In the phase 1/2 trial, 262 patients with advanced-stage HCC were treated with nivolumab within a dose-escalation cohort (n=48) and a dose-expansion cohort (n=214); the target response prices (ORR) had been 15% and 20%, respectively, using a 9-month success up to 66% . to ICI. Furthermore, supplementing ICIs NSC 87877 with agencies concentrating on the microenvironment could attain an elevated response rate, which really is a step of progress in accuracy treatment for HCC. Furthermore, emerging studies have got revealed that liver organ transplantation, epigenetic medications and various other novel strategies provide synergistic results with ICIs in the treating HCC also. strong course=”kwd-title” Keywords: Hepatocellular carcinoma, immune checkpoint inhibitors, resistance, combination therapy Background Rabbit polyclonal to PEX14 Liver cancer was the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide in NSC 87877 2018 . Among all liver cancer cases, hepatocellular carcinoma (HCC) constitutes 75-85%. The main risk factors for HCC have been well demonstrated, including chronic viral hepatitis, heavy alcohol intake and obesity. Due to differences in etiology and high mortality, HCC is regarded as a heterogeneous and refractory disease . Therefore, it is a focus of research to explore strategies to control HCC. Liver transplantation (LT) and hepatectomy are curative treatments for HCC, and the indications have been safely expanded [3,4]. However, some tumors are still too advanced to be cured by surgical resection and orthotopic liver transplantation at diagnosis. Therefore, it is of great importance to administer palliative treatments to achieve downstaging for surgical therapy or delay the progression of tumors. In the past few decades, cancer immunotherapy has experienced a paradigm shift from novelty to common clinical practice, and it has NSC 87877 become one of the most effective treatments and has been validated in various tumors [5,6]. In the tumor microenvironment, tumor cells interact with the host immune response to promote or inhibit tumor progression. The immune system can recognize cancer cells and kill them via the immune response. In the early stages of research, most researchers spared no efforts to enhance the antitumor immune responses directly or indirectly via effector cells, cytokines and antibodies. Cytokines are one of the most important components of the immune system and contribute to the growth, differentiation and activation of immune cells. Most cytokines are produced by immune cells, including interleukins (ILs, e.g., IL-1, IL-1, IL-2, IL-5, etc.) and other cytokines [e.g., tumor necrosis factor (TNF) and interferon (IFN)] . Several studies have revealed that an alteration in cytokine levels is correlated with carcinogenesis and progression in different tumors, including liver cancer [7,8]. T cell receptor (TCR)-engineered T cell therapy and chimeric antigen receptor (CAR) T cell therapy are two types of adoptive T cell therapy that use genetically modified T cells to treat cancers . By genetic engineering, T cells can be endowed with the capacity to react against tumors, generating an intracellular signaling cascade causing the release of cytokines and enhancement of cytotoxic activity [10,11]. However, the unsatisfactory effect and frequent immune-related adverse events of these immune enhancement strategies due to immune escape and immune suppression have been discouraging [12,13]. Since the advent of ICIs, the concept of normalizing the tumor immune microenvironment by correcting dysfunctions of the immune response has drawn attention again to immunotherapy. Immune checkpoint therapy, which is at the forefront of immunotherapy, has demonstrated clinical activity in several malignances, including HCC, although the response rate to ICIs varies in patients [14,15]. In this review, we present a description of the current state of immune checkpoint therapy for HCC and attempt to provide insight into the resistance mechanisms. However, there are still a number of unanswered questions remaining; thus, we give our suggestions carefully and raise some future possible solutions based on current research. Current state of immune checkpoint therapy-an acceptable NSC 87877 strategy for advanced HCC In the tumor microenvironment, a group of cell surface molecules, named immune checkpoints, determine T cell activation and the intensity of the immune response. They can be either stimulatory or inhibitory and participate in various stages of the T cell response . The most studied immune checkpoint molecules include cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), programmed.