完整且肿瘤靶向能力增强。
此外，发现 FTKs 可促进树突状细胞成熟，并具有高载药能力。与化疗联合时，该策略通过重新激活细胞毒性 T 淋巴细胞并促进记忆 T 细胞反应的重新获得，增强了程序性细胞死亡蛋白 1 抑制剂的免疫效应。
展开英文摘要原文
Natural killer (NK) cell-based cancer therapy is a key innovation in immunotherapy.
However, current research on drug delivery systems (DDSs) mediated by NK "dead cells" remains limited. Accordingly, we developed an innovative method to obtain dead NK cells as drug carriers using rapid vitrification freezing and slow-programmed thawing. Freeze-thawed NK cells (FTKs) showed enhanced tumor-targeting ability by upregulating the expression of C-X-C motif chemokine receptor 3 and integrin beta 2.
Therefore, FTKs function as Trojan horse-like carriers, enabling efficient delivery of toxic chemotherapeutic agents.
In addition, FTKs were also found to stimulate the maturation of dendritic cells (DCs) via the release of danger-associated molecular patterns. In conjunction with chemotherapy, this strategy can synergistically leverage the immunomodulatory properties of chemotherapeutic drugs to increase immunogenic cell death, mitigate immunosuppression within the tumor microenvironment, and slow the progression of triple-negative breast cancer (TNBC).
Using a metastatic TNBC mouse model, this strategy enhanced the immunological effect of a programmed cell death protein 1 inhibitor by re-invigorating cytotoxic T lymphocytes and promoting the reacquisition of memory T-cell responses.
Hence, we propose an NK "dead cell"-based enhanced target delivery system that can be rapidly manufactured for clinical use, thus providing insights into innovative immunotherapy drug delivery strategies. STATEMENT OF SIGNIFICANCE: Triple-negative breast cancer is a highly aggressive subtype of breast cancer, for which chemotherapy is the primary treatment modality.
However, conventional chemotherapy is often limited by insufficient target specificity, leading to systemic toxicity. In this study, we developed a drug delivery platform based on natural killer (NK) cells. By processing cells via rapid vitrification freezing and slow-programmed thawing, we obtained freeze-thawed NK cells (FTKs) characterized by an intact membrane architecture and enhanced tumor-targeting capacity.
In addition, FTKs were found to promote dendritic cell maturation and had a high drug-loading capacity. In conjunction with chemotherapy, this strategy enhanced the immunological effect of a programmed cell death protein 1 inhibitor by re-invigorating cytotoxic T lymphocytes and promoting the reacquisition of memory T-cell responses.
论文信息
- 作者
- Wu L、Yao H、Wang Y、Liu H、Lv H、Jiao D、Jiang J
- 单位
- Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130000, ChinaChina
- 期刊
- Acta biomaterialia2026 Jan
- 原文标识
- PubMed 41352624 · DOI 10.1016/j.actbio.2025.12.009