Prognostic signature of mitochondria-related genes and the oncogenic role of NT5DC3 in nasopharyngeal carcinoma progress

Nasopharyngeal carcinoma (NPC) is a significant type of malignant tumor that falls within the category of head and neck squamous cell carcinomas. This form of cancer is particularly notable for its high propensity for recurrence and metastasis, leading to a generally poor prognosis for affected individuals. While immune checkpoint inhibitors have emerged as a critical treatment option for patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC), it is important to recognize that only a limited number of patients experience lasting benefits from these therapies. This observation underscores the presence of complex immune-suppressive mechanisms that still operate within NPC. Mitochondrial autophagy plays a vital role in preserving mitochondrial quality control as well as maintaining cellular homeostasis. This biological process not only aids in the metabolic adaptation and progression of malignant tumor cells but may also influence tumor immune evasion. It does so by modulating the functionality of immune cells and affecting the characteristics of the tumor microenvironment. However, despite the potential implications of mitochondrial autophagy on immune regulation in NPC, its specific role and clinical relevance in this context have yet to be thoroughly investigated. The goal of this study is to develop a prognostic model for NPC that is grounded in mitochondria-related genes. In addition to constructing this model, the research aims to explore how these genes relate to the tumor immune microenvironment, assess the function of CD8⁺ T-cells within this setting, and evaluate the effectiveness of immunotherapy. Furthermore, the study seeks to identify key regulatory genes that possess promising therapeutic value, which could lead to enhanced treatment strategies for individuals diagnosed with NPC. In this study, GEO datasets were utilized for differential expression analysis, alongside least absolute shrinkage and selection operator (LASSO) regression analysis, with the aim of identifying prognostic genes and developing a prognostic model specifically related to mitochondrial function. Through progression-free survival (PFS) and the implementation of time-dependent receiver operating characteristic (ROC) curves, we evaluated the predictive capability of the identified prognostic markers. Additionally, we explored the relationship between the calculated risk score and various immunological characteristics, seeking to understand how these factors interrelate in the context of disease prognosis. Following the identification of NT5DC3 as a significant gene of interest, we conducted a series of expression analyses using reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry. Furthermore, functional assays were carried out to determine the potential of NT5DC3 as a novel biomarker, thereby contributing valuable insights into its role in clinical applications and prognostic evaluations. The present study successfully identified six pivotal genes—NT5DC3, TP63, COX7A1, TMEM71, ADHFE1, and TREM2—and utilized these genes to develop a prognostic model focused on mitochondrial-related factors. Based on PFS, this model demonstrated strong potential in stratifying patients with NPC into different prognostic risk categories. Notably, significant differences in the patterns of immune cell infiltration were observed when comparing the high-risk group with the low-risk group. Specifically, the high-risk cohort demonstrated prominent immunosuppressive traits, characterized by a marked reduction in the infiltration of CD8⁺ T cells, which are crucial for the anti-tumor immune response. Moreover, experiments involving the knockdown of NT5DC3 revealed a significant decrease in the proliferation, migration, and invasive capabilities of NPC cells. Additional investigations indicated that NT5DC3 is regulated by the transcription factor SP1. This relationship suggests that NT5DC3 may facilitate the aggressive biological behaviors typically associated with NPC cells, partially through its association with the AMPK signaling pathway. Furthermore, this gene appears to have implications for the functionality of CD8⁺ T cells, signifying its dual role in both cancer progression and immune evasion. This research presents a novel prognostic model associated with mitochondria specifically designed for NPC. Although external validation in independent cohorts is still needed, The model has the potential to enhance the prediction of PFS-related clinical outcomes for patients and evaluate the likely advantages of immunotherapy treatments. Additionally, the findings highlight significant variations in the tumor immune microenvironment among different risk groups, suggesting that these differences may influence treatment responses. Furthermore, the study identifies NT5DC3 as a potentially valuable biomarker and therapeutic target. Its role in predicting both prognosis and response to immunotherapy may offer new avenues for improving treatment strategies in patients diagnosed with NPC.