Abstract
Background: CD155, an emerging immune checkpoint, contributes to tumor immune evasion and progression, but its roles in metabolic reprogramming and tumor-associated macrophages (TAMs) polarization in lung adenocarcinoma (LUAD) remain uncharacterized. This study combines molecular biology, metabolic imaging, and clinical data to elucidate CD155's dual role in driving LUAD progression through glycolytic rewiring and immunosuppressive TAMs polarization. Methods: Through immunohistochemistry (IHC) and 18F-FDG PET/CT imaging, we analyzed CD155 expression and its association with glycolysis in 80 LUAD patients. Functional assays and molecular studies revealed CD155-mediated regulation of tumor glycolysis and macrophage polarization via YAP/TEAD1-GLUT1 signaling. Xenograft models validated the in vivo findings, with 18F-FDG micro-PET imaging performing noninvasive metabolic profiling. Results: CD155 was significantly overexpressed in LUAD tissues and positively correlated with advanced TNM stage, lymph node metastasis and elevated 18F-FDG uptake. Mechanistically, CD155 interacts with YAP, reducing YAP phosphorylation at Ser127 to promote its nuclear translocation and TEAD1 activation, thereby upregulating GLUT1 transcription. This signaling axis enhanced glycolysis, thereby fueling LUAD proliferation and migration. Notably, CD155-induced lactate production and extracellular acidification drove macrophage polarization toward the immunosuppressive M2 phenotype. In vivo, CD155 silencing suppressed tumor glucose metabolism and growth, whereas overexpression accelerated tumor progression, both dynamically monitored through 18F-FDG PET visualization. Conclusions: We identify a novel CD155/YAP/TEAD1/GLUT1 axis that reprograms LUAD metabolism and facilitates immunosuppressive tumor microenvironment formation. CD155 functions as a metabolic-immune hub in LUAD, and its targeting could simultaneously suppress tumor growth and restore antitumor immunity, offering dual therapeutic advantages. Clinically, 18F-FDG PET/CT represents a noninvasive biomarker for CD155-driven metabolic aggression, potentially guiding precision immunotherapy.