An Exploratory Study for the Association of Gut Microbiome with Efficacy of Immune Checkpoint Inhibitor in Patients with Hepatocellular Carcinoma
Open accessAbstract
Background: Gut microbiome has been associated with the efficacy of immune checkpoint inhibitors (ICI) in patients with various types of cancers but not yet in hepatocellular carcinoma (HCC). Aims: To investigate the association between gut microbiome and efficacy of ICI in patients with HCC. Methods: Patients with HCC who were scheduled to receive ICI were prospectively enrolled. Fecal samples were collected within 7 days before initiation of ICI (baseline) and 8 weeks later. Gut microbiome was assessed using 16S rRNA sequencing and shotgun whole-genome sequencing and correlated with objective response (complete or partial response), disease control (objective response or stable disease for ≥ 16 weeks), and overall survival. Results: Thirty-six patients with HCC were enrolled, and 20 of them provided both baseline and 8-week feces. Alpha diversity, richness, and compositions of baseline gut microbiome indicated no difference between responders and nonresponders or between disease control and nondisease control groups. For the 20 paired feces, immunotherapy did not change any of the major microbiome features. No specific taxa were enriched in patients with objective response. Three taxa— Bifidobacterium, Coprococcus , and Acidaminococcus —were enriched in patients with disease control. However, the baseline abundance of these three taxa did not predict overall survival benefit. Conclusions: In this exploratory study, we failed to disclose any overt association of gut microbiome with the efficacy of ICI in patients with HCC. A larger prospective study is warranted for definite conclusion. Keywords: gut microbiome, biomarkers, immune checkpoint inhibitor, hepatocellular carcinoma
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The composition of gut microbiota remained unchanged between paired fecal samples of the same patient collected at baseline and 8 weeks post-ICI treatment.
“However, our previous study showed that the composition of gut microbiota remained unchanged between paired fecal samples of the same patient collected at baseline and 8 weeks post-ICI treatment, thus indicating that ICI treatment would not alter the features of gut microbiome, and the effects of microbial changes might be less prominent on the treatment outcomes.33”
From Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor–treated unresectable hepatocellular carcinoma (2022) · cites this paper as [33]
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“The main microbiome features remained unaffected by immunotherapy, highlighting significant variations between different studies, likely emerging from experimental workflow, starting from stool sampling to bioinformatic analyses [42].”
BackgroundPotential predictive role of gut microbiota to immunotherapy in HCC patients: a brief review
Muscolino, P., Granata, B., Omero, F., Pasquale, C. D., Campana, S., Calabrò, A., D’Anna, F., Drommi, F., Pezzino, G., Cavaliere, R., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1247614 · Cited by 28 · see citing works
Hepatocellular carcinoma and microbiota: Implications for clinical management and treatment
Spanu, D., Pretta, A., Lai, E., Persano, M., Donisi, C., Mariani, S., Dubois, M., Migliari, M., Saba, G., Ziranu, P., et al. (2022) · World Journal of Hepatology · doi:10.4254/wjh.v14.i7.1319 · Cited by 14 · see citing works
Regulatory role of gut microbiota in immunotherapy of hepatocellular carcinoma
Du, J., Guan, Y., & Zhang, E. (2025) · Hepatology International · doi:10.1007/s12072-025-10822-6 · Cited by 8 · see citing works
“The discrepancies in findings may be attributable to variations in experimental procedures, fecal sampling, and bio-informatics analysis [31].”
Lou, S., Li, W., Wang, G., Qian, H., & Zhou, J. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105217 · Cited by 6 · see citing works
The Crosstalk between Microbiome and Immunotherapeutics: Myth or Reality
Tojjari, A., Abushukair, H. M., & Saeed, A. (2022) · Cancers · doi:10.3390/cancers14194641 · Cited by 8 · see citing works
“Only three taxa—Bifidobacterium, Coprococcus, and Acidaminococcus—were higher in patients with disease control, however, their baseline abundance did not correlate with OS [69].”
BackgroundMethodChen, Q., Feng, X., Wang, J., Zhu, H., Bo, Z., Wang, B., & Zhao, Z. (2026) · European Journal of Cancer · doi:10.1016/j.ejca.2026.116581 · Cited by 3 · see citing works
Takahashi, M., Nakatsukasa, H., Shibano, M., Ishigami, Y., Oka, T., Tani, Y., Kawaguchi, T., Nakamura, Y., & Kaneda, H. (2025) · International Journal of Clinical Oncology · doi:10.1007/s10147-025-02805-2 · Cited by 6 · see citing works
“Blautia and Coprococcus are enriched in ICI responders and are thought to be associated with the efficacy of ICI therapy [38, 39].”
Takahashi, M., Takahashi, K., Uchida‐Kobayashi, S., Sasa, Y., Yamase, H., Fujiwara, D., Yoshikawa, T., Komatsu, Y., Shibano, M., Arie, H., et al. (2025) · International Journal of Clinical Oncology · doi:10.1007/s10147-025-02922-y · Cited by 4 · see citing works
Influence of the gut microbiota on the response to immunotherapy in hepatocellular carcinoma
Wu, X., & Lee, T. K. (2025) · Hepatoma Research · doi:10.20517/2394-5079.2025.07 · Cited by 2 · see citing works
Valsecchi, A. A., Ferrari, G., Paratore, C., Dionisio, R., Vignani, F., Sperone, P., Vellani, G., Novello, S., & Maïo, M. D. (2024) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2024.104328 · Cited by 4 · see citing works
Tanaka, Y., Miki, D., Hayes, C. N., Kawahara, M., Sueda, S., Emori, T., Hashimoto, K., Mitamura, Y., Tanaka, A., Hiraoka, K., et al. (2026) · Microorganisms · doi:10.3390/microorganisms14040867 · Cited by 2 · see citing works
“…a report on 36 HCC patients undergoing ICI therapy showed that Acidaminococcus was detected at a higher rate in the disease-control group (CR/PR or long-term SD) than in the non-disease-control group, suggesting a potential positive association between this genus and ICI treatment response [16].”
Antohi, A. L., Gheorghiță, A. D., Andronic, O., Pîrcălăbioru, G. G., & Treteanu, A. R. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27062538 · Cited by 3 · see citing works
Dai, M., Lui, R. N.-S., & Lau, L. H. S. (2023) · Hepatoma Research · doi:10.20517/2394-5079.2023.33 · Cited by 2 · see citing works
Laface, C., Lauricella, E., Ranieri, G., Ambrogio, F., Maselli, F. M., Parlagreco, E., Bernardi, G., Fea, E., & Numico, G. (2025) · Onco · doi:10.3390/onco5010009 · Cited by 1 · see citing works
Guo, L., HUANG, B., Chen, S., Zheng, H., Huang, W., Hu, J., Zhou, L., & Chen, L. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1928103
Ostafe, M. R., Volovăț, S. R., Clement, A., Litcanu, C.-I., Tabarcea, S., Volovăț, C. C., Panaite, D. I., Augustin, I. G., & Volovăț, C. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27177543
“Similarly, sequencing approaches varied considerably, with most studies relying on 16S rRNA gene sequencing targeting the V3–V4 regions, while others utilized whole-genome shotgun metagenomic sequencing [17,69,70,73].”
Influential
- Authors
- Shen, Y.-C., Lee, P.-C., Kuo, Y.-L., Wu, W.-K., Chen, C.-C., Lei, C.-H., Yeh, C.-P., Hsu, C., Hsu, C.-H., Lin, Z.-Z., Shao, Y.-Y., Lu, L.-C., Liu, T.-H., Chen, C.-H., Wu, M.-S., Huang, Y.-H., & Cheng, A.-L.
- Affiliations
- National Taiwan University (TW)
- Taipei Veterans General Hospital (TW)
- National Taiwan University Hospital (TW)
- Corresponding author
- Cheng, Ann-Lii
- ORCID
- Venue
- Journal of Hepatocellular Carcinoma
- Publisher
- Informa UK Limited
- Published
- 2021-07
- Volume
- Volume 8
- Pages
- 809-822
- ISSN
- 2253-5969 (ISSN-L)
- PMC
- PMC8318216
- OpenAlex
- W3184008142
- Cited by
- 36
- References
- 58
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 5 · 2023: 8 · 2022: 5 · 2021: 2
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Hepatocellular Carcinoma (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Funders
- Ministry of Science and Technology, Taiwan (MOST 109, MOST109-2634-F002-043, MOST110-2634-F002-044, MOST108-2314-B002-024, MOST 108-)
- National Taiwan University Hospital (110-2634-F-002-044)
- National Taiwan University (110-2634-F-002-044)
- Taipei Veterans General Hospital
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- gut microbiota, immune checkpoint inhibitors, hepatocellular carcinoma, immunotherapy response, predictive biomarkers, Bifidobacterium, Coprococcus, Acidaminococcus, microbiome diversity, overall survival
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