B cells in nasopharyngeal carcinoma: From prognostic signal to therapeutic hypothesis—A critical appraisal of the RATIONALE-309 biomarker analysis

The 3-year follow-up of the phase 3 RATIONALE-309 trial confirmed sustained progression-free and overall survival (OS) benefit with tislelizumab plus gemcitabine-cisplatin in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC). An exploratory gene-expression analysis suggested that a high B-cell signature was associated with greater OS benefit from tislelizumab (HR 0.41), whereas low signature patients showed no significant benefit (HR 1.14). This commentary critically examines whether this B-cell signature can be considered a predictive biomarker. We distinguish the published trial findings from our own interpretations, clarify the operational definition of the B-cell signature (composite HTG EdgeSeq score vs. individual markers vs. inferred B-cell abundance), and discuss the critical distinction between predictive and prognostic effects. We propose a pragmatic roadmap for clinical translation, including validation of a multiplex immunohistochemistry (IHC) surrogate, and highlight the need for external validation and prospective stratification. Currently, the B-cell signature remains hypothesis-generating and should not guide treatment selection. We conclude with specific recommendations for the research community to move this promising signal toward clinical utility.