Cholangiocarcinoma (CCA) is a particularly aggressive and challenging type of cancer, known for its poor prognosis, which is worsened by the complex interplay of various biological and environmental factors that contribute to its development. Recently, researchers have increasingly focused on the significant role of the biliary-enteric communication of liver-gut axis in the pathogenesis of CCA, highlighting a complex relationship that has not been thoroughly explored before. This review aims to summarize the key concepts related to the biliary-enteric communication of liver-gut axis and investigate its potential mechanisms that may lead to the onset and progression of CCA, a disease that presents substantial treatment challenges. Important areas of focus will include the microbiome's profound influence, which interacts with host physiology in ways that may worsen cancer development; changes in bile acid metabolism that can create toxic environments favorable for tumor growth; the regulation of inflammatory processes that may either promote or inhibit tumor progression; the immune system's involvement, which is crucial in the body's response to cancer; and the complex interactions within metabolic pathways that can affect cellular behavior and tumor dynamics. By integrating recent research findings from various studies, we aim to explore the multifaceted roles of the biliary-enteric communication of liver-gut axis in CCA, providing new insights and perspectives for future research while identifying promising therapeutic targets that could lead to innovative treatment strategies aimed at improving patient outcomes in this challenging disease.

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.

Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockade, have shown great success in treating melanoma. PD-L1 (B7-H1, CD274), a ligand of PD-1, binds to PD-1 on T cells, inhibiting their activation and proliferation through multiple pathways, thus dampening tumor-reactive T cell activity. Studies have linked PD-L1 expression in melanoma with tumor growth, invasion, and metastasis, making the PD-1/PD-L1 pathway a critical target in melanoma therapy. However, immune-related adverse events are common, reducing the effectiveness of anti-PD-L1 treatments. Recent evidence suggests that the gut microbiome significantly influences anti-tumor immunity, with the microbiome potentially reprogramming the tumor microenvironment and overcoming resistance to anti-PD-1 therapies in melanoma patients. This review explores the mechanisms of PD-1/PD-L1 in melanoma and examines how gut microbiota and its metabolites may help address resistance to anti-PD-1 therapy, offering new insights for improving melanoma treatment strategies.

Hepatocellular carcinoma (HCC) is the third cause of cancer-related mortality worldwide. Current treatments include surgery and immunotherapy with variable response. Despite aggressive treatment, disease progression remains the biggest contributor to mortality. Thus, there is an urgent unmet need to improve current treatments through a better understanding of HCC tumourigenesis. The gut microbiota has been intensively examined in the context of HCC, with evidence showing gut modulation has the potential to modulate tumourigenesis and prognosis. In addition, recent literature suggests the presence of an intratumoural microbiota that may exert significant impacts on the development of solid tumours including HCC. By drawing parallels between the gut and hepatic/tumoural microbiota, we explore in the present review how the hepatic microbiota is established, its impact on tumourigenesis, and how modulation of the gut and hepatic microbiota may be key to improving current treatments of HCC. In particular, we highlight key bacteria that have been discovered in HCC tumours, and how they may affect the tumour immune microenvironment and HCC tumourigenesis. We then explore current therapies that target the intratumoural microbiota. With a deeper understanding of how the intratumoural microbiota is established, how different bacteria may be involved in HCC tumourigenesis, and how they can be targeted, we hope to spark future research in validating intratumoural microbiota as an avenue for improving treatment responses in HCC.

Hepatocellular carcinoma (HCC) is a highly aggressive liver malignancy and one of the most lethal cancers globally, with limited effective therapeutic options. Bile acids (BAs), as primary metabolites of hepatic cholesterol, undergo enterohepatic circulation involving secretion into the intestine and reabsorption into the liver, and their composition is modulated in this process. Recent clinical observations have revealed a correlation between alteration in the BAs profile and HCC incidence, and the effect of various species of BAs on HCC development has been investigated. The regulatory effect of different BA species on cell proliferation, migration, and apoptosis in tumor cells, as well as their interaction with gut microbiota, inflammation, and immunity have been identified to be involved in HCC progression. In this review, we summarize the current understanding of the diverse functions of BAs in HCC pathogenesis and therapy, from elucidating the fundamental mechanisms underlying both tumor-promoting and tumor-suppressive consequences of various BA species to exploring potential strategies for leveraging BAs for HCC therapy. We also discuss ongoing efforts to target specific BA species in HCC treatment while highlighting new frontiers in BA biology that may inspire further exploration regarding their connection to HCC.

Hepatocellular carcinoma (HCC) presents a considerable global health burden due to its late diagnosis and high morbidity. The liver's specific anatomical and physiological features expose it to various antigens, requiring precise immune regulation. To the best of our knowledge, this is the first time that a comprehensive overview of the interactions between the immune system and gut microbiota in the development of HCC, as well as the relevant therapeutic approaches are discussed. Dysregulation of immune compartments within the liver microenvironment drives HCC pathogenesis, characterized by elevated regulatory cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells, and M2 macrophages as well as suppressive molecules, alongside reduced number of effector cells like T cells, natural killer cells, and M1 macrophages. Dysbiosis of gut microbiota also contributes to HCC by disrupting intestinal barrier integrity and triggering overactivated immune responses. Immunotherapy approaches, particularly immune checkpoint inhibitors, have exhibited promise in HCC management, yet adoptive cell therapy and cancer vaccination research are in the early steps with relatively less favorable outcomes. Further understanding of immune dysregulation, gut microbiota involvement, and therapeutic combination strategies are essential for advancing precision immunotherapy in HCC.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver malignancy. The interplay between bile acids (BAs) and the gut microbiota has emerged as a critical factor in HCC development and progression. Under normal conditions, BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs. The gut microbiota plays a critical role in BA metabolism, and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis. Of note, dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis, thereby leading to liver inflammation and fibrosis, and ultimately contributing to HCC development. Therefore, understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis. In this review, we comprehensively explore the roles and functions of BA metabolism, with a focus on the interactions between BAs and gut microorganisms in HCC. Additionally, therapeutic strategies targeting BA metabolism and the gut microbiota are discussed, including the use of BA agonists/antagonists, probiotic/prebiotic and dietary interventions, fecal microbiota transplantation, and engineered bacteria. In summary, understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

Hepatocellular carcinoma (HCC) has been linked to the gut microbiota, with recent studies revealing the potential of gut-generated responses to influence several arms of the immune responses relevant to HCC formation. The pro- or anti-tumor effects of specific bacterial strains or gut microbiota-related metabolites, such as bile acids and short-chain fatty acids, have been highlighted in many human and animal studies. The critical role of the gut microbiota in HCC development has spurred interest in modulating the gut microbiota through dietary interventions, probiotics, and fecal microbiota transplantation as a potential strategy to improve liver cancer outcomes. Encouragingly, preclinical and clinical studies have demonstrated that modulation of the gut microbiota can ameliorate liver function, reduce inflammation, and inhibit liver tumor growth, underscoring the potential of this approach to improve HCC outcomes. As research continues to unravel the complex and dynamic mechanisms underlying the gut-liver axis, the development of safe and effective interventions to target this pathway for liver cancer prevention and treatment appears to be on the horizon, heralding a significant advance in our ongoing efforts to combat this devastating disease.

Metastasis is a fatal status for liver cancer, and the identification of an effective prediction model and promising therapeutic target is essential. Given the known relationship between fatty acid (FA) metabolism and the liver, the present study aimed to investigate dysregulation of genes associated with FA metabolism in liver cancer. Bioinformatics analyses were performed on data from patients with hepatocellular carcinoma (HCC) obtained from The Cancer Genome Atlas database using R software packages. Online public tools such as the Human Protein Atlas, Tumor Immune Single-Cell Hub and the University of Alabama at Birmingham Cancer Data Analysis portal were also utilized. Some essential results were further verified using in vitro experiments using HepG2 liver cancer cells. A signature consisting of three genes associated with the progression and prognosis of HCC and FA metabolism was identified. When samples were scored based on the expression of these genes and divided according to the median value, the higher score group showed a worse outcome and repressive immune microenvironment than the lower score group. Downstream pathways such as hypoxia, IL6/JAK/STAT3 and epithelial-mesenchymal transition were found to be significantly activated in the higher score group. As the core factor in the signature, mitochondrial ribosomal protein L35 (MRPL35) was found to be upregulated in HCC and to have certain impacts on the dysregulation of effective immunity. Further investigations and in vitro experiments indicated that MRPL35 facilitates the migration and invasion abilities of liver cancer, and the resistance of HCC to treatment. These findings have important implications regarding the characteristics and mechanisms of metastasis in liver cancer, and provide a promising signature based on FA metabolism-related genes that may be used to predict outcomes and explored as a novel therapeutic target in liver cancer.

Severe liver diseases, such as liver fibrosis, cirrhosis, and liver cancer, are mainly caused by hepatitis B virus (HBV). This study investigated the differences between gut microbiota in HBeAg-positive and negative groups of patients with chronic hepatitis B (CHB) and investigated the effect of tenofovir alafenamide (TAF) on gut microbiota.

This prospective study included patients with CHB not taking nucleoside antivirals (No-NAs group, n = 95) and those taking TAF (TAF group, n = 60). We divided CHB patients into two groups according to the HBeAg status of the subjects on the day of data collection. Phase 1 are HBeAg-negative patients and phase 2 are HBeAg-positive patients. We investigated the improvement of clinical symptoms by TAF, as well as differences in gut microbiota between different groups by 16S rRNA high-throughput sequencing.

Gut microbiota demonstrated significant differences between patients with HBeAg-positive and -negative CHB. Both the No-NAs and TAF Phase 2 subgroups demonstrated significantly increased microbiota richness and diversity, showing greater heterogeneity. Additionally, the Phase 2 subgroup exhibited a low abundance of pathways associated with glucose metabolism and amino acid metabolism. The TAF group demonstrated a significantly decreased HBV load, alanine aminotransferase, and aspartate aminotransferase and a significant increase in prealbumin compared with the No-NAs group. No significant difference was found in uric acid, creatinine, blood calcium, inorganic phosphorus, eGFR, and β2-microglobulin concentrations between the two groups. Additionally, the urea level in the TAF group was significantly lower than that in the No-NAs group, but with no significant effect on other indicators such as eGFR and β2-microglobulin.

This study revealed significant differences in gut microbiota composition and function between patients with HBeAg-positive and -negative CHB.

The recent evolution of immunotherapy has revolutionised the treatment of hepatocellular carcinoma (HCC) and has led to new therapeutic standards. The advances in immunotherapy have been accompanied by the recognition of the role of the gut-liver axis in the progression of HCC but also of the clinical relevance of the gut microbiota, which influences host homeostasis but also cancer development and the response to treatment. Dysbiosis, by altering the tumour microenvironment, favours the activation of intracellular signalling pathways and promotes carcinogenesis. The gut microbiota, through their composition and immunomodulatory role, are thus strong predictors of the response to immune checkpoint inhibitor (ICI) treatment as well as an available target to improve ICI efficacy and reduce drug toxicities. In this review we examine the novel role of the gut microbiota as biomarkers in both the diagnosis of HCC and the clinical response to immunotherapy as well as its potential impact on clinical practice in the future.

The intestinal flora plays an important role in the occurrence and development of liver cancer, affecting the efficacy and side effects of conventional antitumor therapy. Recently, immunotherapy for liver cancer has been a palliative treatment for patients with advanced liver cancer lacking surgical indications. Representative drugs include immune checkpoint inhibitors, regulators, tumor vaccines, and cellular immunotherapies. The effects of immunotherapy on liver cancer vary because of the heterogeneity of the tumors. Intestinal flora can affect the efficacy and side effects of immunotherapy for liver cancer by regulating host immunity. Therefore, applying probiotics, prebiotics, antibiotics, and fecal transplantation to interfere with the intestinal flora is expected to become an important means of assisting immunotherapy for liver cancer. This article reviews publications that discuss the relationship between intestinal flora and immunotherapy for liver cancer and further clarifies the potential relationship between intestinal flora and immunotherapy for liver cancer.