The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.

Atherosclerosis is a complex process involving various cells and molecules within the atherosclerotic plaque. Recent evidence suggests that plaque-associated fibroblasts (PAFs), also known as atherosclerosis-associated fibroblasts (AAFs), might play a significant role in the development and progression of the disease. The microenvironment of the atherosclerotic plaque, resembling the tumor microenvironment (TME), includes various cellular populations like plaque-associated macrophages (PAMs), plaque-associated neutrophils (PANs), vascular smooth muscle cells (VSMCs), myeloid-derived suppressor cells (MDSCs), and PAFs. Similar to cancer-associated fibroblasts (CAFs) in tumors, PAFs exhibits a wide range of characteristics and functions. Their interactions with endothelial cells, smooth muscle cells, and other stromal cells, including adventitial fibroblast precursors, significantly influence atherosclerosis progression. Moreover, the ability of PAFs to express various markers such as alpha-SMA, Desmin, VEGF, and GFAP, highlights their diverse origins from different precursor cells, including vascular smooth muscle cells, endothelial cells, glial cells of the enteric nervous system, adventitial fibroblast precursors, as well as resident and circulating fibrocytes. This article explores the molecular interactions between PAFs, cells associated with atherosclerosis, and other stromal cells. It further examines the role of PAFs in the development and progression of atherosclerosis, and compares their features with those of CAFs. The research suggests that studying tumor-associated fibroblasts can help understand fibroblast subpopulations in atherosclerotic plaque. Identifying specific subpopulations could provide new insight into atherosclerosis complexity and lead to the development of innovative drugs for medical intervention.

Ferroptosis in the tumor microenvironment (TME) plays a crucial role in the development, metastasis, immune escape, and drug resistance of various types of cancer. A better understanding of ferroptosis in the TME could illuminate novel aspects of this process and promote the development of targeted therapies. Compelling evidence indicates that exosomes are key mediators in regulating the TME. In this respect, it is now understood that exosomes can deliver biologically functional molecules to recipient cells, influencing cancer progression by reprogramming the metabolism of cancer cells and their surrounding stromal cells through ferroptosis. In this review, we focus on the role of exosomes in the TME and describe how they contribute to tumor reprogramming, immunosuppression, and the formation of pre-metastatic niches through ferroptosis. In addition, we highlight exosome-mediated ferroptosis as a potential target for cancer therapy and discuss strategies employing exosomes in ferroptosis treatment. Finally, we outline the current applications and challenges of targeted exosome-mediated ferroptosis therapy in tumor immunotherapy and chemotherapy. Our aim is to advance research on the link between exosomes and ferroptosis in the TME, and we pose questions to guide future studies in this area.

The interaction of Helicobacter pylori with cancer-associated fibroblasts (CAFs) to promote cholangiocarcinoma (CCA) genesis is unclear. We aimed to demonstrate the effect and mechanism of H. pylori on function of CAFs in vitro as well as the role of melatonin as an anti-fibrotic agent capable of modulating CAFs. CAF cells were generated by co-culture of human fibroblasts (OUMS cell line) with O. viverrini-associated CCA cells (KKU-100 cell line). In the presence of H. pylori lysate, these CAF cells exhibited increased proliferation and migration. The interaction of CAFs and H. pylori lysate also promoted KKU-100 cell migration. Proteomic analysis revealed that the fibrosis-associated integrin signaling pathway was enriched in CAFs stimulated by H. pylori lysate. Expression of focal adhesion kinase (FAK), a molecule that plays a pivotal role in cell proliferation and migration and known to be a downstream target of integrin, was upregulated in CAFs exposed to H. pylori lysate. Interestingly, melatonin treatment significantly attenuated both proliferation and migration of CAFs by reducing FAK phosphorylation and its downstream PI3K and β-catenin. These results suggest that H. pylori promotes proliferation and migration of CAFs cells and possibly fibrosis via the integrin/FAK signaling pathway, which could be attenuated by melatonin treatment.

Integrating vessels encapsulating tumor clusters (VETC) and microvascular invasion (MVI) (VM hereafter) is potentially useful in risk stratification of hepatocellular carcinoma (HCC). However, noninvasive assessment methods for VM are lacking.

To investigate the diagnostic performance of tomoelastography in assessing the VM status in HCC.

Retrospective.

One hundred sixty-eight patients with surgically confirmed HCC consisting of 115 training and 53 validation cohorts, divided into negative-VM and positive-VM groups with mild or severe-VMs. Of them, 127 patients completed the follow-up (median: 26.1 months).

3D multifrequency tomoelastography with a single-shot spin-echo echo-planar imaging sequence, and liver MRI including T1-weighted in-phase and opposed-phase gradient echo (GRE), T2-weighted turbo spin echo, diffusion-weighted imaging and dynamic contrast-enhanced T1-weighted GRE sequences at 3.0 T.

Shear wave speed (c) and phase angle of the shear modulus (φ) were calculated on tomoelastograms. Imaging features were visually analyzed and clinical features were collected. Conventional models used clinical and imaging features while nomograms combined tomoelastography, clinical and imaging features.

Univariable and multivariable logistic regression analyses, nomogram, area under the receiver operating characteristic curve (AUC), DeLong test, Kaplan-Meier analysis and log-rank test. P < 0.05 was considered statistically significant.

Tumor-to-liver parenchyma ratio of c (cr) and tumor c were independent risk factors for positive-VM and severe-VM, respectively. In validation cohort, the nomograms including cr and tumor c performed significantly better than the conventional models for diagnosing positive-VM (0.84 [95% CI: 0.72-0.93] vs. 0.77 [95% CI: 0.64-0.88]) and severe-VM (0.86 [95% CI: 0.68-0.96] vs. 0.75 [95% CI: 0.55-0.89]). Patients with estimated positive-VM (9.3 months)/severe-VM (9.2 months) based on nomograms had shorter median recurrence-free survival than those with estimated negative-VM (>20.0 months)/mild-VM (18.0 months) in validation cohort.

Tomoelastography based-nomograms showed good performance for noninvasively assessing VM status in patients with HCC.

3 TECHNICAL EFFICACY: Stage 2.

Hepatocellular carcinoma (HCC) harbors two types of stem cells-epithelial and mesenchymal stem cells. The mechanism by which epithelial EpCAM-positive HCC cells transform into mesenchymal CD90-positive HCC cells remains unclear. On peritumoral fibrotic nodules, epithelial HCC cells form communities with stromal cells, driving tumor growth and malignancy. We aimed to clarify the mechanism by which epithelial cell adhesion molecule (EpCAM)-positive HCC cells contribute to the phenotype of mesenchymal CD90-positive HCC cells that metastasize to distant sites by elucidating the interaction between EpCAM-positive HCC cells and fibroblasts. EpCAM-positive CD90-negative epithelial HCC cells (Huh1, Huh7, and HCC cells) were converted into metastasis-prone CD90-positive HCC cells by co-culture with fibroblasts (Lx-2 and Tig3-20). We identified the transcription factor JUNB as responsible for this altered phenotype. We found that the overexpression of JUNB in CD90-negative epithelial HCC cells resulted in significant transformation to mesenchymal CD90-positive HCC in vitro and in vivo, showing metastatic potential to the lungs. In addition, the JUNB expression in EpCAM-positive hepatoma cells was increased by paracrine stimulation with fibroblast-derived TGFb1. This study unravels the mechanism by which fibroblasts aggravate the malignancy of liver cancer, and the results suggest that JUNB may be a target for treating liver cancer metastasis.

Cancer-associated fibroblasts (CAFs) have garnered significant attention due to their ability to shape the tumor microenvironment, thereby facilitating tumor progression and metastasis. Serpin peptidase inhibitor clade H member 1 (SERPINH1) is known for its role in the proper folding and secretion of collagen. However, its biological significance in hepatocellular carcinoma (HCC) remains unclear. We observed higher levels of SERPINH1 in the conditioned medium (CM) of CAFs compared to normal fibroblasts (NFs) via ELISA assays. To investigate its impact on HCC, we knocked down SERPINH1 in CAFs by shRNA, which led to a notable reduction in HCC cell proliferation, migration, and invasion induced by CM of CAFs, measured by colony formation and Transwell assays. SERPINH1 also inhibited HCC cell apoptosis, decreased the percentage of cells arrested in the G0/G1 phase, and increased the proportion of cells in the S phase, which were detected by flow cytometry. We further performed co-injections of HepG2 cells liver orthotopic transplantation model with either shCtrl-CAFs or shSERPINH1-CAFs. Interestingly, the presence of shCtrl-CAFs significantly enhanced tumor-initiating capacity compared to HepG2 cells alone or when co-injected with shSERPINH1-CAFs. Mechanistically, CAFs-derived SERPINH1 activated the SENP3/SP1 signaling pathways, substantially promoting the growth of HCC cells. Notably, we found that the transcription factor SP1 directly binds to the SQLE promoter and activates its transcription via ChIP-qPCR assay. Inhibition of SP1 expression using the specific inhibitor plicamycin effectively reversed CAFs-derived SERPINH1-induced HCC growth in vivo. Collectively, our findings highlighted the pathological role CAFs-derived SERPINH1 played in driving malignant of HCC cells through the SENP3/SP1/SQLE signaling axis, which offered a explanation of how SERPINH1 promotes HCC progress. Besides, we also demonstrated that targeting SERPINH1 signaling shall be a promising direction to develop effective therapeutical strategies for anti-HCC clinical management.

As mismatch repair status confers differential prognosis in colorectal cancers, this study aimed to determine associations of α-smooth muscle actin (α-SMA) protein expression in mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) colorectal tumors with clinicopathologic and prognostic features.

Tissue microarrays from patients with colorectal cancer, immunostained with α-SMA, were assessed through digital image analysis. Total (n = 962), pMMR (n = 782), and dMMR (n = 156) stromal H-scores were assessed for associations with clinicopathologic and survival data.

Higher α-SMA expression was correlated with pMMR status (P = 5.2223 × 10-8). In the pMMR subgroup, higher α-SMA stromal expression at the tumor periphery was correlated with higher T stage (P = .002), perineural invasion (P = .038), infiltrative tumor edge (P = .01), involved nodal status (P = .036), metastases (P = .013), synchronous metastases (P = .007), recurrence (P = .004), and both 3-year and 5-year survival (P = .018). dMMR tumors showed no significant correlations with α-SMA staining.

The findings highlight that immunostaining with α-SMA in pMMR colorectal tumors, especially at the tumor periphery, has the potential to identify patients with adverse prognostic features. Digital assessment of α-SMA may offer improved objectivity, accuracy, economy of time, and risk stratification for management.

Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant, and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA, one that differentiates the most common macroscopic subtype (eg, mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma is a prominent desmoplastic reaction manifested as a dense fibro-collagenous-enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction. Although the protumor effects of CAFs in iCCA have been increasingly recognized, more recent cell lineage tracing studies, advanced single-cell RNA sequencing, and expanded biomarker analyses have provided new awareness into their ontogeny, as well as underscored their biological complexity as reflected by the presence of multiple subtypes. In addition, evidence supports CAFs' potential to display cancer-restrictive roles, including immunosuppression. However, CAFs also play important roles in facilitating metastasis, as exemplified by lymph node metastasis and peritoneal carcinomatosis, which are common in iCCA. Herein, the authors provide a timely appraisal of the origins and phenotypic and functional complexity of CAFs in iCCA, together with providing mechanistic insights into lymphangiogenesis and peritoneal metastasis relevant to this lethal human cancer.

Hepatic stellate cells (HSCs) are the liver's pericytes, and play key roles in liver homeostasis, regeneration, fibrosis, and cancer. Upon injury, HSCs activate and are the main origin of myofibroblasts and cancer-associated fibroblasts (CAFs) in liver fibrosis and cancer. Primary liver cancer has a grim prognosis, ranking as the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the predominant type, followed by intrahepatic cholangiocarcinoma (iCCA). Moreover, the liver hosts 35% of all metastatic lesions. The distinct spatial distribution and functional roles of HSCs across these malignancies represent a significant challenge for universal therapeutic strategies, requiring a nuanced and tailored understanding of their contributions. This review examines the heterogeneous roles of HSCs in liver cancer, focusing on their spatial localization, dynamic interactions within the tumor microenvironment (TME), and emerging therapeutic opportunities, including strategies to modulate their activity, and harness their potential as targets for antifibrotic and antitumor interventions.

Liver cancer, specifically hepatocellular carcinoma (HCC), stands out as one of the most formidable solid tumors, characterized by a dauntingly low survival rate. At the forefront of the tumor microenvironment (TME) orchestrating the initiation and advancement of HCC are cancer-associated fibroblasts (CAFs). TGF-β, widely recognized as a potent activator of CAFs, not only regulates their activity but also assumes a pivotal role in the metastatic journey of the tumor. In our recent study, drawing from the GEO database, we identified two fibroblast subtypes in HCC through single-cell RNA sequencing (scRNA-seq) and explore the expression and distribution of TGF-β and its receptors in the TME of HCC. Subsequently, we investigated the interactions between tumor cells expressing high levels (TGFB1high) and low levels (TGFB1low) of TGF-β in the HCC TME and the two subtypes of CAFs. We also employed multi-color immunohistochemistry (mIHC) technology to examine the expressions of FAP, α-SMA, CD4, Foxp3, and TGF-β in HCC tissues within a tissue microarray. Additionally, we analyzed clinical associations, prognostic values, and the correlation of these molecules. These insights advance our understanding of the molecular mechanisms driving HCC progression and underscore the intricate interplay between tumor cells and the stromal components of the TME.

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of non-malignant cells that play a crucial role in the tumor microenvironment, increasingly recognized as key contributors to cancer progression, metastasis, and treatment resistance. So, targeting CAFs has always been considered an important part of cancer immunotherapy. However, targeting CAFs to improve the efficacy of tumor therapy is currently a major challenge. Nanomaterials show their unique advantages in the whole process. At present, nanomaterials have achieved significant accomplishments in medical applications, particularly in the field of cancer-targeted therapy, showing enormous potential. It has been confirmed that nanomaterials can not only directly target CAFs, but also interact with the tumor microenvironment (TME) and immune cells to affect tumorigenesis. As for the cancer treatment, nanomaterials could enhance the therapeutic effect in many ways. Therefore, in this review, we first summarized the current understanding of the complex interactions between CAFs and TME, immune cells, and tumor cells. Next, we discussed common nanomaterials in modern medicine and their respective impacts on the TME, CAFs, and interactions with tumors. Finally, we focus on the application of nano drug delivery system targeting CAFs in cancer therapy.

Cholangiocarcinoma is the second most common primary liver cancer, and its global incidence has increased in recent years. Radical surgical resection and systemic chemotherapy have traditionally been the standard treatment options. However, the complexity of cholangiocarcinoma subtypes often presents a challenge for early diagnosis. Additionally, high recurrence rates following radical treatment and resistance to late-stage chemotherapy limit the benefits for patients. Immunotherapy has emerged as an effective strategy for treating various types of cancer, and has shown efficacy when combined with chemotherapy for cholangiocarcinoma. Current immunotherapies targeting cholangiocarcinoma have predominantly focused on T lymphocytes within the tumor microenvironment, and new immunotherapies have yielded unsatisfactory results in clinical trials. Therefore, it is essential to achieve a comprehensive understanding of the unique tumor microenvironment of cholangiocarcinoma and the pivotal role of T lymphocytes within it. In this review, we describe the heterogeneous immune landscape and intercellular communication in cholangiocarcinoma and summarize the specific distribution of T lymphocytes. Finally, we review potential immune checkpoints in cholangiocarcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with poor prognosis. LncRNA MAPKAPK5-AS1 is a potential oncogene and contributes to HCC cell malignant proliferation. This study explores the role of MAPKAPK5-AS1 carried by carcinoma-associated fibroblasts-derived extracellular vesicles (CAF-EVs) in HCC cell proliferation. Our findings reveal that CAF-EVs promotes HCC cell proliferation by delivering MAPKAPK5-AS1, which binds to and inhibits SMURF2 and stabilizes TCF12. SMURF2 leads to TCF12 ubiquitination and degradation. TCF12 upregulates FOXH1 expression. In animal model, CAF-EVs enhances tumor growth by stabilizing TCF12 via MAPKAPK5-AS1 and activating FOXH1 transcription. In conclusion, CAF-EVs carrying MAPKAPK5-AS1 stabilizes TCF12 expression by competitively inhibiting SMURF2, thus promoting TCF12-mediated FOXH1 transcription and driving HCC cell proliferation. Our findings may offer insights for HCC treatment and suggest potential targets for future treatments, opening avenues for HCC therapies.

Progression of liver disease is dependent on intercellular signaling, including those mediated by extracellular vesicles (EVs). Within these EVs, microRNAs (miRNAs) are packaged to selectively silence gene expression in recipient cells for upregulating or downregulating a specific pathway. Injured hepatocytes secrete EV-associated miRNAs which can be taken up by liver sinusoidal endothelial cells, immune cells, hepatic stellate cells, and other cell types. In addition, these recipient cells will secrete their own EV-associated miRNAs to propagate a response throughout the tissue and the circulation. In this review, we comment on the implications of EV-miRNAs in the progression of alcohol-associated liver disease, metabolic dysfunction-associated steatohepatitis, viral and parasitic infections, liver fibrosis, and liver malignancies. We summarize how circulating miRNAs can be used as biomarkers and the potential of utilizing EVs and miRNAs as therapeutic methods to treat liver disease.

Among solid tumors, cholangiocarcinoma (CCA) emerges as one of the most difficult to eradicate. The silent and asymptomatic nature of this tumor, particularly in its early stages, as well as the high heterogeneity at genomic, epigenetic, and molecular levels delay the diagnosis, significantly compromising the efficacy of current therapeutic options and thus contributing to a dismal prognosis. Extensive research has been conducted on the molecular pathobiology of CCA, and recent advances have been made in the classification and characterization of new molecular targets. Both targeted therapy and immunotherapy have emerged as effective and safe strategies for various types of cancers, demonstrating potential benefits in advanced CCA. Furthermore, the deeper comprehension of the cellular and molecular components in the tumor microenvironment (TME) has opened up possibilities for new innovative treatment methods. This review discusses recent evidence in the characterization and molecular biology of CCA, highlighting novel possible druggable targets.

The incidence rate of intrahepatic cholangiocarcinoma (ICC), which has a poor prognosis, is rapidly increasing. To investigate the intratumor heterogeneity in ICC, we analyzed single-cell RNA sequencing data from the primary tumor and adjacent normal tissues of 14 treatment-naïve patients. We identified 10 major cell types, along with 45 subclusters of cells. Notably, we identified a fibroblast cluster, Fibroblast_LUM+, which was preferably enriched in tumor tissues and actively interacted with cholangiocytes. LGALS1 was verified as a marker gene of Fibroblast_LUM+, contributing to the malignant phenotype of ICC. Higher amount of LGALS1+ fibroblasts was associated with poorer overall survival of ICC patients. Mechanistically, LGALS1+ fibroblasts activated the proliferation and migration of tumor cells by upregulating the expression levels of CCR2, ADAM15, and β-integrin. Silencing LGALS1 in cancer-associated fibroblasts (CAFs) suppressed CAF-augmented tumor cell migration and invasion in vitro as well as tumor formation in vivo, suggesting that blockade of LGALS1 serves as a potential therapeutic approach for ICC. Taken together, our single-cell analysis provides insight into the interaction between malignant cells and specific subtypes of fibroblasts, which contributes to better understanding of the intratumor heterogeneity in ICC and the development of novel strategies for the treatment of ICC by targeting fibroblasts in the tumor microenvironment.

Cancer-associated fibroblasts (CAFs) and hepatocellular carcinoma (HCC) cells interact to promote HCC progression, but the underlying mechanisms remain unclear. Serpin family E member 1 (SERPINE1) has conflicting roles in HCC, and microRNAs (miRNAs) are known to regulate tumor progression through intercellular communication. Therefore, we investigated the potential involvement of miRNA/SERPINE1 axis in crosstalk between CAFs and HCC cells.

In this study, candidate miRNAs targeting SERPINE1 3' UTR were predicted using multiple miRNA databases. The miRNAs and SERPINE1 mRNA expression in Huh7 cells was assessed after co-culture with CAFs using RT-qPCR. Huh7 cell proliferation and invasion were detected after SERPINE1 siRNA. The functions of the CAF-derived miR-642a-3p/SERPINE1 axis in HCC cells were examined using CCK-8, wound healing, transwell assays, western blot, and dual-luciferase reporter assays. Moreover, a orthotopic xenograft model was used to investigate the contribution of miR-642a-3p knockdown in HCC.

SERPINE1 mRNA expression decreased, while miR-642a-3p expression increased in Huh7 cells co-cultured with CAFs. SERPINE1 knockdown enhanced Huh7 cell proliferation and invasion as well as miR-642a-3p expression. miR-642a-3p overexpression promoted migration, invasion, and epithelial-mesenchymal transition (EMT) in Huh7 cells by targeting SERPINE1, while miR-642a-3p knockdown yielded the opposite effect. Rescue experiments confirmed that SERPINE1 knockdown attenuated the inhibitory effects of miR-642a-3p knockdown on migration, invasion, and EMT in Huh7 cells. Importantly, miR-642a-3p knockdown suppressed growth and EMT in orthotopic liver tumors.

CAF-derived miR-642a-3p/SERPINE1 axis facilitated migration, invasion, and EMT in the HCC cells, suggesting miR-642a-3p/SERPINE1 axis can be a potential therapeutic target for HCC.

Cancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment. IgA contributes to inflammation and dismantling antitumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in Pil Soo Sung the tumor microenvironment of HCC.

CAF dynamics in HCC tumor microenvironment were analyzed through single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of patients with advanced HCC treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels ( p <0.05). Single-cell analysis showed that subcluster proportions in the CAF-fibroblast activation protein-α matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of fibroblast activation protein in the CD68 + cells from patients with high serum IgA levels ( p <0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 expression levels than those in mock-treated CAFs ( p <0.05). Coculture with CAFs attenuated the cytotoxic function of activated CD8 + T cells. Interestingly, activated CD8 + T cells cocultured with IgA-treated CAFs exhibited increased programmed death-1 expression levels than those cocultured with mock-treated CAFs ( p <0.05).

Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T-cell function. Our study highlighted their potential roles in tumor progression and immune suppression.

Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients.

Liver cancer represents a substantial global health challenge, contributing significantly to worldwide morbidity and mortality. It has long been understood that tumors are not composed solely of cancerous cells, but also include a variety of normal cells within their structure. These tumor-associated normal cells encompass vascular endothelial cells, fibroblasts, and various inflammatory cells, including neutrophils, monocytes, macrophages, mast cells, eosinophils, and lymphocytes. Additionally, tumor cells engage in complex interactions with stromal cells and elements of the extracellular matrix (ECM). Initially, the components of what is now known as the tumor microenvironment (TME) were thought to be passive bystanders in the processes of tumor proliferation and local invasion. However, recent research has significantly advanced our understanding of the TME's active role in tumor growth and metastasis. Tumor progression is now known to be driven by an intricate imbalance of positive and negative regulatory signals, primarily influenced by specific growth factors produced by both inflammatory and neoplastic cells. This review article explores the latest developments and future directions in understanding how the TME modulates liver cancer, with the aim of informing the design of novel therapies that target critical components of the TME.

This study aimed to use visual mapping and bibliometric analysis to summarize valuable information on the tumor microenvironment (TME)-related research on hepatocellular carcinoma (HCC) in the past 20 years and to identify the research hotspots and trends in this field.

We screened all of the relevant literature on the TME of HCC in the Web of Science database from 2003 to 2023 and analysed the research hotspots and trends in this field via VOSviewer and CiteSpace.

A total of 2,157 English studies were collected. According to the prediction, the number of papers that were published in the past three years will be approximately 1,394, accounting for 64.63%. China published the most papers (n=1,525) and had the highest total number of citations (n=32,253). Frontiers In Immunology published the most articles on the TME of HCC (n=75), whereas, Hepatology was the journal with the highest total number of citations (n=4,104) and average number of citations (n=91). The four clusters containing keywords such as "cancer-associated fibroblasts", "hepatic stellate cells", "immune cells", "immunotherapy", "combination therapy", "landscape", "immune infiltration", and "heterogeneity" are currently hot research topics in this field. The keywords "cell death", "ferroptosis", "biomarkers", and "prognostic features" have emerged relatively recently, and these research directions are becoming increasingly popular.

We identified four key areas of focus in the study of the TME in HCC: the main components and roles in the TME, immunotherapy, combination therapy, and the microenvironmental landscape. Moreover, the result of our study indicate that effect of ferroptosis on the TME in HCC may become a future research trend.

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and -extrinsic factors during tumor progression is critical for developing new therapeutic strategies.

The journey of cancer development is a multifaceted and staged process. The array of treatments available for cancer varies significantly, dictated by the disease's type and stage. Cancer-associated fibroblasts (CAFs), prevalent across various cancer types and stages, play a pivotal role in tumor genesis, progression, metastasis, and drug resistance. The strategy of concurrently targeting cancer cells and CAFs holds great promise in cancer therapy. In this review, we focus intently on CAFs, delving into their critical role in cancer's progression. We begin by exploring the origins, classification, and surface markers of CAFs. Following this, we emphasize the key cytokines and signaling pathways involved in the interplay between cancer cells and CAFs and their influence on the tumor immune microenvironment. Additionally, we examine current therapeutic approaches targeting CAFs. This article underscores the multifarious roles of CAFs within the tumor microenvironment and their potential applications in cancer treatment, highlighting their importance as key targets in overcoming drug resistance and enhancing the efficacy of tumor therapies.

Hepatocellular carcinoma (HCC) is the most common liver cancer as well as the most prevalent cause of death in the adult patient population with cirrhosis. The occurrence of HCC is primarily caused by chronic liver inflammation that might occur because of a viral infection, non-alcoholic fatty liver disease (NAFLD), or various lifestyle-associated factors. The objective of this review was to summarize the current knowledge regarding the microenvironment of HCC, indicating how immune- and non-immune-cell stroma might affect the onset and progression of HCC. Therefore, in the following narrative review, we described the role of tumor-infiltrating neutrophils, bone-marrow-derived cells, tumor-associated mast cells, cancer-associated fibroblasts, tumor-associated macrophages, liver-sinusoidal endothelial cells, lymphocytes, and certain cytokines in liver inflammation and the further progression to HCC. A better understanding of the HCC microenvironment might be crucial to introducing novel treatment strategies or combined therapies that could lead to more effective clinical outcomes.

Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer. The primary treatment strategies for HCC currently include liver transplantation and surgical resection. However, these methods often yield unsatisfactory outcomes, leading to a poor prognosis for many patients. This underscores the urgent need to identify and evaluate novel therapeutic targets that can improve the prognosis and survival rate of HCC patients.

To construct a radiomics model that can accurately predict the EZH2 expression in HCC.

Gene expression, clinical parameters, HCC-related radiomics, and fibroblast-related genes were acquired from public databases. A gene model was developed, and its clinical efficacy was assessed statistically. Drug sensitivity analysis was conducted with identified hub genes. Radiomics features were extracted and machine learning algorithms were employed to generate a radiomics model related to the hub genes. A nomogram was used to illustrate the prognostic significance of the computed Radscore and the hub genes in the context of HCC patient outcomes.

EZH2 and NRAS were independent predictors for prognosis of HCC and were utilized to construct a predictive gene model. This model demonstrated robust performance in diagnosing HCC and predicted an unfavorable prognosis. A negative correlation was observed between EZH2 expression and drug sensitivity. Elevated EZH2 expression was linked to poorer prognosis, and its diagnostic value in HCC surpassed that of the risk model. A radiomics model, developed using a logistic algorithm, also showed superior efficiency in predicting EZH2 expression. The Radscore was higher in the group with high EZH2 expression. A nomogram was constructed to visually demonstrate the significant roles of the radiomics model and EZH2 expression in predicting the overall survival of HCC patients.

EZH2 plays significant roles in diagnosing HCC and therapeutic efficacy. A radiomics model, developed using a logistic algorithm, efficiently predicted EZH2 expression and exhibited strong correlation with HCC prognosis.

Hepatocellular carcinoma (HCC) is one of the most common primary neoplasms of the liver and one of the most common solid tumors in the world. Its global incidence is increasing and it has become the third leading cause of cancer-related deaths. There is growing evidence that chemokines play an important role in the tumor microenvironment, regulating the migration and localization of immune cells in tissues and are critical for the function of the immune system. This review comprehensively analyses the expression and activity of chemokines in the TME of HCC and describes their interrelationship with hepatocarcinogenesis and progression. Special attention is given to the role of chemokine-chemokine receptors in the regulation of immune cell accumulation in the TME. Therapeutic strategies targeting tumor-promoting chemokines or the induction/release of beneficial chemokines are reviewed, highlighting the potential value of natural products in modulating chemokines and their receptors in the treatment of HCC. The in-depth discussion in this paper provides a theoretical basis for the treatment of HCC. It is an important reference for new drug development and clinical research.

Background: Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. Methods: A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. Results: Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). FAP + fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The DAB2 + and SPP1 + tumor-associated macrophages (TAMs) reinforce the function of FAP + CAFs through signals such as TGF-β, PDGF, and ADM. Notably, the interaction between DAB2 + TAMs and FAP + CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. Conclusions: The interaction between DAB2 + TAMs and FAP + CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of FAP + CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.

3D hydrogel-based cell cultures provide models for studying cell behavior and can efficiently replicate the physiologic environment. Hydrogels can be tailored to mimic mechanical and biochemical properties of specific tissues and allow to produce gel-in-gel models. In this system, microspheres encapsulating cells are embedded in an outer hydrogel matrix, where cells are able to migrate. To enhance the efficiency of such studies, a lab-on-a-chip named 3D cell migration-chip (3DCM-chip) is designed, which offers substantial advantages over traditional methods. 3DCM-chip facilitates the analysis of biochemical and physical stimuli effects on cell migration/invasion in different cell types, including stem, normal, and tumor cells. 3DCM-chip provides a smart platform for developing more complex cell co-cultures systems. Herein the impact of human fibroblasts on MDA-MB 231 breast cancer cells' invasiveness is investigated. Moreover, how the presence of different cellular lines, including mesenchymal stem cells, normal human dermal fibroblasts, and human umbilical vein endothelial cells, affects the invasive behavior of cancer cells is investigated using 3DCM-chip. Therefore, predictive tumoroid models with a more complex network of interactions between cells and microenvironment are here produced. 3DCM-chip moves closer to the creation of in vitro systems that can potentially replicate key aspects of the physiological tumor microenvironment.

To explore the effect and mechanism of relaxin (RLX) in the growth and metastasis of livercancer after combination treatment with transarterial chemoembolization (TACE).

HCCLM3 and Huh-7 cells were adopted to evaluate the effect of tumor proliferation, migration, and invasion after RLX administration in vitro. The rabbit VX2 model was used to evaluate the biosafety, doxorubicin penetration, local tumor response, tumor metastasis, and survival benefit of RLX combined with TACE treatment.

RLX did not affect the proliferation, migration, or invasion of HCCLM3 and Huh-7 cells, and the expression of E-cadherin and HIF-1α also remained unchanged while the MMP-9 protein was upregulated in vitro. In the rabbit VX2 model, compared to the normal saline group (NS), RLX group (RLX) and TACE mono-therapy group (TACE), the group that received TACE combined with RLX (TACE + RLX) showed an improved local tumor response and survival benefit. Furthermore, TACE combined with RLX was found to reduce tumor metastasis. This combination therapy reduced the fibrotic extracellular matrix in the tumor microenvironment, allowing for better penetration of doxorubicin, improved infiltration of CD8+ T cells and affected the secretion of cytokines. Additionally, RLX combined with TACE was able to decrease the expression of HIF-1α and PD-L1. The biosafety of TACE combined with RLX was also confirmed.

RLX synergized with TACE by mitigating the fibrotic extracellular matrix and tumor hypoxic microenvironment, improving the therapeutic effect and inhibiting metastasis during the treatment of liver cancer.

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population recognized as a key component of the tumour microenvironment (TME). Cancer-associated fibroblasts are known to play an important role in maintaining and remodelling the extracellular matrix (ECM) in the tumour stroma, supporting cancer progression and inhibiting the immune system's response against cancer cells. This review aims to summarize the immunomodulatory roles of CAFs, particularly focussing on their T-cell suppressive effects. Cancer-associated fibroblasts have several ways by which they can affect the tumour's immune microenvironment (TIME). For example, their interactions with macrophages and dendritic cells (DCs) create an immunosuppressive milieu that can indirectly affect T-cell anticancer immunity and enable immune evasion. In addition, a number of recent studies have confirmed CAF-mediated direct suppressive effects on T-cell anticancer capacity through ECM remodelling, promoting the expression of immune checkpoints, cytokine secretion and the release of extracellular vesicles. The consequential impact of CAFs on T-cell function is then reflected in affecting T-cell proliferation and apoptosis, migration and infiltration, differentiation and exhaustion. Emerging evidence highlights the existence of specific CAF subsets with distinct capabilities to modulate the immune landscape of TME in various cancers, suggesting the possibility of their exploitation as possible prognostic biomarkers and therapeutic targets.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressed version of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by inflammation and fibrosis, but also a pathophysiological "hub" that favors the emergence of liver malignancies. Current research efforts aim to identify risk factors, discover disease biomarkers, and aid patient stratification in the context of MASH-induced hepatocellular carcinoma (HCC), the most prevalent cancer among MASLD patients. To investigate the tumorigenic transition in MASH-induced HCC, researchers predominantly exploit preclinical animal-based MASH models and studies based on archived human biopsies and clinical trials. Recapitulating the immune response during tumor development and progression is vital to obtain mechanistic insights into MASH-induced HCC. Notably, the advanced complexity behind MASLD and MASH pathogenesis shifted the research focus towards innate immunity, a fundamental element of the hepatic immune niche that is usually altered robustly in the course of liver disease. During the last few years, however, there has been an increasing interest for deciphering the role of adaptive immunity in MASH-induced HCC, particularly regarding the functions of the various T cell populations. To effectively understand the specific role of T cells in MASH-induced HCC development, scientists should urgently fill the current knowledge gaps in this field. Pinpointing the metabolic signature, sketching the immune landscape, and characterizing the cellular interactions and dynamics of the specific T cells within the MASH-HCC liver are essential to unravel the mechanisms that adaptive immunity exploits to enable the emergence and progression of this cancer. To this end, our review aims to summarize the current state of research regarding the T cell functions linked to MASH-induced HCC.

A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Identifying the molecular underpinnings for such multidirectional crosstalk among the various normal and neoplastic cell types in the TME may provide new targets and novel opportunities for therapeutic intervention. This review highlights recent concepts regarding the complexity of CAF biology in cholangiocarcinoma, a highly desmoplastic cancer. The discussion focuses on CAF heterogeneity, functionality in drug resistance, contributions to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.

Esophageal squamous cell carcinoma (ESCC) is a prevalent and highly lethal malignant disease. The epithelial-mesenchymal transition (EMT) is crucial in promoting ESCC development. However, the molecular heterogeneity of ESCC and the potential inhibitory strategies targeting EMT remain poorly understood. In this study, we analyzed high-resolution single-cell transcriptome data encompassing 209,231 ESCC cells from 39 tumor samples and 16 adjacent samples obtained from 44 individuals. We identified distinct cell populations exhibiting heterogeneous EMT characteristics and identified 87 EMT-associated molecules. The expression profiles of these EMT-associated molecules showed heterogeneity across different stages of ESCC progression. Moreover, we observed that EMT primarily occurred in early-stage tumors, before lymph node metastasis, and significantly promoted the rapid deterioration of ESCC. Notably, we identified SERPINH1 as a potential novel marker for ESCC EMT. By classifying ESCC patients based on EMT gene sets, we found that those with high EMT exhibited poorer prognosis. Furthermore, we predicted and experimentally validated drugs targeting ESCC EMT, including dactolisib, docetaxel, and nutlin, which demonstrated efficacy in inhibiting EMT and metastasis in ESCC. Through the integration of scRNA-seq, RNA-seq, and TCGA data with experimental validation, our comprehensive analysis elucidated the landscape of EMT during the entire course of ESCC development and metastasis. These findings provide valuable insights and a reference for refining ESCC clinical treatment strategies.

This study aims to identify the cancer-associated fibroblasts (CAF)-related genes that can affect immunotherapy and drug sensitivity in hepatocellular carcinoma (HCC). Expression data and survival data associated with HCC were obtained in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted correlation network analysis (WGCNA) analysis was performed to obtain CAF-related genes. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for regression analysis and risk models. Subsequently, Gene Set Enrichment Analysis (GSEA) analysis, Gene Set Enrichment Analysis (ssGSEA) analysis, Tumor Immune Dysfunction and Exclusion (TIDE) analysis and drug sensitivity analysis were performed on the risk models. Survival analysis of CAF scores showed that the survival rate was lower in samples with high CAF scores than those with low scores. However, this difference was not significant, suggesting CAF may not directly influence the prognosis of HCC patients. Further screening of CAF-related genes yielded 33 CAF-related genes. Seven risk models constructed based on CDR2L, SPRED1, PFKP, ENG, KLF2, FSCN1 and VCAN, showed significant differences in immunotherapy and partial drug sensitivity in HCC. Seven CAF-related genes may have important roles in immunotherapy, drug sensitivity and prognostic survival in HCC patients.