ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Microbial Symbioses
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1599691
Tumor-Associated Bacteria Activate PRDX1-Driven Glycolysis to Promote Immune Evasion and PD-1 Antibody Resistance in
Provisionally accepted
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
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Background: Recent studies have highlighted the presence of intratumoral bacteria in hepatocellular carcinoma (HCC), yet their contribution to immunotherapy resistance remains largely unexplored. This study investigates the mechanisms by which bacterial infection reshapes tumor metabolism to undermine the efficacy of anti-PD-1 therapy.We conducted 16S rRNA gene sequencing on 29 HCC clinical samples and integrated the data with single-cell RNA sequencing of 12,487 cells to map microbial, metabolic, and immune interactions within the tumor microenvironment. Functional validation was performed using orthotopic HCC mouse models (n = 8 per group), coupled with flow cytometry-based immune profiling.Results: Enrichment of Streptococcaceae was strongly associated with upregulation of key glycolytic enzymes (LDHA, PKM2; p < 0.001) and dysfunction of natural killer cells (reduced CD56 dim /CD16 bright populations; hazard ratio = 2.15, 95% CI: 1.34-3.42). Mechanistically, bacterial colonization induced peroxiredoxin 1 (PRDX1) expression via the NF-κB pathway. This led to excessive lactate production, which suppressed CD8 + T cell cytotoxicity (p = 0.003) and increased the expression of immune checkpoint molecules (TIM-3: 2.7-fold; LAG-3: 1.9-fold). In vivo, bacterial infection decreased the antitumor efficacy of PD-1 blockade by 43% (tumor volume vs. control; p = 0.008), an effect that was reversed upon PRDX1 inhibition.Our findings identify PRDX1 as a central node in bacteria-driven metabolic reprogramming that facilitates immune evasion and resistance to PD-1 therapy in HCC. These findings provide the first evidence linking intratumoral bacteria to PD-1 resistance via redox-regulated metabolism, proposing dual targeting of PRDX1 and gut microbiota as a novel combinatorial immunotherapy strategy.
Keywords: Hepatocellular Carcinoma, Single-Cell Multomics, Bacterial infection, evasion, PD-1 Antibody Resistance, PRDX1/NF-κB Signaling
Received: 25 Mar 2025; Accepted: 12 Jun 2025.
Copyright: © 2025 Zhang, Lan, Cai, Gao, Gao, Yu, Zhang, Zhang and Tai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Qinwen Tai, Shenzhen Hospital, Southern Medical University, Shenzhen, China
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