Review ArticleReview
Open Access

How the gut microbiome affects the immunotherapy response in hepatocellular carcinoma

Mengrui Wu, Yating Zhang and Jun Yu
Cancer Biology & Medicine May 2026, 23 (5) 561-579; DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0761

Abstract

Hepatocellular carcinoma (HCC) remains a major global health challenge with limited long-term survival despite advances in surgical, locoregional, and systemic treatments. Although immune checkpoint blockade (ICB) has reshaped HCC therapy, only a subset of patients achieves durable responses, reflecting substantial heterogeneity in tumor biology and immune microenvironments. Dysbiosis, involving the loss of beneficial bacteria, like Lactobacillus reuteri and Akkermansia muciniphila, and the expansion of pathogens, such as Klebsiella pneumoniae and Catenibacterium mitsuokai, drives HCC by promoting microbial translocation and chronic inflammation. This process is mediated by microbiota-derived metabolites. Pro-carcinogenic agents, like deoxycholic acid (DCA) and quinolinic acid, induce inflammation and activate oncogenic pathways, while protective short-chain fatty acids (SCFAs), like acetate and butyrate, modulate T-cell and ILC3 responses to influence antitumor immunity. Tryptophan catabolites, acting via the aryl hydrocarbon receptor (AhR), further fine tune immune and barrier functions. In addition, emerging data implicate intratumoral microbiota as active modulators of immune suppression and metastatic behavior. These mechanistic insights have accelerated the development of microbiome-targeted interventions, such as probiotics, prebiotics, engineered bacterial strains, and fecal microbiota transplantation, to enhance ICB responsiveness. This review synthesizes current advances linking the gut microbiome to HCC immunobiology and highlights emerging therapeutic strategies aimed at optimizing immunotherapy through precise microbial modulation.

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Introduction

Hepatocellular carcinoma (HCC) constitutes the principal form of primary liver cancer and represents a significant global public health challenge. According to cancer statistics in 2022 from the <nonjoin>World Health Organization (WHO), liver cancer ranks as the sixth most common malignancy in incidence and the third most common cause of cancer-related deaths globally1. Major risk-factors for HCC include chronic infection with hepatitis B or C virus, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease (MASLD)2. The primary therapeutic strategies for HCC in appropriate patients include surgical resection, thermal ablation [such as radio-frequency ablation (RFA)], transarterial chemoembolization (TACE), and transplantation. Small-molecule targeted therapies, such as tyrosine-kinase inhibitors, were approved by the Food and Drug Administration (FDA) as first-line systemic options in advanced disease in 20083. However, high rates of post-treatment recurrence and acquired resistance to chemotherapy and small-molecule targeted agents continues to be a major clinical obstacle. The 5-year survival rates of patients with advanced or unresectable HCC are often ≤10%–20%4,5. Therefore, immune-based therapy has emerged as a highly promising new therapeutic paradigm in HCC over the past decade6–9.

Immune checkpoint blockade (ICB) therapy targets inhibitory receptors, such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which tumors exploit to evade immune surveillance. PD-1 signaling suppresses effector T-cell activity within the tumor microenvironment (TME), while CTLA-4 dampens T-cell priming in lymphoid tissues. Antibody-mediated blockade of these checkpoints restores cytotoxic T-cell function and enhances anti-tumor immunity. ICB has reshaped systemic therapy among HCC therapeutic strategies (Figure 1). Early monotherapies with nivolumab or pembrolizumab achieved objective response rates (ORRs) of 15%–20% but survival benefits were limited10–12. The combination of atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) in the phase III IMbrave150 trial established a new first-line standard with a median progression-free survival (PFS) of 6.8 months7. Similarly, the STRIDE regimen [single-dose tremelimumab (anti-CTLA-4) plus durvalumab (anti-PD-L1) maintenance] from the HIMALAYA trial improved median overall survival to 16.43 months, marking dual checkpoint blockade as another approved frontline option8. More recently, findings from the CheckMate 9DW trial further substantiated the survival advantage conferred by dual ICB, demonstrating that the combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) significantly improves overall survival (OS) in patients with advanced HCC9.

Landscape of immune checkpoint-based systemic therapies for HCC. Timeline summarizing major first- and second-line immune checkpoint-based therapeutic regimens for advanced HCC from 2018 to 2025, including PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, VEGF-targeting antibodies, and other tyrosine kinase inhibitors. FDA-approved immunotherapy combinations are indicated. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CD80, cluster of differentiation 80 (also known as B7-1); PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TCR, T-cell receptor; MHC, major histocompatibility complex; αVEGF, anti-vascular endothelial growth factor; TKI, tyrosine kinase inhibitor. Figure created using BioRender (www.biorender.com).
Figure 1

Landscape of immune checkpoint-based systemic therapies for HCC. Timeline summarizing major first- and second-line immune checkpoint-based therapeutic regimens for advanced HCC from 2018 to 2025, including PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, VEGF-targeting antibodies, and other tyrosine kinase inhibitors. FDA-approved immunotherapy combinations are indicated. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CD80, cluster of differentiation 80 (also known as B7-1); PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TCR, T-cell receptor; MHC, major histocompatibility complex; αVEGF, anti-vascular endothelial growth factor; TKI, tyrosine kinase inhibitor. Figure created using BioRender (www.biorender.com).

Despite notable advances in ICB therapy, a minority of HCC patients achieve durable responses, reflecting multiple mechanistic and biomarker-related challenges. Heterogeneous expression of immune checkpoints, particularly PD-L1, limits predictive accuracy13. The tumor mutational burden (TMB), while a predictive biomarker in several solid tumors, is generally low in HCC14,15 and substantial heterogeneity exists across etiologic subtypes, including virus-associated, MASLD-related, and WNT/β-catenin-driven tumors, all of which affect neoantigen load and immune visibility16. The tumor immune microenvironment further constrains ICB efficacy because many HCCs are “immune-cold” and characterized by sparse tumor-infiltrating lymphocytes (TILs) and enrichment of immunosuppressive populations, such as regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), and M2-like macrophages17. Intrahepatic and inter-subtype heterogeneity further complicates the immune landscape because individual tumor nodules or molecular subclasses exhibit divergent immune microenvironments, checkpoint expression profiles, and responses to immunotherapy18,19. Thus, integrative strategies that combine multi-dimensional, biomarker-guided approaches are essential to improve response rates and durability in HCC.

The gut microbiome not only regulates local intestinal immunity but also exerts a critical influence on systemic immune regulation in HCC via the gut–liver axis, thereby shaping the hepatic immune microenvironment and responses to immunotherapy. Under physiologic conditions, a balanced microbial community maintains intestinal barrier integrity, modulates bile acid and short-chain fatty acid (SCFA) metabolism, and preserves hepatic immune homeostasis20. In contrast, dysbiosis, which is characterized by the loss of beneficial taxa, increased gut permeability, and altered metabolite composition, facilitates the translocation of microbial-associated molecular patterns (MAMPs), and secondary bile acids21,22. This process drives chronic hepatic inflammation, activates innate immune signaling pathways, and promotes the expansion of immunosuppressive myeloid populations, including MDSCs and M2-polarized macrophages23. Notably, specific microbial metabolites, such as deoxycholic acid, have been shown to impair hepatic natural killer T cell recruitment and attenuate antigen presentation, thereby establishing an immunologically “cold” TME that is less responsive to ICB24,25. These findings highlight the gut microbiome as a central regulator of hepatic immunity and underscore the potential of the gut microbiome as a biomarker and therapeutic target to enhance immunotherapy efficacy in HCC.

The role of the gut microbiome in HCC development via the gut–liver axis

Physiologic connection between the gut and liver

The liver and intestine are intricately linked via the gut–liver axis, encompassing the portal vein, bile ducts, and lymphatic vessels. This connection is essential for maintaining metabolic and immune homeostasis. The intestinal epithelium functions as a selective barrier in healthy individuals, permitting nutrient and metabolite absorption, while restricting microbial translocation26. This barrier consists of a monolayer of epithelial cells reinforced by tight junctions, adherens junctions, and a mucous layer enriched with antimicrobial peptides and secretory IgA. Commensal microbiota contribute to barrier maintenance by producing SCFAs, particularly butyrate, which enhances epithelial integrity, supports colonocyte energy metabolism, and modulates local immune activity27. The gut-associated lymphoid tissue (GALT) provides immunologic surveillance and maintains tolerance to dietary and microbial antigens, while facilitating rapid defense against pathogens28. Metabolites and microbial products absorbed in the intestine reach the liver through the portal circulation, where hepatocytes, Kupffer cells, and sinusoidal endothelial cells integrate these signals to coordinate metabolism and immune responses29–32. Bile acids secreted by the liver into the intestine reciprocally shape the microbial composition, establishing a dynamic feedback loop that maintains immune equilibrium33. This tightly regulated system ensures low-level exposure to microbial components, preventing unwarranted hepatic inflammation and sustaining immune homeostasis.

Microbial dysbiosis and disruption of the gut barrier during HCC development

The gut–liver axis represents a dynamic immunometabolic network and disturbances within this system play a pivotal role in liver disease. The intestinal epithelium and its commensal microbiota maintain mucosal integrity and regulate hepatic immune tolerance through the gut–liver axis under physiologic conditions34 (Figure 2).

Gut–liver axis dysregulation and microbiome-driven mechanisms across the spectrum of hepatocarcinogenesis. Progressive liver disease, from ALD-to-MASLD-to-cirrhosis, is characterized by dysbiosis, impaired gut barrier integrity, microbial translocation, and chronic inflammation. (1) ALD: chronic alcohol use causes an intestinal bloom of the pathobiont, E. faecalis, allowing E. faecalis to translocate to the liver. Alcohol exposure remodels hepatic macrophages, downregulating CRIg on Kupffer cells and impairing bacterial clearance. The accumulated E. faecalis in the liver and blood is sensed by TLR2, which activates inflammatory pathways that drive disease pathology. (2) MASLD: The condition is characterized by an altered gut microbiome and dysregulated bile acid metabolism. This dysbiosis, combined with increased intestinal permeability (a “leaky gut”), allows bacterial metabolites and antigens to translocate from the gut into the portal circulation. Once in the liver, these microbial products are detected by PRRs, which initiate inflammatory and stress-response pathways. This cascade of events drives the key pathogenic features of MASLD: hepatic steatosis; inflammation; and fibrogenesis. (3) Cirrhosis: Severe dysbiosis and endotoxemia result from loss of barrier integrity and overgrowth of oral commensals, fueling Kupffer-cell activation and stellate-cell-mediated fibrosis through TLR4 activation. (4) HCC: Microbial translocation from gut-to-liver introduces tumor-promoting bacteria (e.g., C. mitsuokai and K. pneumoniae) and metabolites (e.g., quinolinic acid), which foster hepatocarcinogenesis. Together, these processes illustrate how gut microbial alterations and leaky gut drive inflammation, immune dysfunction, and liver cancer progression. ALD, alcohol-associated liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; CRIg, complement receptor of the immunoglobulin family; PRRs, pattern recognition receptors; TLR2, Toll-like receptor 2; TLR4, Toll-like receptor 4. Figure created using BioRender (www.biorender.com).
Figure 2

Gut–liver axis dysregulation and microbiome-driven mechanisms across the spectrum of hepatocarcinogenesis. Progressive liver disease, from ALD-to-MASLD-to-cirrhosis, is characterized by dysbiosis, impaired gut barrier integrity, microbial translocation, and chronic inflammation. (1) ALD: chronic alcohol use causes an intestinal bloom of the pathobiont, E. faecalis, allowing E. faecalis to translocate to the liver. Alcohol exposure remodels hepatic macrophages, downregulating CRIg on Kupffer cells and impairing bacterial clearance. The accumulated E. faecalis in the liver and blood is sensed by TLR2, which activates inflammatory pathways that drive disease pathology. (2) MASLD: The condition is characterized by an altered gut microbiome and dysregulated bile acid metabolism. This dysbiosis, combined with increased intestinal permeability (a “leaky gut”), allows bacterial metabolites and antigens to translocate from the gut into the portal circulation. Once in the liver, these microbial products are detected by PRRs, which initiate inflammatory and stress-response pathways. This cascade of events drives the key pathogenic features of MASLD: hepatic steatosis; inflammation; and fibrogenesis. (3) Cirrhosis: Severe dysbiosis and endotoxemia result from loss of barrier integrity and overgrowth of oral commensals, fueling Kupffer-cell activation and stellate-cell-mediated fibrosis through TLR4 activation. (4) HCC: Microbial translocation from gut-to-liver introduces tumor-promoting bacteria (e.g., C. mitsuokai and K. pneumoniae) and metabolites (e.g., quinolinic acid), which foster hepatocarcinogenesis. Together, these processes illustrate how gut microbial alterations and leaky gut drive inflammation, immune dysfunction, and liver cancer progression. ALD, alcohol-associated liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; CRIg, complement receptor of the immunoglobulin family; PRRs, pattern recognition receptors; TLR2, Toll-like receptor 2; TLR4, Toll-like receptor 4. Figure created using BioRender (www.biorender.com).

Chronic liver disease: gut–liver axis disruption alters the disease trajectory

Progressive disruption of gut microbial homeostasis and intestinal barrier integrity represents a fundamental pathogenic mechanism underlying chronic liver disease. Among hepatic disorders, alcohol-associated liver disease (ALD) was one of the earliest identified conditions in which gut-derived endotoxins and pathogen-associated molecular patterns (PAMPs) were shown to have a causal role35. Mechanistic studies demonstrated that ethanol-induced dysbiosis and intestinal barrier damage promote bacterial translocation, endotoxemia, and inflammatory hepatic injury, establishing ALD as a prototypical inflammation-driven disease of the gut–liver axis36,37. Excessive alcohol consumption profoundly alters gut microbial composition38. Recent studies have further linked depletion of beneficial taxa, such as Akkermansia muciniphila, to impaired mucosal integrity and aggravated hepatic injury, while supplementation with this bacterium ameliorates ethanol-induced barrier dysfunction and liver damage39. Enterococcus faecalis has emerged as another key pathogenic driver. Targeted bacteriophage therapy effectively eliminates these strains in humanized mice and significantly reduces hepatic inflammation and necrosis40. Moreover, ethanol exposure suppresses the hepatic complement receptor, compromising bacterial clearance and exacerbating microbial translocation41. Alcohol-induced gut dysbiosis and barrier breakdown cooperate to activate hepatic immune signaling, sustain inflammation, and drive progressive liver injury through the gut–liver axis.

MASLD is a complex metabolic disorder affecting up to 30% of the global population. Increasing evidence underscores the central role of the gut–liver axis in the pathogenesis of MASLD. Impaired intestinal barrier function and endotoxemia, which were initially observed in type 2 diabetes, are prevalent in MASLD and facilitate microbial translocation and hepatic inflammation42. Interestingly, it has been shown that the microbial pattern in MALSD patients is likely alcohol-producing43. Dysregulation of lipid metabolism, particularly ceramide synthesis, drives hepatic steatosis and insulin resistance, while commensal bacteria, including Bacteroidetes spp., modulate ceramide production, linking the microbiota directly to metabolic homeostasis44–46. Gut microbial profiling reveals stage-specific dysbiosis. Advanced fibrosis and cirrhosis are characterized by increased Proteobacteria and Escherichia coli abundance and depletion of Firmicutes, whereas steatosis is associated with lower microbial diversity and enrichment of Coprococcus and Ruminococcus gnavus47,48. Notably, long-term gut microbiome instability correlates with MASLD development and metabolic co-morbidities, suggesting a causal role rather than a mere consequence of diet or metabolic disease49.

Cirrhosis represents the terminal stage of chronic liver disease and exemplifies the cumulative impact of gut–liver axis disruption. Patients with decompensated cirrhosis exhibit marked intestinal inflammation, epithelial barrier loss, and elevated fecal cytokine concentrations, which are biomarkers that correlate more strongly with disease severity than circulating inflammatory mediators50. In patients with liver cirrhosis, gut microbial gene richness is markedly reduced compared to healthy individuals and accompanied by a depletion of beneficial, butyrate-producing taxa, such as Faecalibacterium prausnitzii, Coprococcus comes, and members of Lachnospiraceae and Ruminococcaceae, indicating loss of a health-associated microbiome. Conversely, cirrhotic patients exhibit enrichment of oral-origin bacteria, including Campylobacter, and Haemophilus parainfluenzae, suggesting translocation of oral commensals into the gut, likely facilitated by altered bile composition and intestinal permeability51. Mechanistically, endotoxin-mediated activation of the TLR4 signaling pathway in hepatic macrophages and stellate cells has a pivotal role in driving hepatic inflammation and fibrogenesis52. Collectively, these findings illustrate a mechanistic continuum in which gut microbial dysbiosis and barrier disruption foster endotoxin-mediated hepatic inflammation and fibrosis, ultimately facilitating the transition from cirrhosis to hepatocarcinogenesis.

HCC: gut-liver translocation as a pivotal driver

Emerging evidence indicates that gut microbiota actively shapes the TME in HCC. Tumor-associated microbiota are enriched in Bacteroidetes, Firmicutes, and Proteobacteria, with taxa, such as Ruminococcus gnavus and Stenotrophomonas maltophilia, linked to hepatic stellate cell activation and senescence-associated secretory phenotypes (SASPs)53,54. Dysbiosis is characterized by increased Bacteroides and Ruminococcaceae, reduced Bifidobacterium, and altered lipopolysaccharide (LPS)- and butyrate-producing genera in MASLD- or cirrhosis-associated HCC, which correlates with systemic inflammation and hepatocarcinogenesis55. Hepatitis B virus (HBV)-related HCC displays enrichment of anti-inflammatory taxa, such as Prevotella, Lactobacillus, and Faecalibacterium, indicating virus-specific modulation of gut-immune interactions56. Mechanistic studies have moved beyond correlation to establish causation, demonstrating that gut-derived bacteria can translocate to the liver and directly drive oncogenesis. For example, fecal microbiota transplantation from HCC patients to mice can induce liver disease, a process driven by the pathogen, Klebsiella pneumoniae. This bacterium translocates and promotes hepatocarcinogenesis through the surface protein (PBP1B), which activates the TLR4 signaling pathway57. A recent study revealed a similar mechanism for Catenibacterium mitsuokai, which was shown to be enriched in HCC tumors. This bacterium translocates by binding to γ-catenin on liver cells via the Gtr1/RagA protein and secretes quinolinic acid, which activates the TIE2 receptor and downstream PI3K/AKT pathway to drive tumor growth58. Both studies provided mechanistic evidence that targeting these specific bacteria or the signaling pathways suppress HCC progression, establishing a direct causal role for the gut microbiota in hepatocarcinogenesis. Collectively, these findings underscored the progressive influence of gut microbiota on liver disease, linking early metabolic dysregulation in MASLD to cirrhosis-associated inflammation and ultimately HCC, and highlighting the gut–liver axis as a potential target for biomarker development and therapeutic intervention.

Microbiome–immune interactions relevant to HCC microenvironment

Gut microbiota-derived metabolites shaping the immune response

Gut microbiota-derived metabolites, particularly bile acid derivatives and SCFAs, constitute critical mediators of host–microbe communication that orchestrate hepatic immune homeostasis and influence the immunopathogenesis of HCC. Among these metabolites, bile acid metabolites have emerged as potent immunoregulatory molecules that bridge metabolic and inflammatory signaling (Figure 3).

Gut–liver axis and host immune microenvironment in hepatocarcinogenesis. (1) Dysbiosis and leaky gut: Dysbiotic gut communities enriched in pathogenic species (e.g., C. mitsuokai and K. pneumoniae) enable bacterial dissemination and metabolite flux across the gut–liver axis, contributing to hepatocarcinogenesis. (2) Intratumoral bacteria: Within the liver, intratumoral bacteria (e.g., E. faecalis and S. anginosus) further shape an immunosuppressive tumor microenvironment characterized by increased MDSCs and reduced cytotoxic T-cell infiltration. a. Bile acids: Bile acids, such as DCA, induce SASP in hepatic stellate cells, while LCA modulates the Th17/Treg balance; b. SCFAs: SCFAs, including butyrate and acetate, regulate mucosal immune tolerance, hepatocyte proliferation, fibrosis, and ILC3 function. c. Tryptophan derivatives: tryptophan-derived metabolites, such as IAA and IPA, attenuate hepatocyte inflammation and support mucosal and hepatic immune homeostasis. SCFA, short-chain fatty acids; DCA, deoxycholic acid; LCA, lithocholic acid; SASP, senescence-associated secretory phenotypes; MDSCs, myeloid-derived suppressor cells; IAA, indole-3-acetic acid; IPA, indole-3-propionic acid. Figure created using BioRender (www.biorender.com).
Figure 3

Gut–liver axis and host immune microenvironment in hepatocarcinogenesis. (1) Dysbiosis and leaky gut: Dysbiotic gut communities enriched in pathogenic species (e.g., C. mitsuokai and K. pneumoniae) enable bacterial dissemination and metabolite flux across the gut–liver axis, contributing to hepatocarcinogenesis. (2) Intratumoral bacteria: Within the liver, intratumoral bacteria (e.g., E. faecalis and S. anginosus) further shape an immunosuppressive tumor microenvironment characterized by increased MDSCs and reduced cytotoxic T-cell infiltration. a. Bile acids: Bile acids, such as DCA, induce SASP in hepatic stellate cells, while LCA modulates the Th17/Treg balance; b. SCFAs: SCFAs, including butyrate and acetate, regulate mucosal immune tolerance, hepatocyte proliferation, fibrosis, and ILC3 function. c. Tryptophan derivatives: tryptophan-derived metabolites, such as IAA and IPA, attenuate hepatocyte inflammation and support mucosal and hepatic immune homeostasis. SCFA, short-chain fatty acids; DCA, deoxycholic acid; LCA, lithocholic acid; SASP, senescence-associated secretory phenotypes; MDSCs, myeloid-derived suppressor cells; IAA, indole-3-acetic acid; IPA, indole-3-propionic acid. Figure created using BioRender (www.biorender.com).

Bile acids

Primary bile acids synthesized by hepatocytes are transformed by commensal bacteria into secondary bile acids, which can exert profound effects on innate and adaptive immunity59. Specific bile acid species modulate the balance between proinflammatory Th17 and anti-inflammatory Treg cells through direct engagement of nuclear receptors, such as RORγt and farnesoid X receptor (FXR)60,61. For example, 3-oxo-lithocholic acid (3-oxoLCA) binds RORγt to inhibit Th17 differentiation, while isoallo-lithocholic acid (isoalloLCA) enhances Treg cell generation, collectively contributing to immune tolerance and gut–liver immune equilibrium60. Conversely, bile acids accumulation, particularly deoxycholic acid (DCA), promotes chronic hepatic inflammation under dysbiotic or high-fat dietary conditions. DCA activates hepatic stellate cells (HSCs), induces a SASP, and stimulates the production of prostaglandin E2 (PGE2), which suppresses antitumor immune responses and facilitates hepatocarcinogenesis62. Some secondary bile acids can further impair enterohepatic circulation and hepatic FXR activation by promoting CD8+ T cell-mediated ileitis through TGR5/mTOR-dependent metabolic reprogramming63.

Bile acid signaling also modulates innate immune surveillance through receptor-mediated pathways. Activation of FXR and G protein-coupled receptor TGR5 suppresses NF-κB and NLRP3 inflammasome activation, thereby restraining excessive cytokine release and preventing chronic inflammation64,65. Inhibition or dysregulation of FXR function disrupts immune homeostasis, enhances intestinal permeability, and favors the proliferation of tumor-promoting microbial species. Moreover, bile acid-dependent chemokine signaling in liver sinusoidal endothelial cells regulates CXCL16-mediated recruitment of natural killer T (NKT) cells, linking microbial metabolism to hepatic immune surveillance and tumor control24.

SCFAs

Similarly, SCFAs, which are derived from bacterial fermentation of dietary fibers, are major immunomodulatory metabolites influencing gut and hepatic immune tone66. SCFAs promote intestinal homeostasis by supporting Treg differentiation, and in the case of butyrate, by maintaining mucosal integrity through anti-inflammatory, epigenetic, and antineoplastic mechanisms66. SCFAs act as histone deacetylase inhibitors and ligands for G protein-coupled receptors, such as GPR43, thereby modulating epigenetic and transcriptional programs in immune cells67.

Recent work provided mechanistic insight by showing that acetate availability is markedly reduced in HCC-bearing mice due to loss of Lactobacillus reuteri, coinciding with heightened IL-17A production by ILC3s68. Restoration of acetate via fecal microbiota transplantation or direct supplementation suppresses tumor growth and enhances PD-1 blockade efficacy in HCC. Acetate exerts these effects by inhibiting histone deacetylase activity and promoting Sox13 acetylation to restrain IL-17A production in ILC3s, independent of GPR43 signaling. Together, these findings highlight SCFA acetate as a key microbial metabolite that shapes gut–liver immune crosstalk by modulating ILC3-driven inflammation in HCC. Butyrate promotes Treg differentiation and IL-10 production, reinforcing mucosal immune tolerance, while attenuating proinflammatory cytokine expression in macrophages and dendritic cells66,69,70. However, under conditions of microbial dysbiosis or bile acid depletion, excessive SCFA accumulation, particularly butyrate derived from inulin fermentation, can paradoxically promote hepatocarcinogenesis by altering bile acid signaling and metabolic fluxes71.

Tryptophan catabolites

Tryptophan-derived microbial metabolites constitute a major class of gut microbiota-dependent immunomodulators that shape intestinal and hepatic immune responses through cell type-specific signaling programs. A central mechanism underlying these effects is activation of the aryl hydrocarbon receptor (AhR), which integrates microbial signals to regulate cytokine production, immune barrier function, and inflammatory tone. Indole, for example, attenuates hepatic steatosis and inflammation by promoting PFKFB3 expression and suppressing pro-inflammatory macrophage activation through AhR signaling72. Indole-3-acetic acid (IAA) exerts broader immunoregulatory functions. IAA enhances IL-22 and REG3G expression in group 3 innate lymphoid cells (ILC3s) in the gut, thereby strengthening the mucosal immune barrier73. IAA mitigates inflammation and cytokine-driven lipogenesis in the liver by downregulating macrophage-derived cytokines and repressing FASN and SREBP-1c in hepatocytes through AhR-dependent pathways74. Similarly, indole-3-propionic acid (IPA) supports mucosal and hepatic immune homeostasis by upregulating epithelial tight junction proteins and dampening macrophage inflammatory responses. Together, these metabolite-specific actions underscore the nuanced and multifaceted ways in which gut microbiota-derived tryptophan metabolites fine-tune immune responses along the gut–liver axis. Additional microbial metabolites, such as N,N,N-trimethyl-5-aminovaleric acid, can exacerbate hepatic steatosis by inhibiting γ-butyrobetaine hydroxylase, reducing carnitine synthesis and impairing fatty acid oxidation75.

Despite these advances, several mechanistic ambiguities remain regarding microbiome–immune interactions within the HCC microenvironment. Emerging evidence suggests that the immunologic effects of microbial metabolites are highly context-dependent, being shaped by disease etiology (viral, metabolic, or toxic), liver fibrosis stage, and host genetic variations in receptors, such as FXR, TGR5, and AhR. For example, bile acids may suppress or promote inflammation depending on the concentration and composition, while SCFAs can switch from antitumor-to-protumor functions under dysbiotic or nutrient-rich conditions. Furthermore, potential antagonism among microbial metabolites, such as bile acid-mediated repression of SCFA-producing bacteria or reciprocal inhibition between indole derivatives and secondary bile acids adds another layer of complexity to immune regulation. The origin of intratumoral microbiota is also unresolved. Whether these microbes arise from translocation of gut bacteria through a compromised gut–liver axis or through selective colonization within the immunometabolic niche of the tumor is still debated. It is plausible that gut-derived signals and intratumoral microbial metabolites act synergistically or competitively to modulate local immune states, influencing both immune exhaustion and therapeutic responsiveness. Understanding the crosstalk between microbial metabolism and host immunity offers promising avenues for therapeutic intervention in liver cancer through microbiota-targeted or metabolite-based modulation of immune pathways.

Intratumor microbiota and resident immunity

Beyond the well-recognized influence of the gut microbiota-derived metabolites, accumulating evidence highlights the existence of a distinct intratumor microbiota that exerts localized effects on immune regulation and tumor progression in HCC76. Recent studies have demonstrated that microbial DNA and viable bacteria can be detected within HCC nodules, suggesting that microbes not only translocate from the gut to the liver but may also establish persistent, functionally active communities within the TME77. By integrating metagenomic sequencing, spatial transcriptomics, and immune profiling across 242 tumor nodules and matched non-tumor liver tissues, it was revealed that each tumor nodule harbors a unique bacterial composition, reflecting profound intrahepatic microbial heterogeneity. The microbial signatures associated with intrahepatic metastasis (IM) vs. multicentric occurrence (MO) were further distinguished by two key pathologic subtypes of multifocal HCC with a diagnostic accuracy (AUC ≈ 0.80) based on a nine-bacterium panel. Notably, Enterococcus faecalis and Streptococcus anginosus, which are enriched in IM lesions, were functionally validated as active oncogenic modulators. Colonization by these species promote tumor invasion and metastasis by activating pro-inflammatory signaling pathways and fostering an immunosuppressive TME that is characterized by reduced cytotoxic T-cell infiltration and increased MDSC accumulation. Intratumoral bacteria, such as E. faecalis and S. anginosus, appear to influence resident hepatic immunity through direct and indirect routes. These intratumoral microorganisms interact closely with hepatic immune cells, shaping the local immune milieu and influencing antigen presentation. Furthermore, microbial colonization within the tumor may alter local oxygen gradients and metabolic signaling, particularly hypoxia-inducible and bile acid pathways, contributing to immune exhaustion and resistance to ICB therapy78.

These findings collectively established intratumor bacteria as active participants in the evolution of the HCC immune microenvironment, rather than passive bystanders. The interplay between microbial presence and resident immune cell plasticity suggests that the hepatic microbiota, both gut-derived and intratumoral, represents an integral component of the “immune-microbial axis” in liver cancer. Understanding these complex relationships could elucidate the development of microbiome-based diagnostics to distinguish HCC subtypes, as well as targeted microbial modulation strategies to restore antitumor immunity, and may improve immunotherapy efficacy.

Microbiome influence on HCC immunotherapy efficacy, side effects, and resistance

Accumulating evidence indicates that the gut microbiota is a key determinant of immunotherapy outcomes in HCC, influencing therapeutic efficacy, immune-related adverse events (irAEs), and the development of resistance79–81. Microbial composition and function shape systemic immunity and the TME through a close interaction with the gut–liver axis, underscoring the therapeutic potential of microbiome-targeted strategies in HCC (Figure 4).

The impact of the microbiome on HCC immunotherapy: efficacy; immune-related adverse events, and resistance. (1) Enhanced immunotherapy efficacy in HCC: A. muciniphila and Bifidobacterium, together with the respective metabolites, TUDCA and isobutyrate, enhance the efficacy of immunotherapy by promoting the proliferation and functional activity of CD8+ T cells. (2) Relieved immune-related adverse events: Beneficial commensal microbes, including Bifidobacterium and Lactobacillus, can strengthen the mucosal barrier and inhibit inflammatory responses, thereby alleviating irAEs. (3) Immunotherapy resistance: By contrast, some bacterial species can induce resistance to immunotherapy. For example, P. vulgatus impairs the cytotoxicity of CD8+ T cells in the tumor microenvironment, which in turn suppresses the efficacy of immunotherapy. HCC, hepatocellular carcinoma; TUDCA, tauroursodeoxycholic acid; IAA, indole-3-acetic acid. Figure created using BioRender (www.biorender.com).
Figure 4

The impact of the microbiome on HCC immunotherapy: efficacy; immune-related adverse events, and resistance. (1) Enhanced immunotherapy efficacy in HCC: A. muciniphila and Bifidobacterium, together with the respective metabolites, TUDCA and isobutyrate, enhance the efficacy of immunotherapy by promoting the proliferation and functional activity of CD8+ T cells. (2) Relieved immune-related adverse events: Beneficial commensal microbes, including Bifidobacterium and Lactobacillus, can strengthen the mucosal barrier and inhibit inflammatory responses, thereby alleviating irAEs. (3) Immunotherapy resistance: By contrast, some bacterial species can induce resistance to immunotherapy. For example, P. vulgatus impairs the cytotoxicity of CD8+ T cells in the tumor microenvironment, which in turn suppresses the efficacy of immunotherapy. HCC, hepatocellular carcinoma; TUDCA, tauroursodeoxycholic acid; IAA, indole-3-acetic acid. Figure created using BioRender (www.biorender.com).

Gut microbiota and enhanced immunotherapy efficacy

A diverse, functionally balanced microbial ecosystem is generally associated with more favorable immunotherapy outcomes, whereas dysbiosis promotes immune evasion, tumor progression, and reduced responsiveness to ICB82–84. Multi-strain Enterobacteriaceae formulations combined with PD-1/PD-L1 inhibitors have demonstrated synergistic antitumor effects83. The detrimental impact of broad-spectrum antibiotics further highlights the necessity of an intact microbiome for optimal ICB efficacy85,86, which may involve remodeling the TME, enhancing CD8+ T-cell activation and regulating T-cell differentiation programs.

Notably, bacterial regulation of the immune system is inseparable from bacterial metabolites in HCC. Owing to the intestinal mucosal barrier function, most bacteria exert effects via the gut-liver axis, utilizing metabolic products, such as bile acids, SCFAs, and tryptophan, to modulate immune system function. Studies have shown that Bifidobacterium abundance is positively correlated with isobutyrate levels in the gut microbiota of healthy individuals. Both Bifidobacterium and isobutyrate can inhibit HCC growth by increasing CD8+ T-cell counts and IFN-γ levels, while reducing JAK/STAT3 signaling in the TME87. Another study indicated that Akkermansia muciniphila promotes apoptosis of HCC cells and increases the proportion of CD8+ T cells in the TME. Furthermore, A. muciniphila induces alterations in host bile acid metabolism, leading to a significant increase in serum tauroursodeoxycholic acid (TUDCA) levels, suggesting that A. muciniphila may enhance the efficacy of PD-1 monoclonal antibody immunotherapy against HCC through effects on bile acid metabolism88. Altered immune and microbial landscapes contribute to poor responses to monotherapy in MASLD-related HCC89. A. muciniphila alleviates hepatic steatosis by suppressing cholesterol biosynthesis and bile acid metabolism, while enhancing responsiveness to PD-1 blockade in MASLD-HCC through modulating MDSC activity and inhibiting M2 macrophage polarization90. In addition to bacteria-derived metabolites, a recent study demonstrated that inhibiting bile acid synthesis in hepatocytes enhances tumor-specific T-cell responses, reduces tumor growth, and sensitizes tumors to anti-PD-1 immunotherapy. In addition, different bile acid species exert distinct regulatory effects on CD8+ T cells. Primary bile acids induce oxidative stress, whereas secondary bile acids suppress T-cell function via endoplasmic reticulum stress91. Collectively, these findings underscore the considerable potential of the gut microbiota and the metabolites as targets to enhance immunotherapy efficacy in HCC.

Clinical studies have shown the link between gut microbiota composition and ICB efficacy in HCC, expanding these insights beyond preclinical models. A study examined the dynamic changes in gut microbiota composition and characteristics in fecal samples from HCC patients undergoing anti-PD-1 immunotherapy following prior treatment with sorafenib. The findings revealed that responders exhibited greater microbial diversity in fecal microbiota compared to non-responders. Among the responder-enriched species, four Lactobacillus spp., Bifidobacterium dentium, and Streptococcus thermophilus were probiotic lactic acid bacteria that are beneficial to host metabolism and immunity by inhibiting the growth of pathogenic microorganisms, highlighting the potential of gut microbiota as a therapeutic target92.

Microbiome contributions to irAEs

While ICB offers clinical benefit, irAEs significantly limit ICB use. The gut microbiota has a central role in irAE development with baseline microbial composition predicting susceptibility, especially for ICI-induced colitis93,94. Dysbiosis, whether spontaneous or antibiotic-induced, exacerbates irAEs by impairing epithelial barrier integrity, amplifying mucosal inflammation, and enhancing proinflammatory immune activation. Broad-spectrum antibiotic use not only worsens irAEs but also diminishes ICI efficacy, reflecting the dual role of the microbiome in regulating toxicity and therapeutic responsiveness95,96.

Conversely, targeted microbiome modulation has shown promise in mitigating irAEs97,98. Beneficial microbes, such as Bifidobacterium and Lactobacillus, can reinforce the mucosal barrier, promote regulatory immune networks, and produce SCFAs that suppress inflammation95. Fecal microbiota transplantation (FMT) is currently being evaluated as a therapeutic option for refractory ICI-related colitis with early results demonstrating restoration of microbial diversity and improvement of clinical symptoms99,100. These findings highlight the potential of microbiome-based interventions to improve the safety profile of cancer immunotherapy.

Microbiome-driven immunotherapy resistance

The gut microbiota is increasingly recognized as a critical driver of immunotherapy resistance, which is a major barrier in HCC treatment101,102. Recent evidence has established a causal role for the gut microbiota in shaping immunotherapy resistance in HCC. Comparative analyses of responders and non-responders revealed marked microbial disparities. Specifically, Phocaeicola vulgatus was significantly enriched in non-responders and functioned as a key driver of anti-PD-1 resistance. FMT and single-strain colonization experiments confirmed that P. vulgatus suppresses immunotherapy efficacy, not by promoting tumor growth directly, but by impairing CD8+ T cell cytotoxicity within the TME84. Mechanistically, P. vulgatus disrupts intestinal tryptophan metabolism by diverting IPA away from IAA synthesis due to the absence of IPDC and the presence of IOR, leading to systemic depletion of IAA. These findings identified P. vulgatus abundance and IAA deficiency as potential biomarkers of immunotherapy resistance and highlight the therapeutic promise of microbiota- and metabolite-targeted interventions to personalize and improve immunotherapy outcomes in HCC.

Antibiotic-induced disruption of microbiota composition further aggravates immunotherapy resistance, as demonstrated in clinical studies showing decreased survival among patients receiving antibiotics before or during ICB therapy98. As a result, microbiome preservation or deliberate modulation has emerged as an important strategy to overcome resistance. Notably, a phase II clinical trial (RENMIN-215) is currently evaluating the synergy of FMT with tislelizumab and fruquintinib to reverse anti-PD-1 resistance, exemplifying the translation of microbiome science into clinical intervention103.

Therapeutic strategies of targeting the gut microbiome to enhance immunotherapy

Targeting the gut microbiome represents a novel frontier in enhancing the efficacy of immunotherapy for HCC. These strategies aim to restore a balanced microbial ecosystem, boost anti-tumor immunity, and mitigate irAEs104 (Figure 5).

Microbiome-based therapeutic strategies to enhance immunotherapy efficacy in hepatocellular carcinoma. Conceptual overview of current and emerging microbiota-targeted interventions designed to optimize antitumor immunity in HCC. Strategies include probiotics and prebiotics, dietary interventions, engineered bacterial strains and fecal microbiota transplantation to restore a favorable microbial ecosystem in patients with dysbiosis. Probiotics and prebiotics: Probiotics (e.g., Lactobacillus and Bifidobacterium) and prebiotics (e.g., inulin) enhance the efficacy of immune checkpoint inhibitors and mitigate the toxicities in HCC. Engineered bacteria strains: Genetically modified bacterial strains represent a cutting-edge strategy to precisely modulate the gut-immune axis. Fecal microbiota transplantation: Fecal microbiota transplantation restores gut microbial diversity and function, showing promise in reversing immunotherapy resistance in HCC by restoring the gut microbiota in recipients by introducing a diverse microbial community from healthy donors. Dietary interventions: dietary interventions offer a non-invasive method to shape a favorable gut microbiome that can augment immunotherapy efficacy, highlighting the importance of personalized nutrition in HCC management. HCC, hepatocellular carcinoma. Figure created using BioRender (www.biorender.com).
Figure 5

Microbiome-based therapeutic strategies to enhance immunotherapy efficacy in hepatocellular carcinoma. Conceptual overview of current and emerging microbiota-targeted interventions designed to optimize antitumor immunity in HCC. Strategies include probiotics and prebiotics, dietary interventions, engineered bacterial strains and fecal microbiota transplantation to restore a favorable microbial ecosystem in patients with dysbiosis. Probiotics and prebiotics: Probiotics (e.g., Lactobacillus and Bifidobacterium) and prebiotics (e.g., inulin) enhance the efficacy of immune checkpoint inhibitors and mitigate the toxicities in HCC. Engineered bacteria strains: Genetically modified bacterial strains represent a cutting-edge strategy to precisely modulate the gut-immune axis. Fecal microbiota transplantation: Fecal microbiota transplantation restores gut microbial diversity and function, showing promise in reversing immunotherapy resistance in HCC by restoring the gut microbiota in recipients by introducing a diverse microbial community from healthy donors. Dietary interventions: dietary interventions offer a non-invasive method to shape a favorable gut microbiome that can augment immunotherapy efficacy, highlighting the importance of personalized nutrition in HCC management. HCC, hepatocellular carcinoma. Figure created using BioRender (www.biorender.com).

Probiotics and prebiotics

Probiotics are defined as live microorganisms that confer health benefits when administered. Common examples include well-studied bacterial genera, such as Lactobacillus and Bifidobacterium105,106. Emerging evidence supports the therapeutic potential of combining probiotics with ICB and anti-angiogenic agents in HCC107. Specific probiotic strains have demonstrated the ability to enhance treatment efficacy and mitigate irAEs. Supplementation with Bifidobacterium has been shown to significantly potentiate the anti-tumor effect of PD-1 blockade87. Similarly, L. acidophilus and B. pseudolongum improved intestinal barrier integrity and suppressed MASLD-HCC progression, suggesting the potential to enhance ICB efficacy108,109. Regarding toxicity management, specific probiotics effectively reduced the incidence of ICI-related colitis in mouse models. Bifidobacterium markedly alleviated colitis without compromising the anti-tumor activity of ICIs. This protective effect was abolished in Treg-deficient mice, indicating a Treg-dependent mechanism110. Collectively, these findings substantiated the strategic combination of probiotics with PD-1 inhibitors in HCC therapy.

Prebiotics, non-digestible substrates selectively utilized by beneficial microbes further support these immune-enhancing effects111. Various complex glycans, such as inulin, have been clinically evaluated as prebiotics112. A previous study demonstrated that the commensal bacterium, Parabacteroides distasonis, utilizes inulin to produce pentadecanoic acid, an odd-chain fatty acid, which in turn restores gut barrier function in MASH models. This restoration reduces serum lipopolysaccharide levels and hepatic pro-inflammatory cytokine expression, thereby suppressing disease progression113. Prebiotics also enhance the production of beneficial SCFAs, which subsequently stimulate systemic memory T-cell responses and promote T-cell infiltration and activation within the TME114. This mechanism is exemplified by artificial prebiotics, such as AHCC®, which has been shown to improve the efficacy of ICB by modifying gut microbiota composition and enhancing T-cell function in the TME115.

Engineered bacterial strains

Engineered bacterial strains represent an advanced approach to precisely manipulate the gut–immune axis for therapeutic gain. Bacteria can be modified to produce targeted metabolites through microbial engineering, enhance immunostimulatory activity, or deliver therapeutic molecules directly to the gut or TME116,117. Although the application in HCC immunotherapy remains largely conceptual, the rationale is strong. Specific engineered strains could be designed to restore microbial functions lost in non-responders, promote antitumor immunity, or modulate signaling pathways essential for effective ICB. For example, a study revealed that the engineered E. coli Nissle 1917 strain enhanced the efficacy of PD-L1 blockade by boosting L-arginine-mediated T cell production and activation118. Such precision tools may ultimately overcome limitations of conventional probiotics and offer customizable solutions for microbiome-driven immunotherapy optimization.

FMT

FMT refers to the transfer of fecal microbiota from healthy donors to recipients, aiming to restore the diversity and functional capacity of the recipient gut microbiota. As a promising therapeutic strategy, FMT has demonstrated remarkable efficacy in replacing or modulating the existing gut microbiota of recipients, thereby exerting a positive regulatory effect on host physiologic status and disease outcomes with particularly prominent results in enhancing the responsiveness to immunotherapy in cancer treatment119.

The effectiveness of FMT in regulating gut microbiota primarily lies in an ability to directly reshape the composition of gut microorganisms and restore the normal functions. A growing body of evidence indicates that FMT effectively restores the richness and diversity of gut microbiota in recipients by introducing a diverse microbial community from healthy donors120. The essence of this “ecosystem transplantation” is not targeting a single bacterial strain but introducing a complete, interacting microbial ecosystem, thereby re-establishing intestinal “colonization resistance.” Colonization resistance refers to the inhibition of pathogenic microbial colonization and overgrowth through various mechanisms121. For example, antibiotic treatment disrupts gut microbiota diversity, in Clostridioides difficile infection (CDI), allowing C. difficile to proliferate. In contrast, FMT re-establishes colonization resistance by restoring a healthy microbial community, effectively treating recurrent CDI122,123. Studies have shown that the successful colonization of donor microbiota in the recipient’ gut is crucial for achieving clinical remission in CDI patients undergoing FMT124.

The potential mechanisms through which FMT replaces or modulates the existing gut microbiota to exert therapeutic effects are multifaceted. First, the transplanted healthy fecal microbiota can serve as a “functional donor pool,” directly supplementing the recipient gut with a variety of beneficial microorganisms capable of colonizing the intestinal tract. These colonizing beneficial bacteria then compete with the recipient original harmful microorganisms for nutritional resources and intestinal colonization sites, gradually replacing abnormal microbial populations and establishing a new, balanced microbial community125. Second, the transplanted microbiota can regulate the metabolic functions of the gut microbiota. FMT significantly increases the production of SCFAs126. Butyrate is not only the main energy source for colonic epithelial cells by helping to maintain the integrity of the intestinal barrier but also possesses potent immunomodulatory effects. For example, butyrate can induce the production of Tregs, thereby inhibiting inflammatory responses and restoring immune tolerance127. In addition, FMT can regulate the gut microbiota by improving the intestinal microenvironment and immune homeostasis. Gut microbiota dysbiosis is often accompanied by mucosal inflammation128 and FMT can effectively alleviate mucosal inflammation by re-establishing a healthy microbial community129.

In addition, accumulating evidence suggests that the gut microbiota can regulate antitumor immune responses and influence the efficacy of cancer immunotherapy130,131. As an emerging adjuvant therapy for cancer, FMT has become a research hotspot for improving the efficacy and reducing the toxicity of ICIs by regulating the gut microbiota. For example, the FAB-HCC pilot study exemplifies this emerging translational research effort in HCC. The FAB-HCC pilot study is a phase II trial evaluating the efficacy of FMT combined with atezolizumab/bevacizumab in patients who have developed resistance to previous immunotherapy. This approach aims to overcome ICI resistance by reshaping the gut microbiota into a responder state, thereby re-sensitizing tumors to immunotherapy132.

Dietary interventions

Dietary modification offers a practical, non-invasive means to modulate the gut microbiota and potentially enhance immunotherapy efficacy. Diet strongly influences microbial composition and metabolite production, including SCFAs and BAs. Among 128 melanoma patients receiving ICB therapy, higher dietary fiber intake was associated with significantly prolonged PFS with the most pronounced benefit observed in patients with adequate intake. This finding was corroborated in preclinical models, which demonstrated that a low-fiber diet impaired the response to anti-PD-1 therapy in mice133. The ketogenic diet elevated levels of the commensal bacterium, Eisenbergiella massiliensis, in a colorectal cancer mouse model, which showed a strong correlation with the principal ketone body, 3-hydroxybutyrate (3-HB). This cascade triggered a 3-HB-dependent T-cell antineoplastic response, boosting the efficacy of ICIs and elevating OS134. For the further development of such interventions, it is crucial to determine precisely how diet modulates microbial composition and augments antitumor immunity.

Although specific dietary guidelines for HCC patients undergoing immunotherapy remain emergent, the principle of fostering a diverse and health-promoting microbiome through personalized nutrition represents a promising adjunct strategy.

Ongoing clinical trials

Increasing recognition of the microbiome role in the immunotherapy response has spurred multiple clinical investigations. The FAB-HCC trial is actively evaluating the safety and efficacy of combining FMT with atezolizumab/bevacizumab in HCC patients who failed to sustain responses to first-line immunotherapy132. Beyond FMT-specific studies, broader clinical efforts aim to characterize microbial signatures predictive of immunotherapy outcomes, setting the stage for personalized microbiome-targeted interventions.

Collectively, these trials reflect a rapidly evolving landscape in which microbiome-based therapies, including probiotics, prebiotics, engineered strains, nutritional strategies, and FMT, are poised to complement and enhance immunotherapy for HCC (Table 1).

View this table:
Table 1

Clinical trials initiated over the past 5 years exploring the role of the gut microbiome in HCC immunotherapy

Conclusions and future perspectives

The gut microbiome has emerged as a pivotal regulator of the immunotherapy response in HCC, exerting multifaceted influences on antitumor immunity, therapeutic efficacy, and treatment-related toxicity. The microbiota actively shapes the hepatic immune landscape through the gut–liver axis, microbially derived metabolites, and even intratumoral microbial communities. Dysbiosis can impair immune surveillance, drive irAEs, and contribute to primary or acquired resistance, whereas a balanced microbial ecosystem can enhance effector T-cell function and improve responses to ICIs. This duality highlights the potential of the microbiome as a predictive biomarker and as a modifiable therapeutic target.

Probiotics and prebiotics

Although probiotics and prebiotics demonstrate promising potential in the treatment of HCC81,135,136, several critical challenges remain, significantly hindering the clinical translation and widespread application.

First, the effects exhibit high strain specificity. The impact on gut microbiota modulation, immune function enhancement, and antitumor activity can vary substantially not only between different probiotic strains but even among subtypes of the same strain137,138. The optimal probiotic strain or combination for HCC patients has not been identified. Indiscriminate use may lead to suboptimal efficacy and could potentially exacerbate liver burden by disrupting intestinal microbial balance.

Second, there is a paucity of robust, HCC-specific clinical trial data. Current evidence largely derives from preclinical studies or small-scale clinical observations139,140, which are insufficient to establish consistent, high-level evidence for clinical practice141. Moreover, existing research predominantly focuses on the short-term efficacy and acute adverse events of probiotics combined with ICB therapy142. Critical data regarding long-term safety, enduring antitumor effects, and OS benefits in HCC patients are lacking, undermining the foundation for standardized clinical protocols.

Third, potential drug-drug interactions are poorly understood. HCC patients undergoing immunotherapy often receive concomitant medications, including targeted agents, chemotherapy, and hepatoprotective drugs143. Probiotics may interact with these therapies, yet the mechanisms and clinical significance of such interactions remain unexamined in systematic studies, posing a potential safety concern.

In conclusion, the application of probiotics and prebiotics in HCC immunotherapy remains exploratory. Advancing this field requires identifying the most effective, HCC-specific probiotic strains or combinations, conducting high-quality clinical trials to validate the efficacy and safety, and systematically investigating the interactions with established HCC therapeutics. These steps are essential to facilitate the standardized and personalized use of probiotics in HCC management, ultimately harnessing the full potential as synergistic adjunctive therapy.

Engineered bacteria

Engineered bacteria demonstrates significant potential in the field of HCC immunotherapy. By genetically engineering bacteria to perform targeted functions within the body, this approach offers a promising strategy to overcome the limitations associated with traditional probiotic applications116. However, this technology demands high precision in genetic modification and careful selection of suitable bacterial vectors144. A key challenge that remains to be addressed is achieving precise in vivo targeted delivery and long-term colonization of gene-edited bacteria in specific tissues or regions. Furthermore, the activity and proliferation of these engineered bacteria must be tightly regulated to prevent overgrowth, which could lead to systemic infection or adverse immune reactions. Existing control strategies, such as inducible promoter systems, require further optimization to adapt to the complex in vivo environment, ensuring effective activation when needed and reliable silencing when not118,145.

Despite these challenges, engineered bacteria hold broad prospects in HCC immunotherapy. The precision of gene-editing technology in programming bacterial functions opens new possibilities for developing personalized treatment strategies for liver cancer. Engineered bacteria can counteract tumor drug resistance through various mechanisms, such as remodeling the tumor immune microenvironment, modulating tumor cell metabolism, or directly killing tumor cells. Beyond the therapeutic applications, these modified bacteria also have potential as novel tools for diagnosis and prognosis assessment144.

In summary, engineered bacteria show transformative potential in HCC immunotherapy and provide patients with more effective and precise treatment strategies.

FMT

FMT has been demonstrated across various diseases in reshaping the existing gut microbiome. However, the clinical application still faces multiple challenges, particularly in the treatment of patients with HCC. Future research must focus on addressing these core issues to optimize the therapeutic efficacy and safety of FMT.

First, the safety of FMT remains a major concern, including infection risks and long-term stability. Due to the presence of diverse bacteria, viruses, fungi, and other microorganisms in stool, improper handling during preparation and transplantation may lead to pathogen transmission, resulting in sepsis or other infections146. Moreover, long-term safety data are still limited, and further evaluation is needed regarding the lasting effects of FMT on host physiology, immune function, and potential disease progression. For example, insufficient donor screening or suboptimal stool preparation could facilitate the transmission of pathogenic bacteria146, which may cause severe infections and even fatal outcomes. To mitigate infection risks, rigorous donor screening is essential, typically including criteria, such as age, general health, medical history, recent antibiotic use, and comprehensive laboratory testing. Second, the therapeutic effect of FMT largely depends on the quality and composition of the donor fecal microbiome147. High inter-donor variability in microbial communities is one of the main reasons for inconsistent FMT outcomes. Studies suggest that some “super-donors” may possess particularly beneficial microbial profiles that significantly enhance treatment efficacy. For example, donors with higher gut microbial diversity and an enrichment of specific beneficial taxa may offer greater therapeutic potential148,149. To address donor variability, future research should prioritize the identification of “super-donors” through advanced multi-omics analyses, including metagenomics and metabolomics, to identify biomarkers strongly correlated with positive treatment outcomes. Concurrently, the establishment of rigorously screened donor banks and the implementation of standardized protocols for stool processing and quality control are essential to ensure the consistency and therapeutic effectiveness of FMT products. Finally, current methods for FMT preparation, administration routes, and treatment frequency lack complete standardization, which limits broad clinical application and consistent efficacy evaluation150,151.

These challenges collectively hinder the reproducibility and clinical translation of FMT in HCC therapy, underscoring the urgent need for targeted follow-up studies to overcome these bottlenecks. By addressing these key issues, FMT holds promise as a safe and effective adjunctive therapy for HCC, particularly in enhancing responses to immunotherapy.

In conclusion, the gut microbiome stands as a dynamic and influential regulator of HCC immunotherapy response. By diligently pursuing these future research directions, from precision profiling and next-generation therapeutics-to-personalized nutrition and artificial intelligence (AI) integration, we can unlock the full potential of microbiome-targeted interventions, ultimately transform the landscape of HCC treatment and significantly improve patient prognosis.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Jun Yu.

Wrote the paper: Mengrui Wu and Yating Zhang.

  • Received December 24, 2025.
  • Accepted March 5, 2026.

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