Stem Cell Exhaustion Defines an Immunogenic Niche and a Circulating Biomarker for Nasopharyngeal Carcinoma

Background
The inadequacy of chronological age as an indicator of biological aging has spurred the development of biomarkers that quantify hallmarks of the aging process. Stem cell exhaustion (SCE) is a recognized hallmark of cellular senescence; however, its clinical significance in nasopharyngeal carcinoma (NPC) remains unclear, and scalable tools for its assessment are lacking.
Methods
We computed an SCE score from transcriptomic data of 181 non-metastatic NPC patients. Its relationship with the tumor immune microenvironment was characterized using bioinformatic and spatial transcriptomic analyses. To develop a clinically applicable tool, we derived a Circulating Stemness Exhaustion Signature (CSES) from routine blood parameters via an artificial neural network. The CSES was validated in three independent cohorts: an internal cohort (n = 492), an external cohort (n = 122), and an immunotherapy-treated cohort (n = 42).
Results
A high SCE score independently predicted improved overall survival (HR = 0.03, 95% CI: 0.00-0.65, P = 0.025) and delineated an immunologically active TIME characterized by enhanced T-cell cytotoxicity and elevated MHC-I expression. The CSES strongly correlated with the SCE score (r = 0.844, P < 0.001) and consistently stratified patient survival in validation cohorts. In the immunotherapy cohort, a high CSES predicted a significant survival benefit (difference in restricted mean survival time at 36 months: 7.47 months, P = 0.039) and was independently associated with superior treatment response.
Conclusion
Our study establishes SCE as a critical determinant of the immune niche and prognosis in NPC. Furthermore, we introduce the CSES as a practical, non-invasive biomarker capable of guiding prognostic stratification and informing immunotherapy decisions.