Published online Dec 15, 2025. doi: 10.4251/wjgo.v17.i12.112936
Revised: September 14, 2025
Accepted: October 31, 2025
Published online: December 15, 2025
Processing time: 123 Days and 8.4 Hours
Hepatic malignancies represent the sixth most prevalent cancer globally, with emerging evidence revealing that intratumoral microbes actively modulate carcinogenesis through immunomodulation and metabolic reprogramming. Recent high-throughput sequencing technologies have identified taxonomically diverse microbial communities within tumor tissues, challenging traditional sterility paradigms. Germ-free mouse models have established causal relation
To systematically analyze intratumoral microbes as biomarkers for hepatic malignancies diagnosis, prognosis, and treatment response.
We conducted a systematic literature search in PubMed from inception to July 2025 using keywords combining hepatic malignancies, intratumoral microbiota, and biomarkers. Inclusion criteria encompassed human studies examining intratumoral microbial communities with biomarker applications. Exclusion criteria included animal-only studies, reviews, and research focusing solely on gut microbiota. Data extraction focused on diagnostic accuracy, prognostic signi
Twenty studies (sample sizes: 18-925 patients) examining hepatocellular carcinoma (80%) and intrahepatic cholangiocarcinoma (20%) were included. All studies achieved Newcastle-Ottawa Scale scores ≥ 6, with 60% scoring the maximum 9 points, indicating moderate-to-high quality. Studies predominantly employed 16S rRNA sequencing (100%) targeting V3-V4 regions, with complementary validation techniques including fluorescence in situ hybridization, quantitative PCR, and immunohistochemistry. Specific bacterial taxa demonstrated exceptional diagnostic accuracy [area under the curve (AUC) > 0.9] for tumor discrimination. Notably, Bacilli showed AUC = 0.943 in validation cohorts. Microbial diversity and specific genera (Methylobacterium, Akkermansia, Intestinimonas) showed consistent prognostic associations with survival outcomes, though relationships varied across cancer subtypes. Advanced risk stratification models incorporating multiple bacterial biomarkers showed independent predictive capacity through multivariable Cox regression. Mechanistic investigations revealed microbe-mediated oncogenic pathway activation, particularly NF-κB signaling, immune modulation through M2 macrophage polarization, and drug resistance mechanisms via autophagy regulation. Germ-free mouse models established causal relationships, demonstrating that specific bacterial communities, particularly Klebsiella pneumoniae, can autonomously initiate hepatocarcinogenesis through TLR4-dependent pathways.
Intratumoral microbes represent promising clinical biomarkers for hepatic malignancies across diagnostic, prognostic, and therapeutic applications. While standardization and multicenter validation remain essential prerequisites, mechanistic evidence from human and experimental studies positions microbiome-based biomarkers at the threshold of clinical translation.
Core Tip: Once considered sterile environments, hepatic malignancies are now recognized to harbor distinct microbial communities with significant clinical implications. This systematic review of 20 high-quality studies demonstrates that intratumoral microbes represent promising biomarkers across multiple applications in liver cancer. Specific bacterial taxa achieved exceptional diagnostic accuracy (area under the curve > 0.9), while microbial diversity patterns showed consistent prognostic associations with patient survival outcomes. Mechanistic investigations revealed microbe-mediated oncogenic pathway activation, immune modulation, and drug resistance mechanisms. These findings position tumor-resident microorganisms at the threshold of clinical translation, offering novel opportunities for precision diagnosis, prognostic stratification, and personalized treatment strategies in hepatic malignancy management.