Gliomas are the most prevalent primary malignant brain tumors worldwide, with glioblastoma (GBM) being the most common and aggressive type. Despite two decades of relentless pursuit in exploring novel therapeutic approaches for GBM, there is limited progress in improving patients’ survival outcomes. Numerous obstacles impede the effective treatment of GBM, including the immunosuppressive tumor microenvironment (TME), the blood-brain barrier, and extensive heterogeneity. Despite these challenges, immunotherapies are emerging as a promising avenue that may offer new hope for the treatment of gliomas. There are four main types of immunotherapies for gliomas, immune checkpoint blockades, chimeric antigen receptor T-cell therapies, vaccines, and oncolytic viruses. In addition, gene therapy, bispecific antibody therapy, and combine therapy are also briefly introduced in this review. The significant role of TME in the process of immunotherapies has been emphasized in many studies. Although immunotherapy is a promising treatment for gliomas, enormous effort is required to overcome the existing barriers to its success. Owing to the rapid development and increasing attention paid to immunotherapies for gliomas, this article aims to review the recent advances in immunotherapies for gliomas.

Dysregulation of the insulin-like growth factor type I receptor (IGF1R) has been implicated in the progression and therapeutic resistance of malignancies. In acute myeloid leukemia (AML) cells, IGF1R is one of the most abundantly phosphorylated receptor tyrosine kinases, promoting cell growth through the PI3K/Akt signaling pathway. However, little is known regarding the molecular mechanisms underlying IGF1R gene dysregulation in cancer. We discovered a novel intragenic long noncoding RNA (lncRNA) within the IGF1R locus, named IRAIN, which is transcribed in an antisense direction from an intronic promoter. The IRAIN lncRNA was expressed exclusively from the paternal allele, with the maternal counterpart being silenced. Using both reverse transcription-associated trap and chromatin conformation capture assays, we demonstrate that this lncRNA interacts with chromatin DNA and is involved in the formation of an intrachromosomal enhancer/promoter loop. Knockdown of IRAIN lncRNA with shRNA abolishes this intrachromosomal interaction. In addition, IRAIN was downregulated both in leukemia cell lines and in blood obtained from high-risk AML patients. These data identify IRAIN as a new imprinted lncRNA that is involved in long-range DNA interactions.

Kcnq1ot1 is a long noncoding ribonucleic acid (RNA; lncRNA) that participates in the regulation of genes within the Kcnq1 imprinting domain. Using a novel RNA-guided chromatin conformation capture method, we demonstrate that the 5′ region of Kcnq1ot1 RNA orchestrates a long-range intrachromosomal loop between KvDMR1 and the Kcnq1 promoter that is required for maintenance of imprinting. PRC2 (polycomb repressive complex 2), which participates in the allelic repression of Kcnq1, is also recruited by Kcnq1ot1 RNA via EZH2. Targeted suppression of Kcnq1ot1 lncRNA prevents the creation of this long-range intrachromosomal loop and causes loss of Kcnq1 imprinting. These observations delineate a novel mechanism by which an lncRNA directly builds an intrachromosomal interaction complex to establish allele-specific transcriptional gene silencing over a large chromosomal domain.

RUNX1, a master regulator of hematopoiesis, is the most commonly perturbed target of chromosomal abnormalities in hematopoietic malignancies. The t(8;21) translocation is found in 30–40% of cases of acute myeloid leukemia (AML). Recent whole-exome sequencing also reveals mutations and deletions of RUNX1 in some solid tumors. We describe a RUNX1-intragenic long noncoding RNA RUNXOR that is transcribed as unspliced transcript from an upstream overlapping promoter. RUNXOR was upregulated in AML samples and in response to Ara-C treatment in vitro. RUNXOR utilizes its 3′-terminal fragment to directly interact with the RUNX1 promoter and enhancers and participates in the orchestration of an intrachromosomal loop. The 3′ region of RUNXOR also participates in long-range interchromosomal interactions with chromatin regions that are involved in multiple RUNX1 translocations. These data suggest that RUNXOR noncoding RNA may function as a previously unidentified candidate component that is involved in chromosomal translocation in hematopoietic malignancies.

The CRISPR-associated Cas9 system can modulate disease-causing alleles both in vivo and ex vivo, raising the possibility of therapeutic genome editing. In addition to gene targeting, epigenetic modulation by the catalytically inactive dCas9 may also be a potential form of cancer therapy. Granulin (GRN), a potent pluripotent mitogen and growth factor that promotes cancer progression by maintaining self-renewal of hepatic stem cancer cells, is upregulated in hepatoma tissues and is associated with decreased tumor survival in patients with hepatoma. We synthesized a group of dCas9 epi-suppressors to target GRN by tethering the C terminus of dCas9 with three epigenetic suppressor genes: DNMT3a (DNA methyltransferase), EZH2 (histone 3 lysine 27 methyltransferase), and KRAB (the Krüppel-associated box transcriptional repression domain). In conjunction with guide RNAs (gRNAs), the dCas9 epi-suppressors caused significant decreases in GRN mRNA abundance in Hep3B hepatoma cells. These dCas9 epi-suppressors initiated de novo CpG DNA methylation in the GRN promoter, and they produced histone codes that favor gene suppression, including decreased H3K4 methylation, increased H3K9 methylation, and enhanced HP1a binding. Epigenetic knockdown of GRN led to the inhibition of cell proliferation, decreased tumor sphere formation, and reduced cell invasion. These changes were achieved at least partially through the MMP/TIMP pathway. This study thus demonstrates the potential utility of using dCas9 epi-suppressors in the development of epigenetic targeting against tumors.

Background: Hepatocellular carcinoma (HCC), recognized as a significant global health concern, ranks as the sixth most prevalent form of cancer and is the third leading cause of cancer-associated mortality. Over half of HCC patients are diagnosed at advanced stages, an unfortunate phenomenon primarily attributed to the liver’s robust compensatory mechanisms. Given the limited availability of donor livers, existing clinical surgical approaches have yet to provide universally applicable treatment strategies offering substantial prognostic improvement for late-stage cancer. Although the past few decades have witnessed significant advancements in chemotherapy and targeted therapy for HCC, the emergence of drug resistance poses a substantial impediment to their successful execution. Furthermore, issues such as diminished quality of life post-treatment and high treatment costs warrant critical attention. Consequently, the imperative for an effective treatment strategy for advanced liver cancer is unequivocal. In recent years, notable progress in the development and application of immunotherapy has sparked a revolution in advanced liver cancer treatment. This study aims to elucidate a more comprehensive understanding of the current landscape, knowledge framework, research focal points, and nascent breakthrough trends in the domain of immunotherapy for hepatocellular carcinoma via bibliometric analysis.Method: Our study involved conducting a comprehensive literature search spanning from 1999 through December 31, 2022, by utilizing the Science Citation Index Expanded (SCI-Expanded) database. Our aim was to amass all the papers and reviews related to immunotherapy for hepatocellular carcinoma. Our search strategy yielded a total of 4,486 papers. After exclusion of self-citations, we focused our analysis on 68,925 references. These references were cited 119,523 times (excluding 97,941 self-citations), boasting an average citation frequency of 26.64 times per paper, and achieved an h-index of 135. We employed analytical software tools like Citespace and VOSviewer to perform an intricate analysis of the amassed literature, covering various aspects, including geographical location, research institutions, publishing journals, authors, references, and keywords. Our method incorporated timeline analysis, burst detection, and co-occurrence analysis. The application of these tools facilitated a thorough evaluation of research hotspots, knowledge structure, and emerging advancements within the sphere of immunotherapy for hepatocellular carcinoma.Results: Our bibliometric analysis disclosed a noteworthy escalation in the number of publications in the realm of hepatocellular carcinoma immunotherapy during the years 2021-2022, surpassing the aggregate number of papers published in the preceding decade (2011–2020). This surge underscores a sharp upturn in research interest within this field. Additionally, the research hotspot in hepatocellular carcinoma immunotherapy has perceptibly deviated from the preceding decade’s trends. In terms of geographical distribution, China emerged as the leading country, producing 50.08% of the total publications. This was followed by the United States, with 963 papers, and Japan, contributing 335 papers. Among research institutions, Sun Yat-sen University was the most prolific, while Tim F. Greten stood out as the most published author with 42 papers to his credit. A co-reference network examination uncovered a shift in research emphasis within the field of hepatocellular carcinoma immunotherapy, highlighting the evolving nature of this important area of studyConclusion: Our bibliometric study highlights the significant evolution and growth in HCC immunotherapy research over the past two decades. Looking ahead, research will focus on improving the microenvironment post-drug resistance from immune combination therapy, harnessing adoptive cellular immunity (as CAR-T), subclassify the population and developing new tumor markers. Incorporation of technologies such as nanotechnology, microbiology, and gene editing will further advance HCC treatments. This progressive trajectory in the field promises a brighter future for individuals suffering from HCC.