Liver Cancer Immunotherapy Research Articles

Abstract 5002: The prognostic relevance and underlying mechanisms of the novel oxygen sensor ADO in cancers

Abstract Purpose: Hypoxia is widely recognized as a determiner in cancer. Cysteamine dioxygenase (ADO) is demonstrated to be a novel oxygen sensor, globally expressed in animals and plants. However, the functions of ADO in human cancers remain unclear. This study was to identify the survival association of ADO in cancers and to excavate its underlying mechanisms. Methods: Transcriptional expression profiles, clinical characteristics, single nucleotide variation (SNV) data, and 450K methylation data were downloaded from all cancer types in the cancer genome atlas (TCGA). Two independent liver cancer datasets GSE14520 and GSE36376 were downloaded for further validation. Results: The expression of ADO gene was differentially expressed in various cancers. High expression of ADO indicated a worse OS and PFS in adrenocortical carcinoma (ACC), acute myeloid leukemia, liver hepatocellular carcinoma (LIHC), while predicted better OS and PFS in brain lower-grade glioma (LGG), and kidney renal clear cell carcinoma (KIRC). Across various cancers, ADO was positively correlated with tumor-associated pathways including G2/M_checkpoint, MYC_targets, and TGFB while negatively correlated with Genes_upregulated_by_reactive_oxygen_species (ROS) through ssGSEA analysis. The expression of ADO gene was highly correlated with hypoxic marker HIF1A, HIF2A, KDM5A, and KDM6A in almost all cancer types while poorly correlated with Hallmark_hypoxia geneset and Regulation_of_cellular response_to_hypoxia geneset, which indicated that ADO might work independently with HIF1A-mediated response. ADO was positively correlated with the methylation of most chromatin regulators in LGG and LIHC. ADO expression positively correlated with most immune checkpoint molecules in most cancers. Notably, a highly positive correlation between ADO and CD276, ENTPD1, or HMGB1 was observed in most cancer types. In liver cancer, ADO was positively correlated with the infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, myeloid dendritic cells. However, ADO expression was not strongly relevant to TMB in liver cancer. The increased expression, poor survival indication and immune checkpoint correlation of ADO in liver cancer were further validated by GSE14520 and GSE36376 datasets. Conclusion: ADO was differentially expressed in various cancers and significantly associated with survival in some cancer types including liver cancer. The underlying mechanism might be associated with the G2/M checkpoint, MYC targets and TGFB pathways, and ADO-mediated HIF1A-independent hypoxic response. The immune cell infiltrates and immune checkpoints association hints that ADO might be a biomarker for immunotherapy in liver cancer. Citation Format: Jie Huang, Juan Shen, Yao Qiu, Jiannan Qian, Jiawei Li, Xueqin Chen, Shenglin Ma. The prognostic relevance and underlying mechanisms of the novel oxygen sensor ADO in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5002.

Assessing surrogacy using restricted mean survival time ratio for overall survival in liver cancer immunotherapy studies.

e16222 Background: Recently, immunotherapy has played a crucial role in treating liver cancer, one of the major cancers that contributes to global cancer burden. Overall survival (OS) is widely applied in cancer trials to evaluate the treatment effects of new therapies. However, it requires more patients and longer follow-up time comparing with progression-free survival (PFS). In addition, while assessing the treatment effects of cancer immunotherapy, proportional hazard (PH) assumption is often violated due to issues such as delayed treatment effects. Restricted Mean Survival Time (RMST) ratio is increasingly used for treatment effect evaluation when the PH assumption is violated. Such change prompts an important question whether the surrogacy value of PFS will be affected when RMST ratio is used to characterize treatment effect. The aim of this study is to examine the feasibility of using PFS as a surrogate endpoint for OS when the treatment effect is measured using hazard ratio (HR) versus RMST ratio. Methods: The surrogacy of PFS on OS was evaluated through examining the association between PFS and OS using HR and RMST ratio. Seven immunotherapy studies published between 2000 and 2021 were included (Table). Information of examined studies such as treatment arms information, OS and PFS were collected. RMST ratio for PFS and OS were calculated based on the Kaplan-Meier plots extracted from each article using WebPlotDigitizer 4.4. The weighted least square regression lines and R^2 between OS and PFS for HR and RMST ratio were calculated. Results: Among 7 immunotherapy studies, 4 gave placebos to the control arms as treatments. 2 provided Sorafenib and 1 assigned the same drug as treatment arm but with different schedule. All 7 studies had OS and PFS as the endpoints. 2 studies violated the PH assumptions. Based on the data extracted from examined articles, a moderate correlation (0.52) between PFS and OS was observed for HR while low correlation (0.10) was observed for RMST ratio. Conclusions: The R^2 values differ greatly depending on whether HR or RMST ratio was used for assessing surrogacy. Our finding may have important implications for the design of future immunotherapy liver cancer trials. For future work, increasing the number of included studies for a more comprehensive analysis is needed. Moreover, trial-level surrogacy analysis should be conducted to complement the study-level investigation.[Table: see text]

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis.

In vitro evidence of oncofetal antigen and TLR-9 agonist co-delivery by alginate nanovaccines for liver cancer immunotherapy.

Liver cancer is the most common malignant tumor and liver cancer immunotherapy has been one of the research hotspots. To induce antigen-specific antitumor immune responses against liver cancer, we developed antigen and adjuvant co-delivery nanovaccines (APPCs). Polyanionic alginate (ALG) and polycationic polyethyleneimine (PEI) were utilized to co-deliver a glypican-3 peptide antigen and an unmethylated cytosine-phosphate-guanine (CpG) adjuvant by electrostatic interactions. A cellular uptake study confirmed that APPC could promote antigen and adjuvant uptake by dendritic cells (DCs). Importantly, APPC facilitated the endosomal escape of the peptide for antigen delivery into the cytoplasm. In addition, APPC showed significant stimulation of DC maturation in vitro. APPC could also efficiently prime DCs and induce cytotoxic T lymphocyte responses in vivo. The in vitro cell viability assay and the in vivo histocompatibility showed that APPC was non-toxic within the tested concentration. This study demonstrates that the peptide antigen and the CpG adjuvant co-delivery nanovaccine have potential applications in liver cancer immunotherapy.

Highly Potent Immunotoxins Targeting the Membrane-distal N-lobe of GPC3 for Immunotherapy of Hepatocellular Carcinoma.

Glypican-3 (GPC3) has become a compelling target for immunotherapy of hepatocellular carcinoma, including antibody-drug conjugate (ADC), and ADC-like immunotoxin. To investigate the impact of epitopes on the potency of ADCs, current study generated a large panel of chicken monoclonal antibodies (mAbs) that targeted 12 different and over-lapping epitopes on GPC3. These mAbs demonstrated a very high affinity with Kd values in the range of 10-9-10-14 M, and the highest affinity (Kd value of 0.0214 pM) was 40-fold higher than the previously generated high-affinity mAb YP7 (Kd value of 0.876 nM). Additionally, these mAbs exhibited excellent thermostability with Tm values in the range of 45-82 °C. As a proof-of-concept study for ADC, we made immunotoxins (scFv fused with PE24, the 24-kDa cytotoxic domain of Pseudomonas exotoxin A) based on these mAbs, and we found that immunotoxins targeting the N-lobe of GPC3 were overall much more potent than those targeting the C-lobe and other locations. One representative N-lobe-targeting immunotoxin J80A-PE24 demonstrated 3 to 13-fold more potency than the hitherto best immunotoxin HN3-PE24 that was previously developed. J80A-PE24 could suppress tumor growth much greater than HN3-PE24 in a xenograft mouse model. Combination of J80A-PE24 with an angiogenesis inhibitor FGF401 showed additive effect, which dramatically shrank tumor growth. Our work demonstrated that, due to high affinity, excellent thermostability and potency, chicken mAbs targeting the N-lobe of GPC3 are appealing candidates to develop potent ADCs for immunotherapy of liver cancer.

Global research hotspots and trends in the field of immunotherapy for liver cancer in 2011-2020 based on CiteSpace analysis

Global research hotspots and trends in the field of immunotherapy for liver cancer in 2011-2020 based on CiteSpace analysis

Visual Analysis and Focused Areas of Immunotherapy for Liver Cancer Based on Literature Data

Visual Analysis and Focused Areas of Immunotherapy for Liver Cancer Based on Literature Data

Manipulating Liver Bile Acid Signaling by Nanodelivery of Bile Acid Receptor Modulators for Liver Cancer Immunotherapy.

Gut bacteria and their metabolites influence the immune microenvironment of liver through the gut-liver axis, thus representing emerging therapeutic targets for liver cancer therapy. However, directly manipulating gut microbiota or their metabolites is not practical in clinic since the safety concerns and the complicated mechanism of action. Considering the dysregulated bile acid profiles associated with liver cancer, here we propose a strategy that directly manipulates the primary and secondary bile acid receptors through nanoapproach as an alternative and more precise way for liver cancer therapy. We show that nanodelivery of bile acid receptor modulators elicited robust antitumor immune responses and significantly changed the immune microenvironment in the murine hepatic tumor. In addition, ex vivo stimulation on both murine and patient hepatic tumor tissues suggests the observation here may be meaningful for clinical practice. This study elucidates a novel and precise strategy for liver cancer immunotherapy.

Exploring the optimal dose of low ionizing radiation to enhance immune function: a rabbit model.

Primary liver cancer is one of the most common malignant tumors in China. Currently, immunotherapy for liver cancer is a research hotspot. Experimental studies and epidemiological investigations have confirmed the antineoplastic activity of low ionizing radiation. The aim of this study was to explore the optimal dose of low ionizing radiation to enhance immune function. Twenty-five New Zealand rabbits were randomly divided into five groups (n = 5 each): experimental group 1 (25 mGy), experimental group 2 (50 mGy), experimental group 3 (75 mGy), experimental group 4 (100 mGy), and the control group (0 mGy). VX-2 tumor tissue was injected into rabbits using a high-frequency B-ultrasound probe (3.5 MHz). Rabbits were irradiated, and on day 4 after irradiation, blood was collected from each rabbit. Blood chemistry, interleukin (IL)-4, interferon (IFN)-γ, immunoglobulin (Ig)G, and IgM levels were assessed. On day 15 after irradiation, macrophage phagocytic function was assessed. The rabbits were sacrificed, and the spleen was removed and weighed to calculate its spleen index. Each parameter was highest in the experimental group 3 (75 mGy). Thus, we suspect the optimal low ionizing radiation dose to improve immune function may be 75 mGy.

Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome.

Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.

Analysis of Clinical Trials of New Drugs for Liver Diseases in China.

BackgroundLiver diseases are a major public health concern worldwide, and the development of novel therapeutic drugs is an important research focus. But no overview has been conducted so far on the current research and development for liver-specific drugs in China, and the actual situation regarding the development and evaluation of new drugs in clinical trials.MethodsThe information of all clinical trials on liver diseases were obtained through the “Pharmaceutical Clinical Trial Registration and Information Disclosure Platform” before December 31, 2020.ResultsA total of 751 clinical trials on liver disease-related drugs were published on the above platform, including 574 chemical drugs, 128 biological products, and 49 traditional Chinese medicine (TCM)/natural drugs. The number of annual registrations has increased on an annual basis. The main indications for these clinical trials are viral hepatitis, liver malignancies, liver abscess, liver transplantation, congenital liver metabolic disease, and other hepatitis-related diseases. Hepatitis B, hepatitis C and liver cancer accounted for 72.4% of the total clinical trials, and the majority are related to generic drug research. There are 103 innovative drugs currently in clinical testing, mainly for hepatitis B, hepatitis C and hepatocellular carcinoma.ConclusionThe stronger macro-control is required for the clinical trials conducted in China, and it is necessary to identify new therapeutic targets and develop novel drugs for the key liver diseases, as well as preventive hepatitis C vaccines, and targeted therapy, TCM/natural drugs and immunotherapy for liver cancer.

TGF-β1 Induces Immune Escape by Enhancing PD-1 and CTLA-4 Expression on T Lymphocytes in Hepatocellular Carcinoma.

Primary liver cancer (PLC) is one of the most common types of cancer worldwide. Hepatocellular carcinoma (HCC) accounts for approximately 90% of PLC cases. The HCC microenvironment plays an important role in the occurrence and development of HCC. Immunotherapy for the HCC microenvironment has become an effective treatment strategy. T lymphocytes are an important part of the HCC microenvironment, and programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are the main immunosuppressive molecules of T lymphocytes. Transforming growth factor β1 (TGF-β1) can inhibit the immune function of T lymphocytes and promote the occurrence and development of tumors. However, few studies have explored whether TGF-β1 can upregulate the expression of PD-1 and CTLA-4 on T cells. In this study, we showed that TGF-β1 upregulated the expression of PD-1 and CTLA-4 on T lymphocytes and attenuated the cytotoxicity of T lymphocytes for HCC cells in vitro and in vivo. In addition, TGF-β1 increased the apoptosis of T lymphocytes induced by HCC cells. Finally, we found that the mechanism by which TGF-β1 upregulates the expression of PD-1 and CTLA-4 on T lymphocytes may be related to the calcineurin-nuclear factor of activated T cells 1 (CaN/NFATc1) pathway. This study will provide some experimental basis for liver cancer immunotherapy based on the tumor microenvironment.

The Roles of circRNAs in Liver Cancer Immunity.

Circular RNAs (circRNAs) are stable covalently closed non-coding RNAs (ncRNAs). Many studies indicate that circRNAs are involved in the pathological and physiological processes of liver cancer. However, the functions of circRNAs in liver cancer immunity are less known. In this review, we summarized the functions of circRNAs in liver cancer, including proliferative, metastasis and apoptosis, liver cancer stemness, cell cycle, immune evasion, glycolysis, angiogenesis, drug resistance/sensitizer, and senescence. Immune escape is considered to be one of the hallmarks of cancer development, and circRNA participates in the immune escape of liver cancer cells by regulating natural killer (NK) cell function. CircRNAs may provide new ideas for immunotherapy in liver cancer.

Liver cancer immunotherapy in the context of precision medicine

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Currently, hepatectomy, radiofrequency ablation, interventional therapy, and so on are widely used in the treatment of liver cancer; however the 5-year survival rate of patients is still very poor. The onset of liver cancer is insidious, and most patients do not have the opportunity to undergo surgery when they are initially diagnosed. In addition, patients with advanced liver cancer lack effective treatment, which is mainly due to chronic inflammation of the liver. Immunotherapy has great potential advantages in the treatment of liver cancer, so it has attracted more and more researchers' attention. Importantly, with the development of biomedical science into the era of precision medicine, more precise and effective immunotherapy strategies for HCC treatment have been explored, thus bringing new hope to HCC patients. This article reviews the research status and progress of liver cancer immunotherapy in the context of precision medicine.

Improving the Efficacy of Liver Cancer Immunotherapy: The Power of Combined Preclinical and Clinical Studies

Hepatocellular carcinoma (HCC) is a most deadly malignant disease worldwide, with no effective mechanism-based therapy available. Therefore, following the "miracle" outcomes seen in a few patients at the advanced stages of melanoma or lung cancer, the immune checkpoint inhibitors (ICIs) immediately entered clinical trials for advanced HCC patients without pre-clinical studies. Emerging data of clinical studies showed manageable toxicity and safety but limited therapeutic benefit to HCC patients, suggesting low response rate. Thus, one urgent issue is how to convert the liver tumors from cold to hot and responsive, which may rely on in-depth mechanistic studies in animal models and large scale data analysis in human patients. One ongoing approach is to design combinatorial treatment of different ICIs with other reagents and modalities. Indeed, a phase 3 clinical trial showed that combination of atezolizumab and bevacizumab achieved better overall and progression-free survival rates than sorafenib in unresectable HCC. This review highlights the value of animal models and the power of combining pre-clinical and clinical studies in efforts to improve HCC immunotherapy.

Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy

Primary bile acids were reported to augment secretion of chemokine (C‒X‒C motif) ligand 16 (CXCL16) from liver sinusoidal endothelial cells (LSECs) and trigger natural killer T (NKT) cell-based immunotherapy for liver cancer. However, abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control. Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation, we proposed a strategy using nanoemulsion-loaded obeticholic acid (OCA), a clinically approved selective farnesoid X receptor (FXR) agonist, for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy. The OCA-nanoemulsion (OCA-NE) was prepared via ultrasonic emulsification method, with a diameter of 184 nm and good stability. In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells. As a result, OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model, which performed much better than oral medication of free OCA. Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-γ, as well as increased NKT cell populations inside the tumor. Overall, our research provides a new evidence for the antitumor effect of receptors for primary bile acids, and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy

Translational Considerations to Improve Response and Overcome Therapy Resistance in Immunotherapy for Hepatocellular Carcinoma.

Simple SummaryImmunotherapeutic approaches became a promising treatment option and an intensive field of research in liver cancer. Despite promising results in preclinical studies, only moderate response rates have been reported in phase III clinical trials and predictive biomarkers are still missing. Therefore, translational considerations are important to overcome resistance to immunotherapy. This article reviews potential predictors for response to immunotherapy in hepatocellular carcinoma (HCC) as well as potential mechanisms for therapy resistance. Further, we will discuss translational considerations to overcome therapy resistance in HCC and improve overall response rates.Over the last decade, progress in systemic therapies significantly improved the outcome of primary liver cancer. More recently, precision oncological and immunotherapeutic approaches became the focus of intense scientific and clinical research. Herein, preclinical studies showed promising results with high response rates and improvement of overall survival. However, results of phase III clinical trials revealed that only a subfraction of hepatocellular carcinoma (HCC) patients respond to therapy and display only moderate objective response rates. Further, predictive molecular characteristics are largely missing. In consequence, suitable trial design has emerged as a crucial factor for the success of a novel compound. In addition, increasing knowledge from translational studies indicate the importance of targeting the tumor immune environment to overcome resistance to immunotherapy. Thus, combination of different immunotherapies with other treatment modalities including antibodies, tyrosine kinase inhibitors, or local therapies is highly promising. However, the mechanisms of failure to respond to immunotherapy in liver cancer are still not fully understood and the modulation of the immune system and cellular tumor composition is particularly relevant in this context. Altogether, it is increasingly clear that tailoring of immunotherapy and individualized approaches are required to improve efficacy and patient outcome in liver cancer. This review provides an overview of the current knowledge as well as translational considerations to overcome therapy resistance in immunotherapy of primary liver cancer.

Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy?

Background The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. Purpose To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. Materials and Methods A total of 21 VX2 liver tumor-bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A (n = 3) underwent intra-arterial infusion of gadolinium 160 (160Gd)-labeled anti-human leukocyte antigen-DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B (n = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C (n = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH-buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney U and Kruskal-Wallis tests. Results T1-weighted MRI with 160Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH-specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) (P = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; P = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration (P = .002). Conclusion MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer. © RSNA, 2020 Online supplemental material is available for this article.

Advances in the study of cellular immunotherapy for liver cancer

Liver cancer is one of the most common malignant tumors and currently ranks the fourth in morbidity rate and the second in mortality rate in China. At present, the main clinical treatmentmethod is surgical treatment and other treatments, such as interventional therapy, local radiotherapy and chemotherapy, serve as supplementary treatment methods. However, due to the occult incidence of liver cancer, most patients have entered the advanced stage at the time of diagnosis and lack effective treatment methods, resulting in low overall survival rate, high mortality rate and poor prognosis. Immunotherapy, especially cellular immunotherapy, as an emerging cancer treatment method, can directly kill tumor cells or stimulate the anti-tumor immune response by isolating and activating immune effector cells. Common methods include chimeric antigen receptor T cells, tumor-infiltrating lymphocytes and cytokine-induced killer cells, etc. Recently, cellular immunotherapy has become a research hotspot because it can enhance the immune function, reduce the recurrence rate and prolong the survival time of patients. This article reviews the advances in the study of cellular immunotherapy in the clinical application of liver cancer.

Research progress of immunotherapy alone and in combination for liver cancer

Presently, the incidence of hepatocellular carcinoma (HCC) ranks fourth among common malignant tumors in China, and the mortality rate ranks second. The preferred method of clinical treatment for HCC is early surgical resection at this time, but most patients have reached to mid-advanced stage at the time of diagnosis, so surgery cannot be performed. Traditional radiotherapy and chemotherapy have poor prognosis and many adverse reactions, which make the current clinical treatment of HCC in China full of challenges. Therefore, new treatment strategies are urgently needed to improve the quality of life of liver cancer patients. With the advancement of modern medicine, the treatment of liver cancer is no longer limited to traditional treatments. Immunotherapy as a new treatment has become an important treatment for liver cancer. In recent years, immunotherapy and new targeted drugs for liver cancer have become a research hotspot, and many achievements have been made in the treatment of liver cancer. In this paper, the current situation and progress of single or combined immunotherapy for liver cancer of recent years are briefly reviewed.