Aims: Epidemiological evidence has revealed varying degrees of relationship between physical activity and risk of most cancers, but the association between physical activity and risk for primary liver cancer in Chinese has seldom been reported. This study aims to characterize the associations between different physical activity types and liver cancer risk in Chinese women.

Methods: We collected physical activity information through the physical activity questionnaire (PAQ) and assigned a corresponding metabolic equivalent value according to the physical activity compendium. Multivariable-adjusted Cox regression models were utilized to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships between physical activity and liver cancer.

Results: A total of 72,674 females were enrolled in the cohort, with a median follow-up time of 18.12 years. By the end of 2016, 255 females were identified as incident cases of liver cancer. In Multivariable-adjusted Cox regression analysis, total physical activity (TPA), daily living physical activity (DPA) and leisure-time physical activity (LTPA) were not associated with the liver cancer risk in women. The highest tertile vs. none of HRs (95%CIs) were 0.82 (0.58, 1.17) for TPA, 0.80 (0.56, 1.15) for DPA, and 1.15 (0.82, 1.61) for adult LTPA in terms of measures as the METs-hour/week. For each activity, we found that the HRs (95%CIs) were 0.77 (0.55, 1.08) for stair climbing and 0.78 (0.53, 1.15) for participation in housework after further adjusting for body mass index and type 2 diabetes.

Conclusion: Null significant results were found in the association between physical activity and female liver cancer risk in China.

Intrahepatic cholangiocarcinoma (ICC), a rare but rising global malignancy originating from the bile ducts, poses significant challenges in terms of effective treatment and patient outcomes. While surgical excision remains the curative option, its limited efficacy necessitates more therapeutic strategies, including systemic therapies. The management of ICC involves a multidisciplinary approach, with treatment decisions guided by patient-specific and tumor-specific factors. Gemcitabine-cisplatin (GEMCIS) chemotherapy has been a standard first-line therapy, but recent advancements in immunotherapy, particularly the introduction of durvalumab, have provided new hope. Additionally, gene mutation-based therapies, targeting fibroblast growth factor receptors (FGFRs), isocitrate dehydrogenase-1 (IDH1), human epidermal growth factor receptor-2 (HER2), and B-RAF proto-oncogene (BRAF), offer promising prospects for personalized treatment. High-throughput genomic profiling technologies have facilitated the identification of actionable targets and the development of innovative therapeutic approaches. This review summarizes the mutation-based therapies in ICC, including FDA-approved targeted drugs and ongoing clinical trials, highlighting the evolving landscape of ICC treatment.

Hepatocellular carcinoma (HCC) poses a significant public health challenge within the US, exerting an increasingly substantial influence on cancer-related deaths. However, the HCC burden is not uniformly distributed, with significant disparities related to race, ethnicity, and socioeconomic status. This manuscript comprehensively reviews the multifaceted origins of HCC disparities, exploring their roots in the sociocultural environment, socioeconomics, the physical/built environment, and the healthcare/political systems. The sociocultural environment highlights the unique challenges faced by racial and ethnic minority populations, including language barriers, cultural beliefs, and limited healthcare access. The socioeconomics and the physical/built environment section emphasize the impact of neighborhood poverty, geographic disparities, and healthcare infrastructure on HCC outcomes. The healthcare and political systems play a pivotal role in driving HCC disparities through practice guidelines, healthcare policies, insurance coverage, and access to care. Inconsistent practice guidelines across specialties and variations in insurance coverage contribute to disparities in HCC surveillance and treatment. In conclusion, addressing HCC disparities requires a multifaceted, patient-centered approach that includes cultural competence, infrastructure enhancements, policy changes, and improved access to care. Collaborative efforts among healthcare professionals, researchers, policymakers, and institutions are essential to reducing the burden of HCC on marginalized communities and ensuring equitable care for all individuals affected by this complex disease.

Non-alcoholic steatohepatitis (NASH) is a clinical condition characterized by inflammation and swelling of the hepatocytes. If not adequately treated, NASH can lead to the development of fibrosis and liver cancer. Currently, drug therapies used in the management of NASH patients are deficient and non-specific. Patients’ adherence to a healthy lifestyle with a low-calorie diet is a crucial element in the treatment of NASH. The Mediterranean diet is a diet that, more than any other, has indicated beneficial effects in this pathology. The proposed review summarizes the evidence regarding the beneficial effects of consuming the Mediterranean diet typical foods in NASH.

Liver resection stands as the gold-standard therapeutic approach for selected cases of hepatocellular carcinoma (HCC). The extent of resectable parenchyma hinges upon the underlying liver function and its regenerative potential. Consequently, cirrhosis may impede access to potentially curative interventions for HCC arising within this context. Cirrhotic patients undergoing liver resection face heightened susceptibility to post-hepatectomy liver failure (PHLF). The clinical profile of PHLF bears a resemblance to a well-documented syndrome within the liver transplant (LT) domain: Small-for-size syndrome (SFSS), a form of graft failure observed in the postoperative phase following LT with undersized or partial organs. Management of SFSS targets mitigating the overflow syndrome, achievable through diverse portal diversion techniques. Portal vein flow diversion encompasses procedures redirecting a variable proportion of portal vein flow towards systemic circulation. Consequently, derivative procedures aim to directly alleviate portal hypertension. Side-to-side portocaval shunts emerge as the most straightforward and efficacious means of decompressing the portal system. Furthermore, they afford flow calibration to diminish the incidence and severity of steal syndrome and hepatic encephalopathy, without compromising efficacy or hepatic function. Translating insights gleaned from LT complexities involving SFSS to liver resection, strategies involving portal flow diversion warrant consideration in efforts to forestall PHLF. This approach aims to extend the frontiers of liver surgery, broadening access to hepatectomy with curative intent, either as a standalone intervention or as part of a comprehensive treatment regimen where LT serves as a secondary option.

This review article evaluates the current literature on the role of percutaneous hepatic perfusion (PHP) as a treatment option in cholangiocarcinoma (CCA). CCA is a rare cancer that is mostly diagnosed at a late stage. Patients with advanced, unresectable disease have limited treatment options. PHP is a locoregional therapy that delivers high doses of chemotherapy directly to the liver while minimizing systemic exposure and toxicity. This review allocates PHP in the therapeutic spectrum of CCA and summarizes the available literature with a focus on the clinical efficacy and safety profile. Results from studies evaluating the efficacy and safety of PHP are promising, with several observational studies demonstrating improvements in progression-free survival and overall survival rates. However, PHP is not without side effects; the most commonly reported adverse events include transient hematotoxicity and hepatotoxicity. PHP has the potential to be a valuable treatment option for patients with unresectable CCA. Nonetheless, further trials are needed to optimize patient selection, treatment regimens, and long-term outcomes.

Hepatectomy is a curative procedure in selected patients affected by hepatocellular carcinoma (HCC). However, recurrence rates are as high as 70% five years after resection, and having a valid postoperative systemic regimen would represent a significant improvement in the care of HCC patients. While burgeoning evidence is emerging around the use of immunotherapy in the setting of resected HCC, little is yet known to allow the widespread use of immunotherapy after surgery. Here, we pointed out some reflections and perspectives on adjuvant strategies for patients with resected HCC and discussed potential benefits and drawbacks.

Hepatocellular carcinoma (HCC) is the primary liver cancer type, often seen in individuals with chronic liver disease. Once the patient progresses to the cirrhotic stage, the annual incidence of HCC is approximately 2%-4%. As it exceeds the minimum threshold of 1.0%-1.5% per year, HCC screening every 6 months through abdominal ultrasound is indicated in the cirrhotic population. While the incidence of viral hepatitis-associated HCC is decreasing, there is a notable rise of HCC associated with metabolic dysfunction-related steatotic liver disease and alcohol-related liver disease, particularly in high-income countries. The most effective approach for oncological prevention remains addressing the cause of liver disease. The indications for HCC screening in patients without cirrhosis depend on the etiology of liver disease and the stage of fibrosis, assessed by liver biopsy or noninvasive tests such as FIB-4 or transient elastography. However, clear recommendations for HCC screening in patients without cirrhosis and for the different etiologies are currently unavailable. Research efforts should focus on identifying markers, or combinations thereof, to provide a more accurate estimate of HCC occurrence. Such advancements would enable the effective targeting of populations at the highest risk of HCC and the establishment of the correct timing to start the screening.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This term does not describe the pathogenetic mechanisms and complications associated with NAFLD. The new definition, Metabolic Dysfunction-associated Steatotic Liver disease (MASLD), emphasizes the relationship between NAFLD and cardiometabolic comorbidities. Cardiovascular disease features, such as arterial hypertension and atherosclerosis, are frequently associated with patients with MASLD. Furthermore, these patients have a high risk of developing neoplastic diseases, primarily hepatocellular carcinoma, but also extrahepatic tumors, such as esophageal, gastric, and pancreatic cancers. Moreover, several studies showed the correlation between MASLD and endocrine disease. The imbalance of the gut microbiota, systemic inflammation, obesity, and insulin resistance play a key role in the development of these complications. This narrative review aims to clarify the evolution from NAFLD to the new nomenclature MASLD and evaluate its complications.

Intrahepatic cholangiocarcinoma (ICC) is known to have a high frequency of lymph node metastasis. Lymph node dissection (LND) is recommended for accurate staging, but the survival benefit of LND remains unclear. Knowledge of the pathways and direction of lymphatic drainage to the regional lymph nodes is essential when considering LND to improve patient survival. The liver has three lymphatic drainage pathways: portal, sublobular, and subcapsular. Of these, the portal lymphatic pathway, which lies along with the portal tracts, is the primary pathway. The efferent portal lymphatic vessels from the left-sided liver, which continue from the portal lymphatic pathway of the liver, communicate with the lymphatic vessels and lymph nodes along the hepatic artery at the hepatoduodenal ligament. In addition, lymphatic flow may also present along the left embryonic (aberrant) hepatic artery in the lesser omentum, based on our experience. This pathway is the previously reported pathway from the left-sided ICC to the lesser curvature of the stomach. However, through this pathway, ICC cells reach lymph nodes along the root of the left gastric artery but not the perigastric lymph nodes along the lesser curvature because of the opposite direction of lymph flow. Although further analyses using a large number of cases are needed to confirm these observations, these two pathways, along the hepatic artery at the hepatoduodenal ligament and the left embryonic (aberrant) hepatic artery in the lesser omentum should be considered when performing LND in the case of ICC in the left-sided liver.

Hepatocellular carcinoma (HCC) is a primary liver cancer that occurs with a frequency of 85% in patients with liver cirrhosis. It is the sixth most common type of cancer globally. Asia is the continent with the highest incidence (72%), followed by Europe (8%) and Africa (5%). Men are four times more likely than women to develop this cancer, especially in the 70-80 age group. Risk factors include alcoholic liver disease, tobacco use, genetic predisposition, dysmetabolic comorbidities such as type 2 diabetes mellitus and obesity, hepatitis B virus and hepatitis C virus infections, and non-alcoholic fatty liver disease. Unhealthy dietary regimens and gut dysbiosis are additional risk factors that have been recently investigated. These two factors are closely related because the gut microbiota performs several biological functions, including nutrient metabolism, a process that promotes gut homeostasis, known as eubiosis. With regard to the correlation between diet, gut microbiota, and HCC development, there are several mechanisms that have not yet been fully elucidated. This narrative review aims to evaluate the impact of diet and gut microbiota changes in the development of HCC. Our analysis, performed on several clinical and pre-clinical studies, showed that a high-fat diet promotes gut dysbiosis and hepatic fat accumulation, leading to the progression from simple steatosis to HCC, while the Mediterranean diet, rich in fiber and monounsaturated fatty acids, had a protective role. For this reason, international employment of this dietary regimen for therapeutic purposes should be encouraged.

Hepatocellular carcinoma (HCC) stands as a primary malignant liver tumor characterized by chronic inflammation and complex alterations within the tumor microenvironment (TME). Lymphocyte activation gene 3 (LAG-3), also known as CD223, has gained prominence as a potential next-generation immune checkpoint, maintaining continuous expression in response to persistent antigen exposure within the TME, warranting our attention. In patients with HCC, LAG-3 expression on T cells, regulatory T cells (Tregs), and natural killer (NK) cells contributes to immune evasion, while high expression of LAG-3 leads to increased angiogenesis and poor prognosis. By interacting with major histocompatibility complex class II molecules, LAG-3 promotes T cell exhaustion and suppresses antitumor responses, often in collaboration with other immune checkpoints like programmed cell death protein 1 (PD-1), while on Tregs and NK cells, LAG-3 modulates their suppressive functions, indirectly facilitating tumor immune escape. LAG-3 expression may offer prognostic insights, correlating with disease progression and outcomes in HCC patients, while various preclinical studies highlight the potential of LAG-3-targeted therapies in reinvigorating immune responses against HCC, with a few combination approaches targeting LAG-3 alongside other checkpoints demonstrating synergistic effects in restoring T cell function. Therefore, harnessing LAG-3 as a therapeutic target holds promise for enhancing antitumor immunity and potentially improving HCC treatment outcomes. Our narrative review aims to delve into the full spectrum of LAG-3 signaling in HCC, with the goal of a better understanding of the pathophysiological and immunological basis of its use to arrest HCC growth and development.

Hepatocellular carcinoma (HCC) is a form of liver cancer that commonly arises in patients with chronic liver disease. Patients who present with early-stage disease, even after curative intent resection or ablation, are likely to develop local recurrence or metastatic disease. Chronic inflammation disrupts the tightly relegated immune system of the liver, making it more susceptible to carcinogenesis. In turn, research has focused on leveraging immunotherapy for these patients. This approach has primarily been accomplished through immune checkpoint inhibitors, which are monoclonal antibodies that inhibit immune checkpoints and restore T cells’ activity against cancer cells. The IMbrave150 and HIMALAYA trials established immunotherapy as the first-line treatment for patients with advanced HCC. Therefore, there has been interest in expanding the indications for immunotherapy among patients with HCC to the neoadjuvant and adjuvant settings. Furthermore, locoregional therapies, like radiation therapy, may be able to prime the tumor microenvironment and make it more susceptible to immunotherapy, thereby improving response to treatment. We herein review recent research and clinical trials focused on the use of immunotherapy in the neoadjuvant and adjuvant setting for patients with HCC.

Aim: Hepatocellular carcinoma (HCC) in patients with Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) is expected to be a significant public health issue in the near future. Therefore, understanding the tumor microenvironment interactions in MASLD-induced HCC is crucial, and the development of relevant preclinical models is needed. Hence, we aimed to determine the effects of a MASLD-mimicking microenvironment (ME) on the aggressiveness of HCC cells and identify target genes that drive HCC by developing a 3D-in vitro co-culture system.

Methods: A 3D co-culture system mimicking the MASLD-ME was created with LX-2 liver stellate cells embedded in 3D collagen gel in the lower and SNU-449 HCC cells on the upper parts of Boyden chambers, and cells were grown in an optimized metabolic medium (MM). The effects of MASLD-ME on motility, sphere formation, proliferation, and cell cycle of SNU-449 cells were tested by Boyden chamber, 3D sphere formation, XTT, and Flow cytometry, respectively. The protein expression/activation profiles of motile SNU-449 cells that passed the membrane toward MASLD-ME or control condition were investigated using a multiplex protein profiling system DigiWest and confirmed with RT-PCR, WB, and Flow cytometry. IDH2 levels were examined in primary human HCC and adjacent liver tissues by IHC and in TCGA and CPTAC cohorts by bioinformatics tools.

Results: MM treatment increased fat accumulation, motility, and spheroid formation of both SNU-449 and LX-2 cells. MASLD-ME induced activation of LX2 cells, leading to the formation of bigger colonies with many intrusions compared to related controls. DigiWest analysis showed that metabolism-related proteins such as IDH2 were the most affected molecules in SNU-449 cells that migrated toward the MASLD-ME compared to those that migrated toward the control condition. Downregulation of IDH2 expression was confirmed in SNU-449 cells grown in MASLD-ME, in primary HCC tumor samples by IHC, and in HCC patient cohorts by bioinformatics analysis.

Conclusion: This study reports the potential involvement of MASLD-ME in the downregulation of IDH2 expression and promoted motility and colonization capacity of HCC cells. The 3D MASLD model presented in this study may be useful in investigating the mechanistic roles of MASLD-ME in HCC.

Liver cancer is a heterogeneous disease and is one of the leading causes of cancer deaths worldwide. Hepatocellular carcinoma, comprising approximately 90% of cases, presents a formidable challenge with a less than 20% 5-year survival rate despite recent treatment advancements. The impediments of drug resistance and off-target effects underscore the critical need for innovative and efficacious therapies. Harnessing the growing understanding of RNA function offers a promising avenue to address previously "undruggable" proteins, transcripts, and genes. Various RNAs demonstrate the potential to selectively act on these targets, expanding the scope of therapeutic interventions. With diverse regulatory roles in cancer pathways, RNAs emerge as valuable targets and tools for anticancer therapy development. This article provides an in-depth exploration of current RNA-based therapies, elucidates their mechanisms of action, and discusses their combinations with chemo-/immunotherapies in clinical trials for hepatocellular carcinoma.

Aim: Pneumonia is the most frequent early postoperative complication in liver transplantation (LT) recipients. Inflammation may provide a favorable environment for tumor implantation, so we aimed to evaluate the impact of pneumonia on pulmonary metastasis of hepatocellular carcinoma (HCC) and reveal its underlying mechanism.

Methods: A training cohort with 234 LT recipients were recorded and analyzed. Using the propensity-score method, we matched covariates between patients with and without pneumonia. A model for predicting pulmonary metastasis was built and validated in an independent validating cohort containing 179 subjects. A mouse model was built to mimic HCC pulmonary metastasis. The potential pathway was revealed by cytokine array analysis and validated in vitro.

Results: Pneumonia was an independent risk factor for pulmonary metastasis in liver transplant recipients. It promoted pulmonary metastasis in both the clinical setting and the mouse model. In vitro, LPS-stimulated VEGF secretion from macrophages in the lung significantly reduced cell apoptosis and activated PI3K/AKT/cas-9 signaling. Administration of VEGF receptor2 inhibitor Vatalanib could reduce metastasis and improve prognosis in pneumonia mice.

Conclusion: Pneumonia promotes HCC pulmonary metastasis by activating PI3K/AKT/Cas-9 signaling in HCC cells via macrophage-originated VEGF. Vatalanib might be efficient in reducing HCC pulmonary metastasis in liver transplant recipients with pneumonia.

Hepatocellular carcinoma (HCC) is a formidable global health challenge with rising incidence rates and significant morbidity and mortality. As medical technology evolves, laparoscopic liver resection has emerged as a promising alternative to traditional open surgery for HCC treatment. This manuscript provides a comprehensive review of the contemporary perspectives on laparoscopic liver resection for HCC, with a focus on elucidating its potential benefits and inherent limitations. Our review takes a close look at how laparoscopic liver resection is currently being used to treat HCC, considering its application in various stages of the disease, tumor sizes, and locations. Through a systematic analysis of existing studies and clinical trials, we highlight the main benefits of LLR, such as less blood loss, shorter hospital stays, quicker recovery times, and better cosmetic results. This review delves into the oncological safety and outcomes of laparoscopic HCC resection. Despite its promise, laparoscopic liver resection is not without limitations. The manuscript probes into the challenges associated with this approach, such as technical complexity, restricted access to certain tumor locations, and limited surgical field visualization. Furthermore, we address the critical issue of patient selection, as not all HCC patients are suitable candidates for laparoscopic resection, necessitating a personalized and multidisciplinary treatment approach.

The evolving treatment landscape of hepatocellular carcinoma (HCC) includes curative treatments such as ablation, resection, and transplantation, along with palliative interventions such as locoregional and systemic therapies. Evaluating the response to therapy is critical to planning the next intervention or follow-up needed, as well as for comparing the outcomes across the treatment options. Response to therapy can be measured using serum markers, through pathology, using imaging surrogates, and clinical response. This review provides a brief overview of these measures of treatment response and their relevance to HCC management.

Combined hepatic artery infusion (HAI) and systemic chemotherapy have demonstrated its clinical efficacy in prolonging overall survival in unresectable intrahepatic cholangiocarcinoma and as a conversion to treatment strategy in a small proportion of patients. The utilization of HAI chemotherapy is restricted by the scarcity of surgeons and oncologists who are well-experienced in its use. This represents a significant drawback of this treatment method. In recent years, a solid push to expand its use, mainly in the United States and recently also in Europe, has been made possible by the HAI Consortium Research Network. Results of ongoing Clinical Trials are eagerly awaited to give the basis for further expansion of this technique and oncological treatment outside of historically established centers. In this technical note review, we aim to give a brief historical description of the origins and evolution of intra-arterial chemotherapy for unresectable intrahepatic cholangiocarcinoma. We will, therefore, discuss the surgical technique by providing some tips and tricks without neglecting the difficulties that may be encountered.

Aims: The optimal timing for DAA therapy initiation in patients with chronic hepatitis C (CHC) and HCC is still debated. The aim of our study was to provide real-world data on virological response and overall survival in patients with hepatitis C-related HCC.

Methods: Retrospectively, we included patients with HCV-related HCC between 2015 and 2020. The primary outcome was to compare the SVR rate in the patients with active or historical HCC who were treated with DAA therapy. The secondary outcome was to measure the overall survival of those patients.

Results: 98 patients were included, and the majority were cirrhotic with compensated liver disease. 71.4% received DAA therapy at the time of initial HCC diagnosis and 11.2% received HCV treatment at the time of HCC recurrence (Active HCC cohort). 17.3% had previously received HCC treatment, but there was no evidence of recurrence at the time of DAA (Historical HCC Cohort). The SVR rate was 81.6%, but decreased to 75.7% in patients with active HCC. The presence of active HCC and the number of HCC nodules were the only factors associated with not achieving SVR in the multivariate analysis. The median survival was higher in those who achieved SVR. Active HCC and failure to achieve SVR were the main factors associated with mortality.

Conclusions: Treating hepatitis C in patients with HCC is feasible with significant rates of SVR, even if SVR rates decrease in patients with active HCC and these patients require more than one DAA therapy. Failure to achieve SVR is one of the main factors associated with mortality.

Additional randomized controlled studies and high-level evidence for the diagnosis and management of liver cancer patients have been published since the release of Diagnosis and Treatment of Primary Liver Cancer Guidelines (CNLC-2022 edition). The 2024 version algorithm was updated accordingly by the national expert committee for the standardization and homogenization of liver cancer diagnosis and treatment in China. In this review, with reference to the guidelines of the 2022 version, we interpreted the main update points of the 2024 version to facilitate the nationwide dissemination and implementation of the guidelines.

Treatment of hepatocellular carcinoma with both internal and external radiation therapy is becoming more common, with the recent incorporation of internal radiation therapy (transarterial radioembolization) into the Barcelona Clinic Liver guidelines. With the increasing use of radiation therapy for the treatment of liver cancer, it is essential to understand the expected imaging findings after therapy and establish a consensus on the management of these patients. Recent insights into the unique post-treatment imaging features of HCC treated with radiation have prompted updates to treatment response algorithms to improve inter-reader response assessment. One must understand the type of locoregional treatment, the time interval of post-treatment imaging and the sequence of the treatment strategy to provide an accurate treatment response assessment. Although imaging response systems attempt to predict treatment efficacy, many of these complex cases should be discussed in a multidisciplinary setting for management recommendations.

Aim: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. The Sonic Hedgehog (SHH) signaling pathway participates in the initiation, progression, migration, and recurrence of HCC cancer stem cells. Furthermore, SHH regulates various cellular behaviors such as proliferation, differentiation, survival, self-renewal, epithelial-mesenchymal transition (EMT), and SHH autoregulation. Glioma-associated oncogene (GLI) family zinc finger are key transcription factors in the development of many organs and are deregulated in cancer. In this study, Huh-7 cells were treated with GLI-specific decoy oligodeoxynucleotide (ODN) to evaluate its anticancer impact.

Methods: The transfection efficiency of GLI-specific decoy ODN was measured using fluorescent microscopy. Then, the effects of GLI-specific decoy ODN on apoptosis, viability, proliferation rate, colony formation, and migration capacities of Huh-7 cells were assessed. Furthermore, the expression of genes associated with the alteration of SHH was assessed.

Results: Treatment of Huh-7 cells with GLI-specific decoy ODN decreased cell viability (56.36% ± 3%). Expression of certain genes such as c-MYC, SNAI2, ZEB1, and PROM1 decreased dramatically, while the expression of CDH1 increased significantly. Furthermore, the treated cells’ proliferation, colony formation, and migration capacity decreased considerably. This treatment induced apoptosis in the Huh-7 cells.

Conclusion: Inhibition of the SHH signaling pathway using GLI-specific decoy ODN led to a decline in the growth rate of HCC cells, decreased migration, and attenuated EMT progression.

Hepatocellular carcinoma (HCC) is an aggressive primary liver cancer secondary to chronic liver disease or cirrhosis. In the setting of chronic inflammation, the liver’s tightly regulated immune system is disrupted, resulting in immune cell fatigue. This makes the liver vulnerable to tumorigenesis. Surgery and/or transplantation offer the best long-term survival for patients diagnosed with early HCC. Unfortunately, patients commonly develop recurrent or metastatic disease. Some patients will present with unresectable HCC or liver dysfunction. As such, locoregional therapy options may be limited. Research is focused on leveraging the distinctive liver immune microenvironment and its role in HCC carcinogenesis for the development of more effective systemic therapies. Given the success of immunotherapy in treating advanced HCC, the scientific community is looking to expand the indications of immunotherapy to the neoadjuvant and/or adjuvant setting and in combination with other locoregional therapies. We herein review the most recent data on the use of neoadjuvant or adjuvant immunotherapy and its combination with Yttrium-90 (Y90) radioembolization for HCC for curative intent.

Over the past two decades, minimally invasive liver resection (MILR) has progressively become the standard for minor resection of hepatocellular carcinoma (HCC). In contrast, its implementation in major hepatectomy has been slower due to its higher technical complexity and morbidity. However, studies published in recent years have demonstrated that minimally invasive major hepatectomy (MIMH) is safe and feasible with less blood loss, fewer complications, earlier recovery, decreased hospital stay, and improved cosmetic outcomes compared with open surgery. This review examines the current status of MIMH, focusing on the respective strengths and weaknesses of the laparoscopic and robotic approaches, as well as assessing their cost-effectiveness and possible future directions. The earlier introduction of laparoscopic liver resection has led to its widespread utilization as a safe and accurate alternative to open hepatectomy. Of note is that the robotic approach has also been increasingly utilized, demonstrating better perioperative outcomes and decreased need for conversion to open hepatectomy vs. the laparoscopic approach. Advantages associated with the robotic approach include the three-dimensional large visual field and instrumental flexibility, allowing for improved bleeding control. Even though evidence has been slowly accumulating regarding long-term outcomes, most studies report no notable differences between open, robotic, and laparoscopic resection for HCC. Regarding cost-effectiveness, MIMH has been characterized by higher operating room and anesthesia costs, especially for robotic procedures that require highly expensive equipment. The increase in cost is often offset by the lower morbidity and, thus, shorter hospital stays associated with MIMH. Future developments, such as the implementation of artificial intelligence and augmented reality, may potentially maximize the safety and applicability of MIMH and, in time, lead to improved postoperative and oncological outcomes.

Aim: Hepatocellular carcinoma (HCC) localized to the liver has various treatment options, including external beam radiotherapy (EBRT). Despite many prospective and retrospective reports showing excellent local control (LC) and favorable toxicity, EBRT has not been widely adopted in the first-line setting and this may be due to a perceived lack of evidence. This study aims to share a decade of experience with Stereotactic Body Radiotherapy (SBRT) for HCC, leveraging a homogenous treatment technique.

Methods: This retrospective study at a single institution included patients with HCC treated with SBRT, with a standardized treatment protocol. Freedom from local progression (FFLP), overall survival (OS), and rates of hepatotoxicity post-treatment using child-pugh (CP) and albumin-bilirubin (ALBI) scores were analyzed. A mixed-effects multivariable analysis (MVA) was also performed to assess various factors’ impact on outcomes.

Results: A total of 138 lesions in 106 patients were treated between 2009 and 2020. FFLP was 91% at one year and 86% at three years. OS was 80% and 46% at 1 and 3 years, respectively. Baseline liver function was a significant predictor of FFLP and OS on MVA. CP scores and ALBI grades were stable 3 months after treatment in ≥ 70% of patients.

Conclusion: SBRT provides excellent LC and low toxicity for HCC patients. While long-term survival remains challenging, treatment decisions should consider overall clinical status. Multidisciplinary review and forthcoming prospective trial results will further clarify radiotherapy’s role in HCC management.

Aim: A critical need for hepatocellular carcinoma (HCC) management is understanding how the liver recovers following radiotherapy (RT). We hypothesized that functional liver imaging with ^99mTc-sulfur colloid (SC) SPECT/CT provides additional information on liver injury and recovery after RT compared to conventional imaging.

Methods: The liver function of patients with HCC was assessed using ^99mTc-SC SPECT/CT imaging before and after definitive RT. The anatomical liver volume (ALV) was segmented on CT imaging. Liver function was measured as the total liver function (TLF) encompassing 30% of maximum SC uptake. Changes in ALV and TLF were compared to clinical characteristics.

Results: Of 31 patients with evaluable post-RT SC SPECT/CT scans (total of 32), 23 had pre-treatment Child-Pugh (CP)-A and 9 had CP-B/C scores. The median follow-up post-RT was 57 days. The median change in ALV was -1.7% with no significant difference between CP-A and CP-B/C patients (P = 0.26) or between short- (32-99 days) and long-term (271-1120 days) follow-up imaging groups (P = 0.28). The median change in TLF post-RT was -24% and was significantly different between short- and long-term groups (-39% vs. 2%, P = 0.001) and between CP-A and CP-B/C patients (-19% vs. -57%, P = 0.002). TLF significantly decreased following treatment at all radiation dose levels, with the decline correlating with the dose (P < 0.001).

Conclusion: Functional imaging provides additional information regarding liver injury and recovery following RT that conventional imaging cannot reveal. Patients with CP-A liver status showed less decline following RT and most had liver function near or above pre-treatment levels.

With the predicted rise in metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence over the next decade, strategies to prevent hepatocellular carcinoma (HCC), which is the third most common cause of cancer-related death, are paramount. In this narrative review, we present recent clinical and translational studies from 2020-2024, providing an updated overview of the literature on chemoprevention of HCC associated with MASLD. We specifically focus on statins, aspirin, metformin, and newer diabetes medications. These agents target specific steps in the development of HCC in MASLD, including steatosis resulting in oxidative stress, inflammation, and eventually fibrosis. All offer promising avenues for HCC chemoprevention, although statins have the strongest data at present. Further ongoing prospective studies are needed.

In the areas where viral infections are more common, the incidence of hepatocellular carcinoma (HCC) has declined. This is largely attributed to the availability of vaccines against hepatitis B virus (HBV), antiviral treatments, and a change in diet with healthier foods. However, in the Western world, the HCC incidence rate has risen steadily, probably due to an increased prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD), a condition that has increasingly been considered an important risk factor for HCC. Despite this, in 2019, 41% of HCC cases were diagnosed globally and a majority of diagnosed cases from mainland China were related to HBV. Some HCC cases tested negative for hepatitis B surface antigen (HBsAg) but tested positive for HBV-DNA in blood. This is considered an occult HBV infection (OBI). OBI is related to various mutations in the viral genome, which modifies host immunity, subsequently leading to the long-term persistence of cccDNA in the nucleus of infected hepatocytes. Many OBIs are associated with HBV variants carrying mutations in preS/S genomic regions, which occur either spontaneously or as a result of antiviral treatments. OBIs are also frequently reported in HBV-vaccinated individuals. HBV variants post-HBV vaccination carry mutations in the preS area. This review discusses the relationship between preS variant-related OBIs and the development of HCC in the context of a high-fat diet, one of the preventable behavioral risk factors for MAFLD.

Intrahepatic cholangiocarcinoma (ICC), a highly malignant tumor characterized by poor prognosis, has shown limited response to conventional treatments. Recently, advances in immunotherapy have offered new hope for treating such tumors. This article reviews the tumor immune microenvironment (TIME) of ICC, its pivotal role in immunotherapy, and methods to enhance ICC treatment by converting ‘cold tumors’ to ‘hot tumors’ through immune activation. Additionally, the article examines the characteristics of immune checkpoint inhibitors and their essential role in immunotherapy. Recent research and clinical trial outcomes for various immunotherapeutic approaches - namely immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell therapy (ACT) - are detailed, highlighting challenges in patient variability, side effect management, cost, and treatment accessibility. Furthermore, the article explores future research directions such as identifying new immunotherapy targets, applying precision medicine, and developing integrated therapeutic strategies to enhance immunotherapy efficacy and improve survival rates for ICC patients.

Aim: To evaluate the perioperative outcomes and postoperative survival of applying staging laparoscopy (SL) in intrahepatic cholangiocarcinoma (ICC) patients undergoing surgical resection.

Methods: A retrospective analysis was performed on all selected ICC patients who underwent curative-intent resection with/without applying staging laparoscopy from January 2010 to August December 2021. Perioperative outcomes and postoperative survival were analyzed. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to reduce the bias due to confounding variables in the SL group and the non-SL group. Multivariate Cox analysis was used to ascertain the independent predictor of survival for ICC patients.

Results: A total of 279 patients (24.1%) were included in the SL group, while 881 patients (75.9%) were included in the non-SL group. Compared with the non-SL group, the SL group had lower blood loss, smaller tumor size, higher R0 resection rate, and shorter hospital stay, but a higher incidence of postoperative complications. The OS of the SL group was better than that of the non-SL group (Median OS: 31 months vs. 20 months). The 1-, 3-, and 5-year overall survival rates of the SL group were 77.9%, 45.1%, and 32.9%, respectively, while the non-SL group had rates of 63.9%, 31.3%, and 18.4%. SL was confirmed as an independent predictor of survival by multivariate Cox analysis.

Conclusion: ICC patients receiving SL had better perioperative outcomes and significantly prolonged overall survival after resection surgery. The subgroup analysis results support the use of routine SL.

This article explores the emerging role of metabolic dysfunction-associated steatotic liver disease (MASLD) in the pathophysiology of intrahepatic cholangiocarcinoma (ICC). Despite advances in public health, ICC incidence has risen, suggesting overlooked risk factors. Recent studies indicate a significant association between MASLD and ICC, though causality remains unproven. The article reviews current research, highlighting limitations such as retrospective designs and small sample sizes. It emphasizes the need for comprehensive investigations into MASLD’s role in ICC pathogenesis, prognosis, and management. Future research should focus on integrating advanced methodologies to identify novel biomarkers and therapeutic strategies, aiming to improve patient outcomes and develop tailored prevention and treatment approaches.

Recently, the combination of interventional and systemic therapies has become an essential treatment modality for primary liver cancer (PLC). Interventional therapy might promote tumor necrosis and enhance immunogenicity, while the combination with systemic therapy further augments clinical efficacy. Clinical studies have demonstrated that, compared with interventional therapy alone, the combination of interventional therapy with either immunotherapy or targeted therapy can significantly improve tumor response rate and extend the survival period. Furthermore, the synergistic therapeutic approach may enable patients with initially unresectable hepatocellular carcinoma (HCC) to undergo surgery, thus enhancing the overall therapeutic outcome. The combined therapy not only maintains the occurrence and severity of adverse effects at a manageable level but also ensures that any associated adverse effects remain within a controllable scope. Most recent studies are retrospective analyses with small sample sizes. There is an imperative need for more large-scale, prospective, randomized controlled clinical trials to elucidate the optimal combination therapy modality and to identify the ideal patient group for treatment.

Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths worldwide. It presents a significant and rising global health challenge due to its complex development, high mortality rate, and poor prognosis. The primary treatment methods include chemotherapy, radiotherapy, and surgery, yet each is associated with severe side effects. While combination therapies can enhance outcomes, they also tend to amplify the adverse effects. For this reason, the prevention of HCC has a major impact on world health. Current knowledge indicates that a healthy lifestyle combined with a healthy diet is an excellent preventive strategy. In this respect, the Mediterranean diet represents a valid preventive strategy widely recognized by the scientific community. Its effectiveness is proven by the presence of several polyphenols in its main foods, including quercetin, luteolin, myricetin, and kaempferol. These polyphenols are present in different functional foods and show anticancer activity. This narrative review aims to assess the anti-HCC activity of these polyphenols that characterize the Mediterranean diet.

Hepatocellular carcinoma (HCC) represents a well-recognized indication for liver transplantation (LT), with improving graft and patient survival rates due to medical and surgical advancements over time. Despite the implementation of selection criteria to ensure the highest transplant benefit, post-LT recurrence of HCC is not uncommon and is often associated with poor outcomes. Therefore, a post-transplant surveillance strategy appears to be a cost-effective approach, particularly in the early post-surgery period when the recurrence rate is high. Although specific guidelines are still lacking, emerging strategies tailored to pre-transplant tumor history and explant pathology show promise. Moreover, new immunosuppressive therapy schemes and aggressive management of post-transplant medical complications can be implemented to reduce the risk of cancer recurrence. Finally, multimodal oncological strategies are increasingly used to improve survival even after cancer recurrence. This paper reviews the evidence on HCC recurrence after LT, providing insights into risk factors, targeted surveillance, and management strategies.

Radiomics was first introduced by Lambin et al. in 2012, and since then, research in this field has grown rapidly. Researchers have shown great interest in developing efficient methods for automatically extracting a large number of quantitative features from medical images, aiming to enhance diagnostic accuracy and predictive capability. Although there has been a rise in Radiomics studies focusing on intrahepatic cholangiocarcinoma (ICC) in recent years, comprehensive reviews are still relatively scarce. This study explores how Radiomics technology can be utilized in modeling analyses to predict lymph node metastasis, microvascular invasion, and early recurrence of ICC, as well as the application of deep learning in these analyses. This paper provides a brief overview of the current state of Radiomics research and offers references for future studies.

The circadian system plays a crucial role in regulating metabolic homeostasis at both systemic and tissue levels by synchronizing the central and peripheral clocks with exogenous time cues, known as zeitgebers (such as the light/dark cycle). Our body’s behavioral rhythms, including sleep-wake cycles and feeding-fasting patterns, align with these extrinsic time cues. The body cannot effectively rest and repair itself when circadian rhythms are frequently disrupted. In many shift workers, the internal rhythms fail to fully synchronize with the end and start times of their shifts. Additionally, exposure to artificial light at night (LAN), irregular eating patterns, and sleep deprivation contribute to circadian disruption and misalignment. Shift work and jet lag disrupt the normal circadian rhythm of liver activity, resulting in a condition known as “circadian disruption”. This disturbance adversely affects the metabolism and homeostasis of the liver, contributing to excessive fat accumulation and abnormal liver function. Additionally, extended working hours, such as prolonged night shifts, may worsen the progression of non-alcoholic fatty liver disease (NAFLD) toward non-alcoholic steatohepatitis (NASH) and increase disease severity. Studies have demonstrated a positive correlation between night shift work (NSW) and elevated liver enzymes, indicative of hepatic metabolic dysfunction, potentially increasing the risk of hepatocellular carcinoma (HCC) related to NAFLD. This review consolidates research findings on circadian disruption caused by NSW, late chronotype, jet lag, and social jet lag, drawing insights from studies involving both humans and animal models that investigate the effects of these factors on circadian rhythms in liver metabolism.

Aim: To investigate radiotherapy efficacy and prognostic factors in patients with hepatocellular carcinoma (HCC) with cardiophrenic angle or superior diaphragmatic lymph node metastasis (LNM).

Methods: We retrospectively analyzed 72 patients with HCC presenting with cardiophrenic angle or superior diaphragmatic LNM at Zhongshan Hospital of Fudan University from 2010 to 2023. Response rates, survival rates, local control rates, prognostic risk factors, and side effects of external beam radiation therapy (EBRT) were compared between patients with EBRT (EBRT group) and those without EBRT (non-EBRT group).

Results: The overall response rates in the EBRT group and the non-EBRT group were 68.8% (22/32) and 7.5% (3/40), while median survival was 16.1 (95%CI: 8.09-24.12) and 5.9 months (95%CI: 3.05-7.76) respectively (HR = 2.87, P < 0.001). The survival was significantly prolonged with a daily dose > 4 Gy (P = 0.014). EBRT (P < 0.001) was identified as a factor correlated with the local control rate. Multivariate analysis revealed that tumor thrombosis, multiple intrahepatic tumors, a maximal intrahepatic tumor diameter ≥ 5 cm, abdominal LNM, and lack of EBRT were poor prognostic factors. Gastrointestinal (GI) bleeding in patients with bioequivalent dose 10 (BED10) ≤ 70 and > 70 were 0% (0/22) and 30.0% (3/10), respectively (P = 0.024).

Conclusion: EBRT was a safe and effective treatment for HCC patients with cardiophrenic angle or superior diaphragmatic LNM and might prolong overall survival. Dose > 4 Gy per day and BED10 ≤ 70 would be recommended for LNM. Patients with tumor thrombosis, multiple intrahepatic tumors, a maximal intrahepatic tumor diameter ≥ 5 cm, abdominal LNM, and lack of EBRT had a poor prognosis.

This article reviews the interactions between gut microbiota and cancer immunotherapies and discusses microbiota-based patient stratification strategies such as the prediction of response and the early recognition of toxic events. Additionally, it explores the emerging potential of microbiotherapy to enhance anti-neoplastic efficacy and alleviate toxicity, with the ultimate goal of developing personalized treatment regimens for patients with hepatocellular carcinoma (HCC).

Primary liver cancer, particularly hepatocellular carcinoma (HCC), ranks among the top causes of cancer deaths worldwide. Traditionally, liver cancer has been associated with a dismal prognosis, which has led to extensive research into potential treatments. Over the past decade, there have been substantial advancements, particularly in the area of locoregional therapies such as radioembolization. This paper provides a summary of the expanding role of radioembolization in HCC treatment, emphasizing recent updates in therapeutic guidelines and ongoing clinical research.

Venous thromboembolic events (VTE) represent a significant and common complication in patients with hepatocellular carcinoma (HCC) in the context of cirrhosis. While some patient-related risk factors for VTE are shared with the non-cirrhotic population, the presence of HCC amplifies the risk, potentially due to the pro-thrombotic paraneoplastic alterations associated with the tumor. This review aims to examine the current evidence regarding hemostatic disorders observed specifically in cirrhotic patients with HCC. Additionally, the review comprehensively examines VTE events in cirrhotic patients with HCC, specifically emphasizing portal vein thrombosis (PVT). PVT is the most common thrombotic complication in this population and can have significant implications for the eligibility and success of treatment modalities such as liver transplants or surgical interventions. Identifying risk factors associated with PVT occurrence in these patients is essential to guide preventive measures and enhance patient outcomes. This review aims to provide a clear background for further research and investigations into effective prevention and treatment strategies for VTE in cirrhotic patients with HCC by comprehensively revising the current evidence on these topics.

Activator protein 1 (AP-1) is a family of transcription factors composed of Jun, Fos, activating transcription factor (ATF), and musculoaponeurotic fibrosarcoma (MAF) homodimers and heterodimers that regulate diverse cellular processes such as proliferation, apoptosis, differentiation, survival, and migration. Accordingly, AP-1 plays an essential role in several diseases including cancer. During liver cancer development, AP-1 abnormal activation has been implicated from cancer initiation to cancer progression. This review aims to provide a current integrative understanding of the role of AP-1 in liver carcinogenesis and suggests potential settings for its clinical use in diagnosis and treatment. Novel AP-1-based therapeutic approaches deserve further investigation and clinical application for the benefit of liver cancer patients.

Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related mortality globally. Due to frequently complex disease presentation and comorbid underlying cirrhosis, many patients are not ideal candidates for surgical resection, transplantation, or other local ablative treatments. External beam radiation therapy (EBRT) has emerged as a promising alternative. EBRT has gained prominence due to advancements in targeting and treatment delivery technology. Advanced modalities such as intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), stereotactic body radiation therapy (SBRT), and proton beam therapy (PBT) have dramatically improved the precision of radiation delivery, resulting in a far more favorable therapeutic ratio. Here we cover the evolution of current practice and future prospects of EBRT in treating HCC, emphasizing the enhanced efficacy and reduced toxicity provided by these advanced technologies, and improved integration with other loco-regional and systemic therapies in reviewing the current indications for treatment.

Disparities in the prevalence, progression and prognosis of hepatocellular carcinoma between males and females are well documented, which stem from a complex interplay of various factors. Sex-specific lifestyle, behavioral and psycho-socioeconomic influences, combined with intrinsic hormonal and genetic differences, significantly impact the process of hepatocarcinogenesis. These factors are further augmented by epigenetic mechanisms and co-factors such as hepatitis B and C infections, and metabolic dysfunction-associated steatotic liver disease. Further research is required to elucidate the mechanisms driving these clear sex differences, in order to optimize future prevention and treatment strategies.

Aim: The aim of this study was to compare the effects of conventionally fractionated radiotherapy (CFRT) and stereotactic body radiotherapy (SBRT) on peripheral lymphocyte subset levels in patients with hepatocellular carcinoma (HCC), and to assess the association between radiotherapy (RT)-induced lymphopenia and patient prognosis.

Methods: A retrospective analysis was conducted on 137 HCC patients who underwent either CFRT or SBRT between July 2011 and January 2018. Variables were obtained within 1 week before RT, and 1 day and 2 months post-RT, respectively. Peripheral lymphocyte subsets, including CD4+, CD8+, CD19+, and NK cells, were measured using flow cytometry. Univariate and multivariate Cox regression analyses were conducted to investigate independent prognostic factors for overall survival (OS).

Results: The one-year and two-year OS rates were 80.0% and 55.0%, respectively. Multivariate analysis identified tumor size > 4.5 cm, multiple tumors, and post-RT CD4+ T cell count < 231/μL and CD8+ T cell count < 179/μL as independent factors associated with inferior OS in HCC patients. Severe lymphopenia (< 0.5 × 10⁹/L) occurred in 70.0% of patients following CFRT compared to 23.0% in SBRT patients. Patients who received SBRT exhibited higher total lymphocyte counts and subset levels 1 day and 2 months post-treatment compared to those receiving CFRT (P < 0.05). Logistic regression analysis identified the number of RT fractions as an independent factor for severe lymphopenia. Further analysis revealed that CD19+ B cells were predominantly depleted and recovered more slowly than other populations, whereas CD8+ T cells demonstrated rapid recovery. Among SBRT patients, higher levels of CD4+ and CD8+ T cells post-treatment were associated with longer OS (P < 0.05).

Conclusion: SBRT may induce less severe lymphopenia than CFRT. Decreases in CD4+ and CD8+ T cell levels post-SBRT may independently predict worse OS in HCC patients.

Aim: This study aims to evaluate the feasibility of examining circulating tumor DNA (ctDNA) in urine samples from hepatocellular carcinoma (HCC) patients by droplet digital PCR (ddPCR) and to assess its value in predicting HCC recurrence after surgery.

Methods: HCC cases who accepted surgical resection were included. Perioperative urine, tissue and peripheral blood specimens were collected. Four hotspot mutants [TP53-rs28934571 (c.747G>T), TRET-rs1242535815 (c.1-124C>T), CTNNB1-rs121913412 (c.121A>G), and CTNNB1-rs121913407 (c.133T>C)] were chosen for ctDNA analysis, and mutant allele frequency (MAF) was worked out. Sanger sequencing was performed on matched tumor tissues and peripheral blood mononuclear cells (PBMCs). The patients’ clinicopathologic characteristics were retrospectively analyzed. The predictive abilities of urine ctDNA for postoperative recurrence were evaluated using the Kaplan-Meier method.

Results: Forty-six patients were enrolled, and 18 patients (39.1%, 18/46) exhibited detectable circulating mutants, with the MAF in the range of 0.07% to 0.91%. The consistency test indicated moderate to substantial concordance between urine and paired tumor tissue mutations. The mutation level dropped dramatically or disappeared after surgery. Positive urine ctDNA before surgery was closely related to greater tumor size and recurrence. Kaplan-Meier curves revealed significantly shorter disease-free survival (DFS) for ctDNA-positive patients. Multivariate analysis identified detectable urine ctDNA as an independent risk factor for tumor recurrence. More than that, receiver operating characteristic (ROC) curves demonstrated that urine ctDNA had the largest area under the curve (AUC) for predicting HCC recurrence.

Conclusion: Detecting ctDNA in urine using ddPCR is feasible and holds significant potential for predicting and monitoring HCC recurrence.

Cholangiocarcinoma (CCA) is a highly aggressive tumor of the biliary tree characterized by an intense desmoplastic tumor microenvironment (TME). To date, treatment of CCA remains challenging; tumor resection is the only curative treatment with a high recurrence probability. Besides resection, therapeutic options have moved forward with the advent of immunotherapies, but these remain limited and low effective. Our knowledge about the cellular interplays in CCA is still fragmentary. An area is currently emerging regarding the potential role of cell plasticity in the genesis of an immunosuppressive microenvironment. The cancer cells’ ability to acquire stemness properties and to disseminate through an epithelial-mesenchymal transition (EMT) shape a tumor immune microenvironment that supports cancer progression by attracting immunosuppressive cells including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and by increasing the expression of inhibitory immune checkpoints such as PD-1/PD-L-1. EMT-inducing transcription factors (EMT-TF) have recently emerged as regulators of tumor immunity by creating an immunosuppressive microenvironment. This review delves into the molecular mechanisms underlying the existing links between EMT/stemness and tumor immune microenvironment, as well as the last discoveries in CCA.