A macrophage-associated immunosuppressive subtype defined by Lactobacillus/Bifidobacterium-associated host genes characterizes prognosis and the immune microenvironment in hepatocellular carcinoma.
- 1Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, China.
- 2Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission, Minhang Hospital, Fudan University, Shanghai, China.
- 3Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China.
Abstract
Lactobacillus/Bifidobacterium-associated host target genes curated in gutMGene v2.0 may reflect expression programs related to the immune microenvironment in hepatocellular carcinoma (HCC), but their significance in prognostic stratification and macrophage states remains unclear. To investigate whether operationally defined Lactobacillus/Bifidobacterium-associated host genes (LBHGs) can define prognostic subtypes of HCC and reveal the corresponding immunosuppressive macrophage features. LBHGs were operationally defined from Lactobacillus/Bifidobacterium-related host target genes in gutMGene v2.0 human records. TCGA-LIHC was used as the discovery cohort for differential expression, univariate Cox, consensus clustering, LASSO-Cox modeling, and survival analysis; GSE76427 was used for expression pattern, subtype projection, and external validation of the risk model; GSE149614 single-cell data were used to calculate the LBHG score, recluster macrophages, and operationally define LBHG-IMac as the subgroup with the highest median LBHG score and significant upregulation of at least 3 prespecified immunosuppressive/pro-tumor markers, representing an LBHG-high immunosuppressive TAM-like macrophage state, and its top-30 marker signature was quantified in TCGA-LIHC and GSE76427 using ssGSEA with within-cohort z-score standardization. Among 94 cross-cohort detectable LBHGs, 12 core LBHGs were identified. The LBHG subtype constructed based on these genes showed that LBHG-C2 had worse overall survival (OS) (log-rank P = 0.003). The 7-gene risk model effectively distinguished high- and low-risk patients in TCGA-LIHC (log-rank P = 0.001; the 1-, 3-, and 5-year AUCs were 0.744, 0.711, and 0.736, respectively), and risk score was an independent prognostic factor (HR = 1.94, P = 0.005); this model was externally validated in GSE76427 (log-rank P = 0.006; the AUCs were 0.708, 0.691, and 0.721, respectively). Single-cell analysis identified LBHG-IMac as a LBHG-high immunosuppressive TAM-like macrophage state, which was enriched in primary tumors (P < 0.001). LBHG-IMac score was positively correlated with risk score (both P < 0.001), and the high LBHG-IMac group showed worse OS and positive correlations with the expression of immune checkpoint and immunosuppression-related genes. The operationally defined LBHG framework can define an adverse prognostic pattern in HCC and are associated with a LBHG-IMac-enriched immunosuppressive microenvironment.
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BibTeX
@article{chang2026macrophageassociated,
title = {{A macrophage-associated immunosuppressive subtype defined by Lactobacillus/Bifidobacterium-associated host genes characterizes prognosis and the immune microenvironment in hepatocellular carcinoma.}},
author = {Qimeng Chang and Huarong Mao and Jinfeng Feng and Longhua Rao and Weiguo Tang and Ziping Zhang and Zhiqiu Hu},
journal = {Frontiers in cellular and infection microbiology},
year = {2026},
month = oct,
doi = {10.3389/fcimb.2026.1918319},
url = {https://europepmc.org/article/MED/42952588},
note = {CC BY},
}
RIS
TY - JOUR
TI - A macrophage-associated immunosuppressive subtype defined by Lactobacillus/Bifidobacterium-associated host genes characterizes prognosis and the immune microenvironment in hepatocellular carcinoma.
AU - Qimeng Chang
AU - Huarong Mao
AU - Jinfeng Feng
AU - Longhua Rao
AU - Weiguo Tang
AU - Ziping Zhang
AU - Zhiqiu Hu
PY - 2026
DA - 2026/10/14
JO - Frontiers in cellular and infection microbiology
DO - 10.3389/fcimb.2026.1918319
UR - https://europepmc.org/article/MED/42952588
AB - Lactobacillus/Bifidobacterium-associated host target genes curated in gutMGene v2.0 may reflect expression programs related to the immune microenvironment in hepatocellular carcinoma (HCC), but their significance in prognostic stratification and macrophage states remains unclear. To investigate whether operationally defined Lactobacillus/Bifidobacterium-associated host genes (LBHGs) can define prognostic subtypes of HCC and reveal the corresponding immunosuppressive macrophage features. LBHGs were operationally defined from Lactobacillus/Bifidobacterium-related host target genes in gutMGene v2.0 human records. TCGA-LIHC was used as the discovery cohort for differential expression, univariate Cox, consensus clustering, LASSO-Cox modeling, and survival analysis; GSE76427 was used for expression pattern, subtype projection, and external validation of the risk model; GSE149614 single-cell data were used to calculate the LBHG score, recluster macrophages, and operationally define LBHG-IMac as the subgroup with the highest median LBHG score and significant upregulation of at least 3 prespecified immunosuppressive/pro-tumor markers, representing an LBHG-high immunosuppressive TAM-like macrophage state, and its top-30 marker signature was quantified in TCGA-LIHC and GSE76427 using ssGSEA with within-cohort z-score standardization. Among 94 cross-cohort detectable LBHGs, 12 core LBHGs were identified. The LBHG subtype constructed based on these genes showed that LBHG-C2 had worse overall survival (OS) (log-rank P = 0.003). The 7-gene risk model effectively distinguished high- and low-risk patients in TCGA-LIHC (log-rank P = 0.001; the 1-, 3-, and 5-year AUCs were 0.744, 0.711, and 0.736, respectively), and risk score was an independent prognostic factor (HR = 1.94, P = 0.005); this model was externally validated in GSE76427 (log-rank P = 0.006; the AUCs were 0.708, 0.691, and 0.721, respectively). Single-cell analysis identified LBHG-IMac as a LBHG-high immunosuppressive TAM-like macrophage state, which was enriched in primary tumors (P < 0.001). LBHG-IMac score was positively correlated with risk score (both P < 0.001), and the high LBHG-IMac group showed worse OS and positive correlations with the expression of immune checkpoint and immunosuppression-related genes. The operationally defined LBHG framework can define an adverse prognostic pattern in HCC and are associated with a LBHG-IMac-enriched immunosuppressive microenvironment.
SN - 2235-2988
ER -