Neutrophil-related gene signature predicts prognosis and immune microenvironment patterns in thyroid cancer

Thyroid carcinoma (THCA) represents the most prevalent malignancy of the endocrine system. Although the majority of patients exhibit favorable clinical outcomes, a subset still faces significant clinical challenges, including distant metastasis, recurrence, and poor response to therapeutic interventions, all of which substantially compromise quality of life and overall survival (OS).

Neutrophils, as pivotal components of the innate immune system, exhibit dichotomous roles in cancer biology, exerting both tumor-promoting and tumor-suppressive functions. However, the prognostic value of neutrophil-related genes (NRGs) and their contribution to the molecular stratification of THCA remain poorly defined. Our aim was to identify and evaluate NRG biomarkers with the potential to inform personalized therapeutic strategies for patients with THCA.

We first identified differentially expressed genes (DEGs) between THCA tumor and normal samples. Prognosis-associated DEGs were filtered using univariate Cox regression analysis. Subsequently, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox analysis were employed to identify a core set of prognostic NRGs. A risk model was constructed based on these core genes and validated in independent testing cohorts. Furthermore, consensus clustering was applied to delineate THCA molecular subtypes based on NRG expression profiles, followed by comprehensive analyses of functional enrichment and immune microenvironment characteristics.

The prognostic signature derived from NRGs demonstrated robust and consistent predictive performance across the training and validation datasets. Patients with high NRG-based risk scores exhibited significantly poorer OS and a more immunologically complex tumor microenvironment (TME) than their low-risk counterparts. Consensus clustering further revealed 2 distinct molecular subtypes of THCA, each characterized by divergent immune infiltration patterns and functional pathway enrichment, suggesting biological heterogeneity with potential therapeutic implications.

Our study highlights NRGs as promising prognostic biomarkers in THCA, uncovering distinct molecular subtypes with potential relevance for personalized therapeutic stratification. These findings underscore the clinical value of NRGs and emphasize the need for further mechanistic investigations to advance our understanding of THCA biology and refine precision treatment strategies.