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Intratumoral microbiota for hepatocellular carcinoma: from preclinical mechanisms to clinical cancer treatment

Cancer Cell International volume 25, Article number: 152 (2025) Cite this article

Abstract

Intratumoral microbiota has been found to be a crucial component of hepatocellular carcinoma (HCC). Due to insufficient recognition, technical limitations, and low biomass of intratumoral microbiota, it is poorly understood. Intratumoral microbiota exhibit significant diversity in HCC tissues. It is involved in the development of HCC through several mechanisms, such as remodeling the immunosuppressive microenvironment, metabolic reprogramming, and genetic alterations. Moreover, intratumoral microbiota is associated with the metastasis of HCC cells. Herein, we reviewed the history of intratumoral microbiota, applied biotechnology to depict the signatures of intratumoral microbiota, investigated the potential sources of intratumoral microbiota, and assessed their functions, mechanisms, and heterogeneity. Furthermore, in this review, we summarized the development of therapeutics that can be used in the treatment of HCC and proposed future perspectives for research in this field.

Highlights

  1. 1.

    The use of biotechnology to depict the signatures of intratumoral microbiota.

  2. 2.

    The source of intratumoral microbiota in HCC.

  3. 3.

    Intratumoral microbiota involved in tumorigenesis and metastasis in HCC.

  4. 4.

    Application of intratumoral microbiota to optimize the treatment of HCC.

Introduction

Primary liver cancer is one of the most prevalent cancers. It is the third leading cause of cancer-related mortality [1]. Hepatocellular carcinoma (HCC) accounts for 75–85% of cases of total primary liver cancer [2]. HCC is the only solid tumor that can be routinely diagnosed without pathological assessment. Over the past decades, tremendous breakthroughs have been made in understanding cancer biology, identifying diagnostic biomarkers, and developing therapeutic agents for HCC, thereby improving the prognosis for patients with HCC [3]. However, there are still many unknown aspects of HCC. Recently, intratumoral microbiota has received much attention in cancer research, particularly in HCC [4, 5].

Microbiota including bacteria, fungi, viruses, parasites, and archaea, co-habit in individuals at a certain time point [6]. The gut, pharynx orails, and skin serve as primary common foci for human microbiota [7]. Based on the Human Microbiome Project Consortium (HMPC), the number of studies assessing the role of microbiota in cancer biology is increasing [8]. Until 2020, the role of intratumoral microbiota was reported in several tumors, indicating that each tumor type has a distinct composition of microbiota [9]. The findings of this study are recognized as a landmark in the field of intratumoral microbiota. Using data from The Cancer Genome Atlas (TCGA), Poore and colleagues analyzed whole-genome and whole-transcriptome sequencing for microbial reads of 33 cancers from treatment-naive patients and proposed a brand-new diagnostic tool for cancer [10]. Intratumoral microbiome is predominantly located in the intracellular milieu, cancer cells, and immune cells [9]. It was found that the intratumoral bacteria in HCC are located in the intracellular space and are found in both cancer cells and immune cells [9]. Intratumoral microbiota possesses several biological functions, such as tumorigenesis, metastasis, metabolism, immunity, and drug resistance [11,12,13,14,15] (Fig. 1). For example, the efficacy of chemoimmunotherapy in esophageal squamous cell carcinoma was shown to be modulated by intratumoral microbiota composition [16].

Fig. 1
figure 1

History of intratumoral microbiota

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In this review, we attempted to comprehensively summarize the latest progress of intratumoral microbiota in HCC. This study summarized the use of biotechnology for studying intratumoral microbiota in HCC, elucidated the role of intratumoral microbiota in the biological behavior of HCC, introduced its potential as a novel biomarker for predicting the prognosis of HCC, and delineated the approaches used to modulate intratumoral microbiota as a promising treatment for HCC. In conclusion, our work can provide a potential direction for future studies on the role of intratumoral microbiota in HCC Table 1.

Table 1 Types of intratumoral microbiota in HCC
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The use of biotechnology to depict the signatures of intratumoral microbiota

Intratumoral microbiota is predominantly localized in the intracellular space, with low abundance and low diversity [17]. In addition, contamination in low microbial biomass microbiome studies is a critical issue that needs to be solved [17]. Therefore, biotechnology plays a decisive role in studying intratumoral microbiota. Fortunately, advances in biotechnologies have facilitated studies on intratumoral microbiota.

Fluorescence in situ hybridization (FISH) detects microbial genes in tumor tissues using nucleic acid probes for 16S rRNA genes on fluorescent molecules. Hybridization can be observed under fluorescence microscope and laser scanning confocal microscope [18]. For its convenience and visibility, FISH has been applied to studies on intratumoral microbiota in several types of cancer, such as intrahepatic cholangiocarcinoma, HCC, neuroendocrine neoplasms, colon cancer, and pancreatic ductal adenocarcinoma [19,20,21,22,23]. FISH is used for the rapid identification of microbial pathogens without being restricted to materials [24]. Therefore, FISH is a bridging technology between microbiota, biochemistry, and molecular diagnosis. Correlative light and electron microscopy (CLEM) helps the precise imaging of the cellular location in light microscopy (LM) and electron microscopy (EM) [25]. CLEM can show the presence of dynamic biological processes, with a wide field of view and superior resolution. Scientists have utilized CLEM to detect intracellular bacteria in human breast cancer [9]. 16S rRNA gene sequencing is primarily used to accurately identify and classify bacteria into different taxonomic groups, since all bacteria have at least one copy of the 16S gene [26]. Moreover, high-throughput, full-length 16S sequencing data can accurately classify individual organisms at very high taxonomic resolution [27]. In addition, 16S rRNA gene sequencing is less expensive compared to whole-genome sequencing. Whole metagenome-based shotgun sequencing (WMS) can characterize microbial communities by reviewing three major metagenomic research areas, including assembly, community profiling, and functional profiling [28]. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) is a mass spectrometry (MS)-based proteomics method [29]. Due to its convenience, rapid use, and accuracy, MALDI-TOF MS is widely applied to identify microorganisms in clinical samples. It is an effective technique used to classify specific microbiota [30]. However, its high price makes it less affordable. Single-cell RNA sequencing (scRNA-seq) is an advanced technology for analyzing transcriptional heterogeneity of cell types and cell states [31]. Compared to the above techniques, scRNA-seq can elucidate the complexity of intratumoral microbiota. Ma and colleagues reported that bacterial droplet-based scRNA-seq can be used to elucidate transcriptionally distinct bacterial subpopulations associated with antibiotic resistance and persistence [32]. Using in situ spatial profiling technologies and scRNA-seq, Jorge and colleagues observed spatial, cellular, and molecular host-microbe interactions in oral squamous cell carcinoma and colorectal cancer [33]. Spatial meta-transcriptomics can simultaneously detect the expression level of 1811 host genes and 3 microbe targets (bacteria, fungi, and cytomegalovirus) [34]. In other words, spatial meta-transcriptomics assesses intratumoral bacteria burden in cancer (Fig. 2). Co-Detection by Indexing (CODEX) is an emerging technology that has shown significant potential in the field of intratumoral microbiota detection. CODEX enable simultaneous imaging of more than 40 protein biomarkers, leading to more insights into cellular interactions. However, the limitations of its applications are the low speed for high-plex data and the high price [35].

Fig. 2
figure 2

The use of biotechnology to depict the signatures of intratumoral microbiota

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Understanding the role of intratumoral microbiota in HCC

Source of intratumoral microbiota in HCC

For the first time, intratumoral microbes have been discovered in HCC [11, 13, 22, 36,37,38,39,40,41,42,43]. However, the sources of intratumoral microbes still remain unclear. As reported, the tumor microenvironment provides excellent living conditions for bacteria, due to vascular leakage, low oxygen concentration, weak immune response, and nutrient-rich regions [44]. In this review, we discussed the following potential sources for intratumoral microbes in HCC.

Bacterial translocation is a process, in which bacteria from the gastrointestinal tract migrate to extraintestinal sites, such as the liver [45]. HBV and HCV infections are the most common cause of HCC (~ 60–70%) [46], and chronic viral hepatitis always leads to gut dysbiosis via the gut-liver axis [47]. Alterations in intestinal flora, damaged intestinal mucosal barrier, and immune deficiencies have been proposed as the main reasons for bacterial translocation. In addition, the liver receives portal vein blood from the intestines, and HCC-associated intratumoral bacteria may originate from the intestine via the portal vein [48]. Bacteria originating from colorectal cancer can penetrate the intestinal vascular barrier, and migrate to the liver, forming a premetastatic disease niche and promoting the recruitment of metastatic cells [49, 50]. As major members of the gut commensal microbiota, Bacteroidetes, Firmicutes, and Proteobacteria have been detected in liver cancer [43, 51]. Therefore, as the largest bacterial reservoir, the gut microbiota may be a source of intratumoral microbiota in liver cancer [43,44,45].

Circulating cancer cells can carry intratumoral microbiota and help their dissemination, facilitating their invasion into tumor tissues. For example, these intratumoral bacteria in metastatic lung lesions originated from the circulatory system in a murine spontaneous breast-tumor model MMTV-PyMT [52]. This explains why the tumor microbiome and the corresponding normal tissue microbiome share similar features [9].

In conclusion, some studies support bacterial translocation from the gut in HCC. Apart from the gut, intratumoral bacteria may also originate from adjacent tissues or may be transferred through the circulatory system (Fig. 3).

Fig. 3
figure 3

Source of intratumoral microbiota in HCC. (A) Gut microbiota. Gut microbiota enter tumor sites through gut-liver axis. (B) Circulatory system. Intratumoral microbiota enter tumor sites via hematogenous spread. (C) Adjacent tissues. Adjacent tissues is a potential source of intratumoral microbiota

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Intratumoral microbiota and development of HCC

Studies have indicated a complex relationship between intratumoral microbiota and HCC development. Chakladar and colleagues indicated that variations in the intratumoral microbiome in HCC can significantly alter the progression of HCC [36]. Understanding how HBV and alcohol can promote tumor development through intratumoral microbes may be critical for suppressing or reversing the progression of HCC.

Intratumoral microbial diversity in HCC was significantly higher than that in adjacent normal tissues [41]. A detailed analysis of intratumoral microbiota in HCC indicated that the quantity of amplicon sequence variants in intratumoral microbiota was significantly more than that in para-cancerous regions [43]. Bacteroidetes, Firmicutes, and Proteobacteria are the dominant phyla in HCC. A study deeply explored the intratumoral microbiota in HBV-associated HCC and revealed that Ruminococcus gnavus is a signature taxon [43]. Another study discovered that the Caulobacter branch and Staphylococcus branch are selectively enriched in HBV-negative HCC [22]. Nevertheless, the intratumoral microbiome did not exhibit significant differences between viral HCC and non-HBV/non-HCV HCC [40]. A significantly diverse intratumoral microbiome was only detected in HBV‐related HCC, and Cutibacterium was a representative taxa biomarker.

However, another study showed that intratumoral microbial heterogeneity in HBV-related HCC tissues was lower than that in para-tumor tissues and chronic hepatitis tissues. Interestingly, microbial diversity was also verified in HCC tissues [5, 11]. For example, M2 macrophage infiltration and many metabolic pathways were upregulated in the bacteria-dominant subtype than in the virus-dominant subtype [11]. Song and colleagues developed a microbiome-related score model based on 27- intratumor microbe prognostic signatures in patients with HCC, which independently predicted overall survival [39]. Thus, targeting intratumoral microbiome may improve the prognosis of patients with HCC. Similarly, Sun and colleagues found that the intratumoral microbiome is heterogeneous in HCC. Based on heterogeneity at the phylum level, hepatotypes were categorized into A and B. Hepatotype A was positively associated with phyla Actinobacteria and Proteobacteria with worse survival, unlike hepatotype B. Therefore, the authors believed that intratumoral microbiome can predict the prognosis of HCC after surgery [37]. Thus, hepatotype carried a significant prognostic value when removing confounding factors. However, whether the heterogeneity of the intratumoural microbiota in HCC impacts clinical outcomes needs further investigations. It would be a target to potentially guiding more personalized and effective therapeutic strategies for HCC.

Moreover, primary liver cancer tissue and matched adjacent non-tumor tissue have different microbial populations [53]. The abundance of certain bacteria, such as Pseudomonadaceae, with tumor inhibitory effects, was decreased at the family and genus levels in primary liver cancer tissue [53]. Consistently, the abundance of Enterobacteriaceae, Fusobacterium, and Neisseria was significantly increased, whereas the abundance of certain anti-tumor bacteria, such as Pseudomonas, was decreased in HCC tissues [41]. Furthermore, fatty acid and lipid synthesis was significantly enhanced in intratumoral microbiota, thereby facilitating the progression of HCC [41]. An in-depth understanding of the dynamics of intratumoral microbiota in the liver may provide new diagnostic biomarkers, and improve the prognosis of HCC.

Remodeling the immunosuppressive microenvironment is a common phenomenon in HCC [54, 55]. Intratumoral microbiota in HBV-associated HCC is positively correlated with the abundance of tumor‐infiltrating CD8+ T lymphocytes, monocytic MDSCs, and polymorphonuclear MDSCs, but not CD56+ NK cells [40]. These results indicate that HBV infection in HCC may provide a unique microenvironment for balancing microbiota colonization and immune cells. Still, there are no studies on cancer-associated fibroblasts (CAF) and intratumoral microbiota in HCC. Intratumoural bacteria appears to be mostly intracellular [22], which is expected as the extracellular environment is immune-active and hostile to habitation of foreign microbes. The current hypothesis is that neoplastic tissue serves as the perfect habitat for microbiota [56]. As a favourable condition, immunosuppressive allows the growth of intratumoral microbiota in the liver. In return, these intratumoral microbiota foster a pro-tumour habitat [57]. Building upon the use of C. novyi for treatment of advanced solid tumours, there is currently a Phase Ib trial (NCT03435952) looking at combining C. novyi with Pembrolizumab [58]. Intratumoral C. novyi-NT with pembrolizumab demonstrates clinical activity with favorable tolerability in patients regardless of tumor histology [58]. Therefore, combining immunotherapy and anti-microbiota therapy may be a new strategy to enhance treatment responses and patient outcomes [59].

Metabolic reprogramming is a hallmark of cancer [60, 61]. A recent study confirmed the association between different bacteria and metabolites, such as Pseudomonas koreensis and N-acetyl-d-glucosamine (positive correlation), citrulline (negative correlation) [42].

Interestingly, intratumoral microbiota not only interact with metabolites but also are associated with genetic alterations in HCC [13]. For example, Halomonas was significantly and positively correlated with some metabolites but negatively correlated with l-arginine, O-phosphoethanolamine, acetaminophen, and rosmarinic acid in HCC. Alcaligenes was positively associated with SOX5, AGXT2, ST3GAL6, and KANK4, and negatively associated with PITX1, GOLM1, OSBPL3, and PKMYT1 in HCC [13]. Besides, a study in patients with NAFLD found a link between the host genetics and the intrahepatic microbiome. Gammaproteobacteria class including Enterobacter and Pseudoalteromonas genera were highly enriched in carriers of the PNPLA3-rs738409 and TM6SF2-rs58542926 risk-alleles [62]. Thus, Liver microbiota play a important role in liver diseases [63].

Moreover, another study reported that decreased intratumoral microbial diversity affects intrahepatic microbiota [64]. As a bacterium with higher abundance in HCC, S. maltophilia provoked senescence-associated secretory phenotype in hepatic stellate cells. It induced the formation of NLRP3 inflammasome complex and enhanced the secretion of several inflammatory factors through the TLR4/NF-κb/NLRP3 pathway, finally promoting HCC progression in mice [64,65,66]. Therefore, tumor microbiota may contribute to the malignant progression of HCC (Fig. 4).

Fig. 4
figure 4

Intratumoral microbiota involved in tumorigenesis and metastasis in HCC. (A) Intratumoral microbiota plays a vital role in remodeling the immunosuppressive microenvironment. (B) Pseudomonas koreensis was positively correlated with N-acetyl-D-glucosamine, and negatively correlated with citrulline. (C) Alcaligenes was positively associated with SOX5, AGXT2, ST3GAL6, and KANK4, and negatively associated with PITX1, GOLM1, OSBPL3, and PKMYT1 in HCC. (D) S. maltophilia provoked senescence-associated secretory phenotype in hepatic stellate cells

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Intratumoral microbiota and liver metastasis

Liver metastasis is a leading cause of mortality among patients with cancer. An ancillary study of the SHIVA clinical trial indicated that intratumoral microbiota is associated with liver metastasis [67]. Mechanistically, it is widely believed that bacteria can affect metastasis by regulating the immune environment through both distant and local mechanisms [50]. Intratumoral microbiota reshape the tumor microenvironment to facilitate metastasis. They act via epithelial-mesenchymal transition (EMT), adhesion molecules, mechanical stress response, stem cell/plasticity, immune response modulation, and exosomes [14]. In addition, intratumoral microbiota can impair the gut vascular barrier, then migrate and colonize to establish a premetastatic niche (PMN). In particular, they modulate the release of chemoattractant agents and extracellular matrix (ECM) deposition to promote liver cancer metastasis [50, 68].

One study indicated that the number of amplicon sequence variants of non-cancer regions was lower than that of cancer regions in metastatic liver cancer [43]. Moreover, intratumoral microbiomes were identified as signature taxa for metastatic liver cancer, including an unclassified genus belonging to the Lachnospiraceae family, the Lachnospiraceae NK4 A136 group, and an uncultured bacterium belonging to the Muribaculaceae family [43]. Hence, metastasis of liver cancer has a specific intratumoral microbiome, which necessitates more studies to elucidate the underlying mechanisms.

Intratumoral microbiota as a potential biomarker for prognosis in HCC

Numerous studies have reported significant differences in the quantity and composition of intratumoral microbiota between tumor tissues and adjacent non-tumor tissues [11, 22, 36, 37, 41, 42, 53]. Furthermore, pan-cancer analyses revealed the presence of cancer-type-specific fungi [69]. More and more microbiota can be identified with the development of new detection techniques and deeper research. Similarly, intratumoral microbiota can serve as prognostic biomarkers. For example, Lejia Sun and colleagues found that high levels of Akkermansia in HCC tissues are associated with a favorable prognosis [37]. Furthermore, intratumoral microbiome-related score (MRS) model was established to predict the overall survival (OS) of patients with HCC [39]. Therefore, this field has a broad prospect.

Applying intratumoral microbiota to optimize the treatment of HCC

The application of microbiota in the treatment of liver cancer has been recently investigated in many studies [48, 70,71,72,73]. A specific member of the gut microbiota enhances the anti-tumor efficacy of immunotherapy by colonizing the tumor site [74]. Although most studies have focused on gut microbiota, it is essential to incorporate intratumoral microbiota into the treatment regimen of patients with liver cancer [75,76,77]. Specifically, as an adjuvant treatment, anti-microbial treatment can promote response to treatment and mitigate the toxic effects of immunotherapy for liver cancer [77,78,79]. These results indicate a close association between liver immunity and liver biology. Considering the intracellular localization of intratumoral microbiota, they may only affect local immunity. Here, we propose intratumoral microbiota as an adjuvant treatment for HCC (Fig. 5).

Fig. 5
figure 5

Application of intratumoral microbiota to optimize the treatment of HCC. (A) Fecal microbiota transplantation. (B) Antibiotics. (C) Probiotics

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Fecal microbiota transplantation

The gut-liver axis is known as a close and bidirectional relationship between the liver and gut microbiota [80,81,82]. Pre-clinical and clinical studies have confirmed the modulation of the gut-liver axis via gut microbiota. Dysbiosis of the gut microbiota is associated with liver damage and inflammation through increased translocation of bacteria [70, 83, 84]. As a latent treatment of HCC, fecal microbiota transplantation (FMT) can regulate the gut microbiota, and control hepatic inflammation and the development of HCC [85]. FMT inhibited tumor progression by enhancing CD8 + T cell response and impairing the function of Treg and Th17 cells [86]. Furthermore, FMT exhibited therapeutic potential in cancers and reduced immune-related adverse events [87]. FMT significantly modulated the gut flora and decreased the density of Treg cells in tumor tissue. However, FMT could not significantly improve the anti-tumor effects in dirty rats with liver cancer [88]. Besides, FMT modulated radiotherapy-associated anti-tumor immune responses against hepatocellular carcinoma by enhancing antigen presentation and potentiating the function of effector T cells through a pivotal link between bacterial c-di-AMP (mostly synthesized by gram-positive bacteria) and the host cGAS–STING pathway [89,90,91]. Of course, there are limitations of the FMT, such as the unknown long-term effects, potential infection, and delivery method issues [92]. Donor variability and infection risks are common challenges related to FMT. The above-mentioned issues could be overcomed through bacteriophage-mediated treatments [93]. Hence, FMT may be a new strategy to promote sensitivity to radiation and immunotherapy in liver cancer.

Antibiotics

It is well known that antibiotics can alter human microbiota composition and decrease the diversity of gut microbiota [94]. Interestingly, it was observed that the development of soluble fiber-induced cholestatic liver cancer relies on microbiota, and this cancer was not observed in mice receiving ampicillin and neomycin in their drinking water [95]. High-fat diet alters gut microbiota, thus increasing the serum levels of deoxycholic acid (DCA), inducing the development of obesity-associated HCC in mice. In contrast, treatment with antibiotics reduced DCA levels [65, 96]. Antibiotic treatment improved the efficacy of γδT cells by modulating tryptophan metabolism and increasing the concentration of 3-indopropionic acid in the gut, stimulating γδT cells to produce more cytotoxic cytokines in a mouse model of HCC [97]. In a large international cohort with 450 participants receiving immunotherapy, treatment with antibiotics within 30 days before or after immunotherapy was associated with improved efficacy of immunotherapy [79]. However, the use of antibiotics against anaerobic germs was associated with a poor prognosis of patients with HCC who underwent chemotherapy [98]. A territory-wide retrospective cohort study showed that the combination of antibiotics and immunotherapy was associated with higher mortality in patients with advanced HCC [77]. Given the trade-off between effectiveness, safety, and risk of antibiotic resistance, patient screening is critical for administration of antibiotics [99]. In summary, the results of previous studies were contradictory, necessitating future multi-dimensional studies.

Probiotics

In 2001, FAO/WHO defined probiotics as “live microorganisms which when administered in adequate amounts, confer a health benefit on the host” [100, 101]. Recently, new technologies have been applied to develop next-generation probiotics [102, 103]. In the field of liver cancer treatment, probiotics can enhance the efficacy of other anti-cancer drugs [104, 105]. Probiotics suppressed the development of liver cancer by regulating T-cell differentiation in the gut [86, 106,107,108]. However, there was little change in the microbial community after inoculation with probiotics (VSL#3), and it did not suppress tumor progression in dirty rats with liver cancer [88]. Furthermore, probiotics improved the prognosis of immunotherapy in patients with cancer [109]. Bifidobacterium is a well-defined commensal probiotic that can localize to the TME and facilitate CD47-based immunotherapy via the STING signaling [74]. With low toxicity and low chance of survival in normal tissues, Bifidobacterium can be an effective tumor-targeting bacteria for clinical application. Other bacteria, such as Akkermansia and Faecalibacterium, have also been shown to improve the response to immunotherapy in HCC [48, 110,111,112]. However, it difficult to maintain a sufficient number of live probiotics to reach the target sites and exert their original probiotic effects, mainly due to probiotics may suffer from harsh environments and colonization resistance. Encapsulation of probiotics is an effective strategy [113]. Ensuring the viability of probiotics is a great challenge [114]. For example,"armor probiotics”, a novel technology of probiotic encapsulation based on single-cell coating is a good choice [115]. Besides, Novel nano-encapsulated probiotic agents is also a developmental direction [114].

Conclusions and future perspectives

As a crucial component of HCC, intratumoral microbiota is involved in the development and metastasis of HCC through remodeling the immunosuppressive microenvironment, metabolic reprogramming, and genetic alterations. Furthermore, we summarized the development of therapeutics that can be used in the treatment of HCC and proposed future perspectives for research in this field.

Based on the correlations between intratumoral microbiota and the development, progression, and metastasis of liver cancer, more studies are needed to deepen our understanding. Despite the proven relationship between intratumoral microbiota and the development and treatment of primary liver cancer, there are still some limitations.

On the one hand, there are some confounding factors, such as sex, age, or sample size, that can affect the constitution of intratumoral microbiota. Confounding factors were not considered in most studies, making it challenging to extrapolate these results to clinical practice. On the other hand, only in vitro intratumoral microbiota were evaluated and the results may be different in vivo. Moreover, other intratumoral microbiota, like fungi, viruses, mycoplasma, and parasites, are as important as bacteria.

These limitations should be taken into account in future studies. The evaluation and characterization of intratumoral microbiota should be standardized. Furthermore, studies should be conducted in living organisms. Moreover, attention should be paid to intratumoral fungi, viruses, mycoplasma, and parasites.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

Funding

This work was supported by the grant from the National Natural Science Foundation Cultivation fund of Zhejiang Cancer Hospital (PY2022035), Zhejiang Medical Health Science and Technology Plan (2024 KY790).

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  1. Muhua Chen, Lei Bie contributed equally.

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  1. Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China

    Muhua Chen

  2. Department of Thoracic Surgery, Wuhan No.1 Hospital, Wuhan, 430030, Hubei, China

    Lei Bie

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MC, and LB wrote the manuscript. MC supervised the manuscript. All authors read and approved the final manuscript.

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Chen, M., Bie, L. Intratumoral microbiota for hepatocellular carcinoma: from preclinical mechanisms to clinical cancer treatment. Cancer Cell Int 25, 152 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03745-7

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Cancer Cell International

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