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Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generate a single-cell atlas of the multicellular ecosystem of HCC from four tissue sites. We show the enrichment of central memory T cells (T CM ) in the early tertiary lymphoid structures (E-TLSs) in HCC and assess the relationships between chronic HBV/HCV infection and T cell infiltration and exhaustion. We find the MMP9 + macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and PPARγ to be the pivotal transcription factor driving their differentiation. We also characterize the heterogeneous subpopulations of malignant hepatocytes and their multifaceted functions in shaping the immune microenvironment of HCC. Finally, we identify seven microenvironment-based subtypes that can predict prognosis of HCC patients. Collectively, this large-scale atlas deepens our understanding of the HCC microenvironment, which might facilitate the development of new immune therapy strategies for this malignancy. The immune cell constituents and localisation within human hepatocellular carcinoma is not fully understood. Here the authors use single cell RNA sequencing of HCC from four different tissue sites and show differences between primary and metastatic tumours, tumour associated macrophages and immune cell populations.

Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.Immunotherapy is revolutionizing the treatment of many cancers and hepatocellular carcinoma (HCC) is no exception. This Review describes the heterogeneous immune microenvironments of HCC as well as their links with the various aetiologies underlying this malignancy and with response or resistance to immunotherapies. In addition, the authors provide an overview of the current landscape of clinical trials evaluating immunotherapies across all stages of HCC.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal causes of cancer-related death worldwide. The treatment of HCC remains challenging and is largely predicated on early diagnosis. Surveillance of high-risk groups using abdominal ultrasonography, with or without serum analysis of α-fetoprotein (AFP), can permit detection of early, potentially curable tumours, but is limited by its insensitivity. Reviewed here are two current approaches that aim to address this limitation. The first is to use old re-emerged empirically derived biomarkers such as AFP, now applied within statistical models. The second is to use circulating nucleic acid biomarkers, which include cell-free DNA (for example, circulating tumour DNA, cell-free mitochondrial DNA and cell-free viral DNA) and cell-free RNA, applying modern molecular biology-based technologies and machine learning techniques closely allied to the underlying biology of cancer. Taken together, these approaches are likely to be complementary. Both hold considerable promise for achieving earlier diagnosis as well as offering additional functionalities including improved monitoring of therapy and prediction of response thereto.Surveillance of hepatocellular carcinoma (HCC), one of the most lethal solid cancers globally, is insensitive for the detection of early-stage tumours. In this Review, the authors discuss HCC biomarkers that can improve early diagnosis, therapy monitoring and prediction of therapy response.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Surveillance for HCC is critical for early detection and treatment, but fewer than one-quarter of individuals at risk of HCC undergo surveillance. Multiple failures across the screening process contribute to the underutilization of surveillance, including limited disease awareness among patients and health-care providers, knowledge gaps, and difficulty recognizing patients who are at risk. Non-alcoholic fatty liver disease and alcohol-associated liver disease are the fastest-rising causes of HCC-related death worldwide and are associated with unique barriers to surveillance. In particular, more than one-third of patients with HCC related to non-alcoholic fatty liver disease do not have cirrhosis and therefore lack a routine indication for HCC surveillance on the basis of current practice guidelines. Semi-annual abdominal ultrasound with measurement of α-fetoprotein levels is recommended for HCC surveillance, but the sensitivity of this approach for early HCC is limited, especially for patients with cirrhosis or obesity. In this Review, we discuss the current status of HCC surveillance and the remaining challenges, including the changing aetiology of liver disease. We also discuss strategies to improve the utilization and quality of surveillance for HCC.In this Review, Huang et al. discuss the current status of hepatocellular carcinoma surveillance, the remaining challenges, including the changing aetiology of liver disease, and strategies to improve the utilization and quality of surveillance.

Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5′-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy. Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape. Here, the authors show that in hepatocellular carcinoma, hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5′-AMP, which in turn promote the maintenance of MDSCs by preventing their differentiation.

Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.The complexity of hepatocellular carcinoma (HCC) hinders effective treatment. Here, Lee and colleagues summarize cancer stem cell (CSC) origin and plasticity, CSC–immune system interactions and the effects of the microenvironmental niche on cancer stemness in HCC. Potential CSC-based therapies for HCC are also presented.

Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment. Wu et al. show that, upon activation by insulin-like growth factor 1 receptor and AKT, creatine kinase B exhibits a moonlighting function as protein kinase to phosphorylate glutathione peroxidase 4 to prevent its degradation, thereby suppressing ferroptosis and enhancing tumour growth in mice.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.

Hepatocellular carcinoma is the most prevalent form of primary liver cancer with a multifactorial aetiology comprising genetic, environmental, and behavioural factors. Evading cell death is a defining hallmark of hepatocellular carcinoma, underpinning tumour growth, progression, and therapy resistance. Ferroptosis is a form of nonapoptotic cell death driven by an array of cellular events, including intracellular iron overload, free radical production, lipid peroxidation and activation of various cell death effectors, ultimately leading to rupture of the plasma membrane. Although induction of ferroptosis is an emerging strategy to suppress hepatocellular carcinoma, malignant cells manage to develop adaptive mechanisms, conferring resistance to ferroptosis and ferroptosis-inducing drugs. Herein, we aim at elucidating molecular mechanisms and signalling pathways involved in ferroptosis and offer our opinions on druggable targets and new therapeutic strategy in an attempt to restrain the growth and progression of hepatocellular carcinoma through induction of ferroptotic cell death.

Induction of tumor vascular normalization is a crucial measure to enhance immunotherapy efficacy. cGAS-STING pathway is vital for anti-tumor immunity, but its role in tumor vasculature is unclear. Herein, using preclinical liver cancer models in Cgas / Sting -deficient male mice, we report that the interdependence between tumor cGAS and host STING mediates vascular normalization and anti-tumor immune response. Mechanistically, TET2 mediated IL-2/STAT5A signaling epigenetically upregulates tumor cGAS expression and produces cGAMP. Subsequently, cGAMP is transported via LRRC8C channels to activate STING in endothelial cells, enhancing recruitment and transendothelial migration of lymphocytes. In vivo studies in male mice also reveal that administration of vitamin C, a promising anti-cancer agent, stimulates TET2 activity, induces tumor vascular normalization and enhances the efficacy of anti-PD-L1 therapy alone or in combination with IL-2. Our findings elucidate a crosstalk between tumor and vascular endothelial cells in the tumor immune microenvironment, providing strategies to enhance the efficacy of combinational immunotherapy for liver cancer. Activation of the cGAS-STING pathway has been associated with the promotion of anti-tumor immunity. Here the authors show that TET2 upregulates tumor cGAS to activate STING in endothelial cells, inducing tumor vascular normalization and enhancing efficacy of anti-PD-L1 alone or combined with IL-2 in liver cancer preclinical models.