Journal for immunotherapy of cancer · 2026
Modulating Bacteroides to boost anti-PD-1 immunotherapy in HCC.
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Qi Xiaoqiang, Yang Ming, Liu Xinjian, Ma Lixin, Kaifi Jussuf T, Ericsson Aaron C, Kimchi Eric T, Staveley-O'Carroll Kevin F, Li Guangfu
Аннотация
BACKGROUND: The gut microbiota is increasingly recognized as a critical external regulator along the gut-liver axis, influencing hepatocarcinogenesis and modulating responses to immunotherapy. However, the specific microbial determinants, underlying mechanisms, and potential clinical applications remain incompletely elucidated.
METHODS: Building on the observed association between gut microbiota and anti-programmed cell death protein-1 (PD-1) immunotherapeutic efficacy in patients with hepatocellular carcinoma (HCC), we leveraged a suite of clinically relevant murine HCC models to comprehensively characterize tumor-associated microbial signatures using 16S ribosomal RNA gene sequencing. By precisely manipulating microbial composition through a non-hepatotoxic antibiotic cocktail 3 (ABX-3), targeted microbial supplementation, human fecal microbiota transplant (FMT), and controlled Bacteroides thetaiotaomicron (B.th) repopulation following gut sterilization with ABX-5, we demonstrated a direct causal relationship between microbiota modulation and intrahepatic immune activation. Single-cell RNA sequencing of hepatic non-parenchymal cells, together with functional validation experiments, was performed to elucidate the underlying immune mechanisms.
RESULTS: Bacteroides-enriched gut microbiota derived from anti-PD-1-responsive patients with HCC significantly suppressed tumor growth in murine HCC models. In parallel, within our murine HCC system, ABX-3 administration, implemented as both a preventive and therapeutic intervention, attenuated tumor initiation and progression by selectively enriching Bacteroides within the gut microbial community. Functionally, ABX-3 enhanced the capacity of tumor antigen-specific T-cell receptor-I T cells to mount robust immune responses, culminating in targeted tumor regression following antigen-specific immunization. Among the Bacteroides species, B.th emerged as a critical mediator that potentiated αPD-1 immunotherapy in HCC by relieving Krüppel-like factor 2 (KLF2)-dependent suppression in dendritic cells (DCs). Mechanistically, the KLF2-toll-like receptor 9 (TLR9) signaling axis in DCs governed the activation of antigen-specific CD8+ T cells, thereby amplifying antitumor immunity within the HCC microenvironment.
CONCLUSIONS: B.th is identified as a key immunomodulatory species that enhances anti-PD-1 efficacy by reprogramming DCs through the KLF2/TLR9 signaling pathway. These findings reveal a novel microbiota-informed strategy to improve immunotherapeutic outcomes in HCC.
METHODS: Building on the observed association between gut microbiota and anti-programmed cell death protein-1 (PD-1) immunotherapeutic efficacy in patients with hepatocellular carcinoma (HCC), we leveraged a suite of clinically relevant murine HCC models to comprehensively characterize tumor-associated microbial signatures using 16S ribosomal RNA gene sequencing. By precisely manipulating microbial composition through a non-hepatotoxic antibiotic cocktail 3 (ABX-3), targeted microbial supplementation, human fecal microbiota transplant (FMT), and controlled Bacteroides thetaiotaomicron (B.th) repopulation following gut sterilization with ABX-5, we demonstrated a direct causal relationship between microbiota modulation and intrahepatic immune activation. Single-cell RNA sequencing of hepatic non-parenchymal cells, together with functional validation experiments, was performed to elucidate the underlying immune mechanisms.
RESULTS: Bacteroides-enriched gut microbiota derived from anti-PD-1-responsive patients with HCC significantly suppressed tumor growth in murine HCC models. In parallel, within our murine HCC system, ABX-3 administration, implemented as both a preventive and therapeutic intervention, attenuated tumor initiation and progression by selectively enriching Bacteroides within the gut microbial community. Functionally, ABX-3 enhanced the capacity of tumor antigen-specific T-cell receptor-I T cells to mount robust immune responses, culminating in targeted tumor regression following antigen-specific immunization. Among the Bacteroides species, B.th emerged as a critical mediator that potentiated αPD-1 immunotherapy in HCC by relieving Krüppel-like factor 2 (KLF2)-dependent suppression in dendritic cells (DCs). Mechanistically, the KLF2-toll-like receptor 9 (TLR9) signaling axis in DCs governed the activation of antigen-specific CD8+ T cells, thereby amplifying antitumor immunity within the HCC microenvironment.
CONCLUSIONS: B.th is identified as a key immunomodulatory species that enhances anti-PD-1 efficacy by reprogramming DCs through the KLF2/TLR9 signaling pathway. These findings reveal a novel microbiota-informed strategy to improve immunotherapeutic outcomes in HCC.