Integrative microbiome and functional profiling identify Streptococcus anginosus as a pro-tumorigenic driver in nasopharyngeal carcinoma.

Oral microbial dysbiosis is associated with nasopharyngeal carcinoma (NPC), yet specific microbial drivers within this niche remain poorly characterized. Through multi-cohort profiling of saliva microbiota, we identified Streptococcus as consistently enriched in NPC, whose abundance positively correlates with advanced clinical stages and poor prognosis. Subsequent functional screening across multiple Streptococcus species revealed S. anginosus as the most potent promoter of NPC progression. At the molecular level, we established the interaction between the bacterial surface protein TMPC and host receptor ANXA2 as the primary signaling axis driving S. anginosus-induced tumorigenesis. Structural analysis revealed that specific conserved residues on TMPC confer S. anginosus with superior ANXA2-binding affinity compared with other streptococci, thereby triggering a robust NF-κB/TNFα-mediated pro-inflammatory program. Further underscoring its clinical relevance, high host ANXA2 expression significantly correlates with poorer overall survival in NPC patients. Targeted blockade of this interface using a competitive peptide effectively reduced intratumoral S. anginosus persistence and attenuated tumor progression in vivo. Collectively, our findings identify S. anginosus as a critical functional driver of NPC, with TMPC-ANXA2 acting as the pivotal molecular bridge coupling intratumoral persistence to a pro-tumorigenic inflammatory program. Targeting this specific host-microbe interface offers a promising non-antibiotic, precision therapeutic approach against microbiome-promoted NPC.IMPORTANCENasopharyngeal carcinoma (NPC) has complex etiological links to microbial dysbiosis. Our study identifies S. anginosus as a key microbial driver, hijacking host ANXA2 via its surface protein TMPC to activate NF-κB/TNFα inflammatory signaling, promoting tumor progression. Structural insights into this interaction reveal targets for therapeutic intervention, with a competitive peptide showing efficacy in reducing bacterial persistence and tumor growth in vivo. This work redefines S. anginosus as a functional contributor to NPC, offering novel non-antibiotic strategies for targeting microbiota-driven cancers.