Tumor

Introduction: A prior retrospective analysis demonstrated that quantifying Programmed Cell Death Ligand 1 (PD-L1) expression using a phosphor-integrated dot (PID) score effectively predicted immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC) and other cancers. However, PD-L1 expression proved unreliable in some patients with low PD-L1 levels, highlighting the need for alternative biomarkers. A previous cohort study in NSCLC patients linked intestinal Methods: We retrospectively analyzed tumor tissues from 60 metastatic or recurrent NSCLC patients treated with ICIs. Immunohistochemical (IHC) staining was performed to assess Akk and PD-L1 expression, along with CD3 and CD68 in PD-L1-low samples. Transcriptomic profiling using RNA-sequencing was conducted on tumor samples to identify Akk-related gene expression patterns. Results: Tumor Akk expression showed no correlation with PD-L1 levels assessed via PID. Survival and multivariable Cox regression analyses revealed no association between Akk expression and progression-free survival (PFS) or overall survival (OS). In high PD-L1 patients, Akk status did not influence outcomes. However, among low PD-L1 patients, Akk-positive cases exhibited significantly worse PFS compared to Akk-negative cases (OS remained unchanged). Transcriptome analysis indicated that Akk positivity in low PD-L1 samples exhibited enrichment in oxidative phosphorylation and amyotrophic lateral sclerosis-related pathways and downregulation of spliceosome-associated pathways. No significant differences in tumor-infiltrating CD3+ T cells or CD68+ macrophages were observed between Akk-positive and Akk-negative tumors in the PD-L1-low group. Conclusions: Tumor-associated Akk may serve as a negative predictive biomarker for ICI efficacy in NSCLC patients with low PD-L1 expression. Our findings suggest that tumor microbiota profiling, particularly targeting Akk, could refine patient stratification and therapeutic decision-making.