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
放疗联合封装 tRF5-GlyGCC 抑制剂的自凝胶粉末增强 NK 细胞免疫以预防肝细胞癌复发
英文原题：Radiotherapy plus a self-gelation powder encapsulating tRF5-GlyGCC inhibitor potentiates natural kill cell immunity to prevent hepatocellular carcinoma recurrence.
查看英文原题
Radiotherapy plus a self-gelation powder encapsulating tRF5-GlyGCC inhibitor potentiates natural kill cell immunity to prevent hepatocellular carcinoma recurrence.
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中文摘要
肝细胞癌（HCC）切除术后复发是临床实践中的一个棘手问题，其中自然杀伤（NK）细胞细胞毒性受损是重要原因之一。除复发外，肝切除术诱导的腹腔粘连也带来巨大的临床挑战，如腹痛、肠梗阻和穿孔。有证据表明，放疗可上调肿瘤细胞上NKG2D配体表达以增强NK细胞细胞毒性，提示其在抑制HCC复发方面具有巨大潜力。
然而，放疗也被发现可引起NK抗肿瘤细胞免疫抑制。在此，我们揭示，甘胆酸（GCA）/tRNA衍生片段5（tRF5）-GlyGCC信号轴在小鼠HCC模型放疗后被激活，其削弱NK细胞抗肿瘤免疫，从而限制治疗效果。
机制上，tRF5-GlyGCC可与KDM6B相互作用，以表观遗传方式上调Runx2，随后在HCC细胞中转录激活ITGBL1和S100A9表达，这分别进一步直接降低NK细胞细胞毒性，以及吸引髓源性抑制细胞（MDSC）间接抑制NK细胞功能。
因此，放疗联合靶向tRF5-GlyGCC可能是一种针对HCC复发的优化术后辅助治疗。随后，设计了一种纳米复合粉末，用于tRF5-GlyGCC抑制剂的肝脏局部递送。将其喷洒到小鼠HCC模型的肝脏切除缘后，该粉末可迅速形成原位Janus黏附水凝胶，从而实现tRF5-GlyGCC抑制剂的持续递送。
重要的是，其可与放疗协同，增强NK细胞抗肿瘤免疫并预防HCC切除术后复发。此外，将其应用于手术创面也能在大鼠肝切除模型中有效减轻腹腔粘连。
总之，我们的工作开发了一种靶向 tRF5-GlyGCC 的纳米复合物，用于增敏放疗以阻遏 HCC 复发并预防腹腔粘连。
展开英文摘要原文
Hepatocellular carcinoma (HCC) recurrence postresection represents a thorny problem in clinical practice, of which impaired natural killer (NK) cell cytotoxicity represents one of crucial causes. Apart from recurrence, hepatectomy-induced abdominal adhesion also poses huge clinical challenges such as abdominal pain, intestinal obstruction, and perforation.
Evidence demonstrates that radiotherapy can upregulate NK group 2D ligand expression on tumor cells to enhance NK cell cytotoxicity, indicating its great potential of curbing HCC recurrence. Nevertheless, radiotherapy has also been disclosed to incur suppression on NK antitumor cell immunity.
Herein, we reveal that glycocholic acid (GCA)/tRNA-derived fragment 5 (tRF5)-GlyGCC signaling axis is activated in mouse HCC model after radiotherapy, which dampens NK cell antitumor immunity to limit therapeutic efficacy.
Mechanistically, tRF5-GlyGCC can interact with KDM6B to epigenetically upregulate Runx2 and then transcriptionally activate ITGBL1 and S100A9 expression in HCC cells, which further reduces NK cell cytotoxicity directly and attracts myeloid-derived suppressor cell (MDSC) to inhibit NK cell function indirectly, respectively.
Therefore, radiotherapy plus targeting tRF5-GlyGCC may be an optimized postoperative adjuvant therapy against HCC recurrence. Then, a nanocomposite powder is designed for liver-localized delivery of tRF5-GlyGCC inhibitor. After sprayed to liver resection margin of mouse HCC model, this powder can rapidly form an in-situ Janus-adhesive hydrogel, which allows for sustained delivery of tRF5-GlyGCC inhibitor.
Importantly, it can synergize with radiotherapy to potentiate NK cell antitumor immunity and prevent HCC recurrence postresection.
Moreover, its application to surgical bed also effectively mitigates abdominal adhesion in a rat hepatectomy model. Altogether, our work develops a tRF5-GlyGCC-targeting nanocomposite power for sensitizing radiotherapy to thwart HCC recurrence and preventing abdominal adhesion.
论文信息
- 作者
- Gong Y、Zeng F、Zhang F、Liu X、Li Z、Chen W、Liu H、Li X
- 第一作者单位
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Organ Transplantation Institute, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Sun Yat-Sen University, Guangzhou, 510630, China.China
- 通讯作者单位
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Organ Transplantation Institute, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Sun Yat-Sen University, Guangzhou, 510630, China. zhangtongxa@163.com.China
- 期刊
- Journal of nanobiotechnology2025 Feb 10
- 原文标识
- PubMed 39930495 · DOI 10.1186/s12951-025-03133-3
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