内源性CD155通过PI3K/AKT/HIF-1α-糖酵解轴驱动代谢重编程，介导非小细胞肺癌的抗PD-1耐药
Endogenous CD155 drives metabolic reprogramming via PI3K/AKT/HIF-1α-glycolysis axis to mediate anti-PD-1 resistance in non-small cell lung cancer.
作者
作者单位
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
- Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
摘要
中文
抗PD-1治疗耐药仍然是晚期非小细胞肺癌（NSCLC）治疗的关键障碍，其潜在机制尚未完全明确。我们利用CRISPR-Cas9系统生成了CD155敲除（KO）的NSCLC细胞系，并进行了系统的多组学分析，包括单细胞RNA测序、批量RNA测序、蛋白质组学和代谢组学。通过免疫组织化学（IHC）、蛋白质印迹和染色质免疫沉淀（ChIP）进一步验证了关键分子机制。功能实验评估了细胞增殖、迁移和代谢表型，体内通过AAV9_shCD155评估了治疗效果。单细胞测序显示，对抗PD-1治疗反应不佳的NSCLC患者中CD155异常高表达。NSCLC组织中CD155高表达与不良预后相关。ETS1被确定为CD155的直接转录驱动因子。多组学分析和功能实验表明，CD155通过激活PI3K/AKT/HIF-1α信号轴上调关键糖酵解蛋白（GLUT1、GLUT3、LDHB）的表达，从而驱动肿瘤细胞的糖酵解代谢、增殖和迁移。CD155敲除显著抑制了这些恶性表型。在异种移植小鼠模型中，AAV9_shCD155单药治疗有效抑制了肿瘤生长和术后复发。更重要的是，在人源化小鼠模型中，AAV9_shCD155与帕博利珠单抗联合产生了协同抗肿瘤作用，更显著地抑制肿瘤生长并促进免疫细胞浸润到肿瘤微环境中。CD155通过激活PI3K/AKT/HIF-1α驱动的糖酵解重编程介导抗PD-1耐药。靶向CD155联合抗PD-1治疗可克服耐药，支持双靶点治疗策略。CD155被确定为NSCLC中抗PD-1耐药的关键驱动因子。CD155通过PI3K/AKT/HIF-1α信号轴促进肿瘤糖酵解和恶性进展。AAV9_shCD155联合抗PD-1显著抑制肿瘤生长并促进免疫浸润。
English
Anti-PD-1 therapy resistance remains a critical barrier in non-small cell lung cancer (NSCLC) management, and the underlying mechanisms are incompletely defined. We generated CD155‑knockout (KO) NSCLC cell lines using the CRISPR‑Cas9 system and performed systematic multi‑omics analyses, including single‑cell RNA‑seq, bulk RNA‑seq, proteomics, and metabolomics. The key molecular mechanisms were further validated by immunohistochemistry (IHC), western blotting, and chromatin immunoprecipitation (ChIP). Functional assays assessed cell proliferation, migration, and metabolic phenotypes, while the therapeutic efficacy was assessed in vivo using AAV9_shCD155. Single-cell sequencing revealed aberrantly high CD155 expression in NSCLC patients with poor response to anti-PD-1 therapy. High CD155 expression in NSCLC tissues correlated with unfavourable prognosis. ETS1 was identified as a direct transcriptional driver of CD155. Multi-omics analysis and functional assays demonstrated that CD155 upregulates the expression of key glycolytic proteins (GLUT1, GLUT3, LDHB) by activating the PI3K/AKT/HIF-1α signalling axis, thereby driving glycolytic metabolism, proliferation, and migration of tumour cells. CD155 knockout significantly suppressed these malignant phenotypes. In xenograft mouse models, monotherapy with AAV9_shCD155 effectively inhibited tumour growth and postoperative recurrence. More importantly, in humanised mouse models, combining AAV9_shCD155 with pembrolizumab produced synergistic anti-tumour effects, more significantly suppressing tumour growth and promoting immune cell infiltration into the tumour microenvironment. CD155 mediates anti-PD-1 resistance by activating PI3K/AKT/HIF-1α-driven glycolytic reprogramming. Targeting CD155 combined with anti-PD-1 overcomes resistance, supporting a dual-target therapeutic strategy. CD155 is identified as a key driver of anti-PD-1 resistance in NSCLC. CD155 promotes tumour glycolysis and malignant progression via the PI3K/AKT/HIF-1α signalling axis. AAV9_shCD155 combined with anti-PD-1 markedly inhibits tumour growth and promotes immune infiltration.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 7.9
- 新锐分区
- 2区