Endogenous CD155 drives metabolic reprogramming via PI3K/AKT/HIF‐1α‐glycolysis axis to mediate anti‐PD‐1 resistance in non‐small cell lung cancer
TL;DR
CD155 is identified as a key driver of anti‐PD‐1 resistance in NSCLC and targeting CD155 combined with anti‐PD‐1 overcomes resistance, supporting a dual‐target therapeutic strategy.
Abstract
Abstract Objective Anti‐PD‐1 therapy resistance remains a critical barrier in non‐small cell lung cancer (NSCLC) management, and the underlying mechanisms are incompletely defined. Methods 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. Results 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. Conclusion 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. Key points 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.