<b>Mechanisms and therapeutic strategies of CD155-mediated resistance to anti-PD-1 therapy in non-small cell lung cancer</b>

<b>背景：</b> 非小细胞肺癌 （NSCLC） 是全球肿瘤相关死亡的主要原因。对抗 PD-1 治疗的耐药性仍然是 NSCLC 治疗的重大挑战。CD155 是一种共抑制免疫检查点，在 NSCLC 的抗 PD-1 耐药中起着至关重要的作用，但其机制尚不清楚。<b>方法： </b>外部单细胞数据验证 CD155 是抗 PD-1 治疗耐药的关键分子;免疫组化评价 CD155 的表达。采用 ScRNA-seq 、 RNA-seq 和蛋白质组学探讨 CD155 在 NSCLC 中的潜在作用，并进行代谢组学分析以评估 CD155 对能量代谢的总体影响;通过体外实验验证了 CD155 在 NSCLC 增殖、迁移和糖酵解中的表型 体外 ，最后，在临床前模型中评价了以携带 shCD155 序列 （AAV9_shCD155） 的腺相关病毒 （AAV9） 载体为主的联合治疗的疗效。<b>结果： </b>CD155 是抗 PD-1 治疗耐药的关键分子，在 NSCLC 组织中高表达，这与患者预后不良有关。我们的多组学分析表明，CD155 通过 PI3K/AKT 信号通路介导 NSCLC 中的糖酵解过程，导致关键酶 GLUT1、GLUT3 和 LDHB 的表达增加，从而影响肿瘤增殖。在 体内 以 AAV9_shCD155 为主的体内应用中，肿瘤对抗 PD-1 药物的反应增强，解决了对抗 PD-1 药物的耐药问题。<b>结论： </b>总体而言，我们已经证实 CD155 与抗 PD-1 治疗的耐药性密切相关。使用多组学方法，我们绘制了从基因到蛋白质水平的 CD155 表达图谱，并阐明了其调节机制。CD155 通过 PI3K/AKT 通路诱导代谢重编程，改变肿瘤细胞糖酵解并有利于显性克隆扩增。在临床前模型中，靶向 CD155 的 AAV9 与抗 PD-1 药物相结合可增强肿瘤反应并抑制进展，为克服耐药性提供了一种潜在的策略。<b>Background:</b> Non-small cell lung cancer (NSCLC) is a leading cause of tumor-related deaths worldwide. Resistance to anti-PD-1 therapy remains a major challenge in NSCLC treatment. CD155, a co-inhibitory immune checkpoint, plays a crucial role in anti-PD-1 resistance in NSCLC, but its underlying mechanism is still unclear. <b>Methods:</b> External single-cell data verified that CD155 is a key molecule associated with anti-PD-1 therapy resistance; immunohistochemistry was used to evaluate CD155 expression. scRNA-seq, RNA-seq, and proteomics were employed to explore the potential role of CD155 in NSCLC, and metabolomics analysis was performed to assess the overall impact of CD155 on energy metabolism; the phenotypes of CD155 in NSCLC proliferation, migration, and glycolysis were validated via in vitro experiments. Finally, the efficacy of combination therapy based on an adeno-associated virus (AAV9) vector carrying the shCD155 sequence (AAV9_shCD155) was evaluated in preclinical models. <b>Results:</b> CD155 is a key molecule for anti-PD-1 therapy resistance, and its high expression in NSCLC tissues is associated with poor patient prognosis. Our multi-omics analysis showed that CD155 mediates glycolysis in NSCLC through the PI3K/AKT signaling pathway, leading to increased expression of key enzymes GLUT1, GLUT3, and LDHB, thereby affecting tumor proliferation. In in vivo applications of AAV9_shCD155, tumor responses to anti-PD-1 drugs were enhanced, resolving resistance to anti-PD-1 drugs. <b>Conclusion:</b> Overall, we confirmed that CD155 is closely associated with resistance to anti-PD-1 therapy. Using multi-omics approaches, we mapped the CD155 expression profile from the gene to protein level and elucidated its regulatory mechanism. CD155 induces metabolic reprogramming via the PI3K/AKT pathway, altering tumor cell glycolysis and favoring dominant clonal expansion. In preclinical models, AAV9 targeting CD155 combined with anti-PD-1 drugs enhanced tumor responses and inhibited progression, providing a potential strategy to overcome resistance.