Low NDFIP1-driven metabolic alterations in CD8 + T cells: implications for immune evasion and therapy resistance in HNSC

Head and neck squamous cell carcinoma (HNSC) is an aggressive malignancy often resistant to therapy, especially in advanced stages. Metabolic reprogramming, marked by shifts in glycolysis and oxidative phosphorylation (OXPHOS), is crucial for tumor progression and immune evasion. This study provided a single-cell transcriptomic map of 53,660 CD8 + T cells from primary and metastatic HNSC samples, identifying 11 distinct CD8 + T cell subsets. Notably, PDCD1 + CD8+ T cells were enriched in metastatic sites, exhibiting heightened expression of PD-1 and LAG3, as well as activation of JAK-STAT and PD-L1/PD-1 signaling pathways. A focused analysis revealed five key driver genes-PLS3, NDFIP1, MED15, JCHAIN, and FTH1-associated with prognosis, as identified using machine learning models. NDFIP1 was downregulated in various tumors, including HNSC, and its expression correlated strongly with increased CD8 + T cell infiltration, OXPHOS activity, and enhanced immune pathways. Patients with higher NDFIP1 expression showed better survival outcomes and were linked to an immune subtype characterized by robust CD8 + T cell activity and IFN-γ signaling. Thus, NDFIP1 emerges as a crucial biomarker for predicting immunotherapy response and offers insight into targeting metabolic pathways in cancer treatment, as its downregulation is associated with immune evasion and worse clinical outcomes.