The integration of PD-1 inhibitors into standard chemotherapy and radiotherapy regimens has revolutionized nasopharyngeal carcinoma treatment, yet only a minority of patients achieve durable responses, creating an urgent need for reliable biomarkers that can predict immunotherapy benefit. Recent investigations have identified multiple candidate predictors spanning both the tumor microenvironment and macroenvironment, ranging from tumor-intrinsic factors like PD-L1 expression and Epstein-Barr virus DNA levels to systemic indicators including peripheral blood cell counts and circulating cytokines. These biomarkers reflect the complex interplay between tumor biology, host immunity, and environmental factors that ultimately determine treatment outcomes.
Within the tumor microenvironment, PD-L1 expression represents the most extensively studied biomarker, with higher expression levels generally correlating with improved responses to anti-PD-1 therapy, though significant heterogeneity exists between primary tumors and metastatic lesions. Tumor mutational burden and neoantigen load serve as indirect measures of immunogenicity, as nasopharyngeal carcinomas with Epstein-Barr virus infection typically exhibit lower mutational burdens but generate virus-specific antigens that can drive effective immune responses. The density and spatial distribution of tumor-infiltrating lymphocytes, particularly CD8-positive cytotoxic T cells and their proximity to PD-L1-expressing tumor cells, provide crucial information about pre-existing anti-tumor immunity that can be unleashed by checkpoint blockade. Additionally, gene expression signatures reflecting interferon-gamma signaling and immune cytolytic activity have demonstrated predictive value in multiple cohorts.
Epstein-Barr virus DNA quantification in plasma has emerged as a unique biomarker for nasopharyngeal carcinoma, as virtually all endemic cases are associated with latent viral infection. Baseline EBV DNA levels correlate with tumor burden and prognosis, while early changes during treatment predict response and survival outcomes. Patients with undetectable or rapidly declining EBV DNA after immunotherapy initiation show significantly better progression-free and overall survival compared to those with persistent elevation. The combination of EBV DNA monitoring with imaging-based response assessment enables more accurate evaluation of treatment efficacy and earlier detection of resistant disease.
Systemic biomarkers in the peripheral blood reflect the broader tumor macroenvironment and host immune status. Absolute lymphocyte counts and neutrophil-to-lymphocyte ratios provide simple yet powerful indicators of immune competence, with higher lymphocyte counts and lower neutrophil predominance associated with better immunotherapy responses. Circulating cytokine profiles, particularly elevated baseline levels of pro-inflammatory markers like interleukin-6 and tumor necrosis factor-alpha, predict resistance to checkpoint inhibitors and may guide combination strategies targeting systemic inflammation. The presence and phenotype of circulating tumor cells and circulating tumor DNA offer non-invasive windows into tumor evolution and heterogeneity, potentially identifying molecular mechanisms of resistance before clinical progression occurs.
Despite promising advances, significant challenges remain in validating and implementing predictive biomarkers for clinical practice. Tumor heterogeneity both within individual lesions and between primary and metastatic sites complicates biomarker assessment, as single biopsies may not capture the full molecular landscape. Dynamic changes during treatment further complicate interpretation, requiring serial sampling strategies that balance clinical feasibility with scientific rigor. Standardization of biomarker assays and cutoff values across different institutions and clinical trials remains incomplete, limiting cross-study comparisons and meta-analyses. The integration of multiple biomarkers into composite scores or machine learning algorithms may improve predictive accuracy but requires large, well-annotated datasets for validation.
Future directions emphasize the development of minimally invasive or non-invasive biomarker approaches that enable real-time monitoring of treatment response and resistance. Liquid biopsy techniques analyzing circulating tumor DNA, exosomal RNA, and immune cell subsets offer promising alternatives to repeated tissue biopsies. Single-cell sequencing technologies provide unprecedented resolution of tumor-immune interactions, potentially revealing new biomarker targets and mechanisms of resistance. The incorporation of radiomics features from baseline imaging studies may capture tumor characteristics not apparent through molecular analysis alone. Ultimately, prospective validation of biomarker-guided treatment algorithms through randomized controlled trials will be essential to demonstrate clinical utility and establish evidence-based guidelines for personalized immunotherapy in nasopharyngeal carcinoma.

DOI
10.1007/s11684-025-1151-5