Xiaoshan Xie, Yue Wei, Jiaying Zheng, Zhikai Zheng, Xijie Chen, Jiarui Wang, Ning Ma, Xiaoling Huang, Peng Zhang, Boyu Zhang, Hanyong Cai, Li Ma, Lishi Xiao, Qingxin Liu, Wenyu Wang, Sachiyo Nomura, Shi Chen, Xiangqi Meng, Mong-Hong Lee
First-line treatment for gastric cancer (GC) includes PD-1 blockade with chemotherapy, but resistance challenges treatment success. We identify Streptococcus anginosus (SA) as a tumor-resident oncobacterium driving GC progression and immune evasion. SA is enriched in GC patient tumors and drives tumor growth in mice. SA extracellular vesicles (saEVs) translocate the bacterial chromatin remodeler saSNF2 into host cells. saSNF2 partners with host transcription factor TEAD1-through its ATPase activity and participation in BRG1/BRM-associated factor (BAF) complex assembly-to activate oncogenic transcription. This transkingdom interaction upregulates the palmitoyltransferase ZDHHC11, which stabilizes PD-L1 via palmitoylation to establish an immunosuppressive niche, while amplifying other TEAD1 target genes to fuel tumor progression. saEVs promote tumor growth and limit CD8+ T cell infiltration in vivo. Pharmacological inhibition of ZDHHC11 reverses immune evasion and synergizes with anti-PD-1 checkpoint blockade. These findings establish SA as a multifaceted driver of GC and highlight the saSNF2-ZDHHC11 axis as a target to potentiate immunotherapy.