TME remodeling and clinical challenges of immune checkpoint blockade in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-driven malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) that severely limits the efficacy of immune checkpoint blockade (ICB). In the modern comprehensive treatment era, the 5-year overall survival rate for non-metastatic NPC has reached 80-90%, and the prognosis of newly diagnosed non-metastatic patients is substantially better than that of more prevalent cancers such as lung and colorectal cancer. Although ICB has improved survival in recurrent/metastatic NPC, clinical benefits are restricted by primary and acquired resistance, the lack of effective predictive biomarkers, and immune-related adverse events. In this review, we elaborate on the core mechanisms by which EBV orchestrates immune evasion by shaping immunosuppressive cell infiltration, T-cell dysfunction, metabolic disorders, and physical stromal barriers. We systematically summarize recent advances in ICB-mediated remodeling of the NPC TME, including the reversal of T-cell exhaustion, restoration of metabolic balance, and normalization of vascular and stromal compartments. We highlight the unique EBV-driven resistance programs, including antigen silencing, compensatory immune checkpoint expression, and exosomal miRNA-mediated remote immunosuppression. We also discuss major challenges in current biomarker development and the clinical management of immune-related toxicities. Finally, we propose future strategies focusing on EBV-targeted intervention, multi-omics-based predictive models, and mechanism-driven combination immunotherapy to overcome resistance and improve precision treatment. This review provides a comprehensive mechanistic and translational overview that may facilitate the rational design of novel immunotherapeutic approaches for EBV-associated NPC.