Targeting intratumoral Streptococcus mitis suppresses the progression of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy worldwide with limited therapeutic options. Emerging evidence implicates intratumoral bacteria in ESCC pathogenesis. Here, we identified enriched levels of the Gram-positive bacterium Streptococcus mitis (S. mitis) in ESCC patient tumor tissues, which facilitated ESCC progression both in vitro and in vivo. Mechanistically, mitilysin (MLY), a virulence factor secreted by S. mitis, interacted with zinc finger protein 460 (ZNF460) and promoted its proteasomal degradation. Downregulation of this transcription factor suppressed the transcription of circular RNA circAAGAB, subsequently activating the miR-671-5p/GAS7c and PABP1/TNFAIP2 pathways to enhance ESCC cell proliferation and metastasis. Furthermore, we developed an S. mitis-targeted, mesoporous silica nanoparticle (MSN)-based drug delivery system, in which the MSN surface was decorated with an antibody against lipoteichoic acid (LTA), a major cell wall component of Gram-positive bacteria (LTA-MSNs). When loaded with penicillin, circAAGAB, or both, LTA-MSNs precisely targeted intratumoral S. mitis in ESCC patient-derived xenograft (PDX) models, demonstrating potent tumor-suppressive efficacy. Collectively, our findings reveal that intratumoral S. mitis critically drives ESCC tumorigenesis and represents a promising therapeutic target.