Mechanisms and clinical challenges of ICB-mediated remodeling of the tumor microenvironment 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.