PD-L1 mediated immune escape in nasopharyngeal carcinoma: Impact of LMP1 and IFN-γ on immune surveillance

Nasopharyngeal carcinoma (NPC) is a distinct malignancy in head and neck cancer, notably linked to Epstein-Barr virus (EBV) infections in regions with high prevalence. NPC's tumor microenvironment fosters immune escape mechanisms that support tumor cell survival, with programmed death-ligand 1 (PD-L1) as a key player. PD-L1 expression on NPC cells binds to the programmed death-1 (PD-1) receptor on T cells, thereby creating an immunosuppressive environment that impairs immune surveillance. Two significant modulators of PD-L1 expression in NPC include the EBV-encoded latent membrane protein 1 (LMP1) and the immune cytokine interferon-gamma (IFN-γ). Together, they contribute to the intricate regulation of PD-L1, enhancing immune evasion and complicating the landscape for effective treatment approaches. This review explores the molecular mechanisms underlying PD-L1 upregulation, focusing on LMP1's activation of the NF-κB and JAK/STAT pathways and IFN-γ′s paradoxical role in facilitating immune escape. Clinical evidence indicates that PD-L1 expression correlates with poor prognosis and resistance to standard therapies in NPC patients. Understanding these regulatory pathways may inform potential therapeutic strategies, including immune checkpoint inhibitors, combination therapies, and novel immune-based approaches tailored to NPC's unique etiology. By providing a comprehensive synthesis of existing studies, this review highlights the interplay between PD-L1, LMP1, and IFN-γ, offering a framework for innovative therapeutic strategies targeting immune escape mechanisms. Identifying patients most likely to benefit from immune-targeted approaches and leveraging combination treatments could improve outcomes for NPC patients facing advanced or resistant disease.