Background: Germline alleles near genes encoding certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetics. Methods: Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. Results: Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with p < 5 × 10-8 associated with at least one of the cancer types at p < 10-3 and one of the autoimmune/autoinflammatory diseases at p < 10-3. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping led variants to nearest genes as putative functional targets and focusing on immune-related genes implicated 32 genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (IRF1, IKZF1, SPI1, SH2B3, LAT) was each strongly correlated (Spearman's ρ > 0.5) with at least one intra-tumor T/myeloid cell infiltration marker (CD4, CD8A, CD11B, CD45) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via the expression of quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable. Conclusions: We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3 and LAT as possible targets for cancer immunotherapy.

Precision treatment of gastric cancer requires specific biomarkers, and CLDN18.2 emerges as a promising target for patients' stratification and therapeutic guidance. In 563 cases, 54.4% of patients are identified as CLDN18.2-positive, with CLDN18.2 expression negatively correlated with immune-related factors like PD-L1, indicating a "cold" tumor microenvironment. Here, a novel CLDN18.2 monoclonal antibody 1D5 is created with superior high specificity and affinity, and the antibody-dependent fluorescence-magnetic nanoparticle is developed for specific detection and magnetic hyperthermia (MHT). Under the assistance of sensitive fluorescence and deep-penetrating magnetic particle imaging for tracing and timing the optimal nanoparticle dosage, MHT induces robust immunogenic response via DNA mismatch repair and tumor-associated antigen release. It recruits CD11c+ dendritic cells, compensates PD-1 in CD8+ T cells, and enhances CD86+ macrophage polarization. The combination of anti-PD-1 therapy increased TNF-α and IFN-γ secretion and further boosted the cytotoxic efficacy of CD8+ T cells. Excellent therapeutic efficacy is found simultaneously on cell-derived allografts and patient-derived xenografts based on this spatiotemporally manipulated strategy, presenting a therapeutic option for enhancing responsiveness to immunotherapy for CLDN18.2-positive individuals.

Decades of research have defined the function of interferon regulatory factors (IRFs) in the antiviral immune response. Interferon regulatory factor-1 (IRF-1) is the founding member of the IRF family, with recognized antiviral effects across diverse virus infections. While most antiviral activities of IRF-1 were defined in vitro, fewer studies examined the role of IRF-1 during viral infection of an intact host. Taking advantage of mouse models of global or cell type-specific IRF-1 deficiency, recent studies demonstrate intriguing virus- and cell type-specific functions of IRF-1 during in vivo infection, underlining the complexity of this ancient transcription factor. Here, we review the role of IRF-1 during acute and chronic viral infections of an intact host, with particular focus on relating observations found in mouse models to those observed in a recent study of pediatric patients with IRF-1 insufficiency. By appreciating the complexity of IRF-1 in the immune response, we highlight several virus- and cell type-specific functions of IRF-1 in contributing to host antiviral immunity.

Hepatocellular carcinoma (HCC) is an inflammation-associated tumor with a dismal prognosis. Immunotherapy has become an important treatment strategy for HCC, as immunity is closely related to inflammation in the tumor microenvironment. Inflammation regulates the expression of programmed death ligand-1 (PD-L1) in the immunosuppressive tumor microenvironment and affects immunotherapy efficacy. Interleukin-17A (IL-17A) is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors. We hypothesized that IL-17A participates in tumor progression by affecting the level of immune checkpoint molecules in HCC.

To investigate the effect and mechanism of action of IL-17A on PD-L1 expression and to identify attractive candidates for the treatment of HCC.

The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR, western blotting, and flow cytometry. Mechanistic studies were conducted with gene knockout models and pathway inhibitors. The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells. The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro, and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.

IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner, whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A. IL-17A enhanced the survival of HCC cells in the coculture system. IL-17A increased the viability, G2/M ratio, and migration of HCC cells and decreased the apoptotic index. Cyclin D1, VEGF, MMP9, and Bcl-1 expression increased after IL-17A treatment, whereas BAX expression decreased. The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8 + T lymphocyte infiltration in an HCC mouse model.

IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 signaling pathway in HCC cells. Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.

Unlike other mammals, bats serve as natural reservoirs for several highly pathogenic viruses without exhibiting symptoms of infection. Recent research has explored the complex mechanisms underlying the balance between bats' antiviral defenses and their pathological responses. However, the evolution of the molecular drivers behind bats' antiviral strategies remains largely unknown. Interferon regulatory factors (IRFs) are essential transcription factors that bind to DNA and regulate the expression of numerous genes involved in antiviral defense, inflammation, immune cell differentiation, apoptosis, and oncogenesis. Our research focused on members of the IRF family, using 17 bat species and four terrestrial mammals available in GenBank. We employed CodeML to detect signs of positive selection through three different models. Statistically significant results were obtained for the IRF-1, IRF-4, IRF-5, IRF-6, and IRF-9 genes, which are known to play pivotal roles in various regulation mechanisms. Specifically, IRF-4 and IRF-5 are key in modulating the inflammatory response, while IRF-1 is essential for antiviral defense in bats, and IRF-9 regulates genes activated by type I interferon. Although the role of IRF-6 in these mechanisms requires further investigation in bats, all these genes show signs of positive selection, suggesting an optimization of the processes they regulate. These findings highlight the adaptive role of IRF elements in enhancing, among other things, the bat immune system, potentially improving their resilience and efficacy. Our study not only provides new genetic insights into bats but also underscores the remarkable molecular evolution within this unique group of mammals.

Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1). The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body's immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis, influencing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer. Hence, this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.

Neutrophils, the most abundant type of granulocyte, are widely recognized as one of the pivotal contributors to the acute inflammatory response. Initially, neutrophils were considered the mobile infantry of the innate immune system, tasked with the immediate response to invading pathogens. However, recent studies have demonstrated that neutrophils are versatile cells, capable of regulating various biological processes and impacting both human health and disease. Cytokines and other active mediators regulate the functional activity of neutrophils by activating multiple receptors on these cells, thereby initiating downstream signal transduction pathways. Dysfunctions in neutrophils and disruptions in neutrophil homeostasis have been implicated in the pathogenesis of numerous diseases, including cancer and inflammatory disorders, often due to aberrant intracellular signaling. This review provides a comprehensive synthesis of neutrophil biological functions, integrating recent advancements in this field. Moreover, it examines the biological roles of receptors on neutrophils and downstream signaling pathways involved in the regulation of neutrophil activity. The pathophysiology of neutrophils in numerous human diseases and emerging therapeutic approaches targeting them are also elaborated. This review also addresses the current limitations within the field of neutrophil research, highlighting critical gaps in knowledge that warrant further investigation. In summary, this review seeks to establish a comprehensive and multidimensional model of neutrophil regulation, providing new perspectives for potential clinical applications and further research.

Interferon regulatory factor 1 (IRF1) significantly affects tumour occurrence and development. This study aimed to analyse its function as a pan-cancer prognostic indicator. We compared IRF1 expression and prognostic significance in normal and tumour samples from different databases. Accordingly, we performed in vitro experiments and immunohistochemistry (IHC) to investigate the role of IRF1 in non-small cell lung cancer (NSCLC). Our findings indicate that IRF1 expression is significantly correlated with prognosis, the tumour microenvironment, and immune cell infiltration. Furthermore, receiver operating characteristic (ROC) analysis revealed that IRF1 had high accuracy in distinguishing cancerous tissues from normal ones. Notably, IRF1 expression was linked to immune-related and immune checkpoint genes. Cell proliferation, invasion, and migration were significantly related to IRF1 expression. IHC indicated that IRF1 was downregulated in NSCLC tissues. Our study provides comprehensive bioinformatic analysis and experimental verification of IRF1, suggesting its potential as a prognostic biomarker in cancer.

Recent massively-parallel approaches to decipher gene regulatory circuits have focused on the discovery of either cis -regulatory elements (CREs) or trans -acting factors. Here, we develop a scalable approach that pairs cis - and trans -regulatory CRISPR screens to systematically dissect how the key immune checkpoint PD-L1 is regulated. In human pancreatic ductal adenocarcinoma (PDAC) cells, we tile the PD-L1 locus using ∼25,000 CRISPR perturbations in constitutive and IFNγ-stimulated conditions. We discover 67 enhancer- or repressor-like CREs and show that distal CREs tend to contact the promoter of PD-L1 and related genes. Next, we measure how loss of all ∼2,000 transcription factors (TFs) in the human genome impacts PD-L1 expression and, using this, we link specific TFs to individual CREs and reveal novel PD-L1 regulatory circuits. For one of these regulatory circuits, we confirm the binding of predicted trans -factors (SRF and BPTF) using CUT&RUN and show that loss of either the CRE or TFs potentiates the anti-cancer activity of primary T cells engineered with a chimeric antigen receptor. Finally, we show that expression of these TFs correlates with PD-L1 expression in vivo in primary PDAC tumors and that somatic mutations in TFs can alter response and overall survival in immune checkpoint blockade-treated patients. Taken together, our approach establishes a generalizable toolkit for decoding the regulatory landscape of any gene or locus in the human genome, yielding insights into gene regulation and clinical impact.

Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores the diverse functions of nine mammalian IRF members, each featuring conserved domains essential for interactions with other transcription factors and cofactors. These interactions allow IRFs to modulate a broad spectrum of physiological processes, encompassing host defense, immune response, and cell development. Conversely, their pivotal role in immune regulation implicates them in the pathophysiology of various diseases, such as infectious diseases, autoimmune disorders, metabolic diseases, and cancers. In this context, IRFs display a dichotomous nature, functioning as both tumor suppressors and promoters, contingent upon the specific disease milieu. Post-translational modifications of IRFs, including phosphorylation and ubiquitination, play a crucial role in modulating their function, stability, and activation. As prospective biomarkers and therapeutic targets, IRFs present promising opportunities for disease intervention. Further research is needed to elucidate the precise mechanisms governing IRF regulation, potentially pioneering innovative therapeutic strategies, particularly in cancer treatment, where the equilibrium of IRF activities is of paramount importance.

In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms.

Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo.

Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI.

Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics.

SUMOylation plays a crucial role in numerous cellular biological and pathophysiological processes associated with human disease; however, the mechanisms regulating the genes involved in SUMOylation remain unclear. In the present study, E2F transcription factor 4 (E2F4) was identified as an E2F member related to hepatocellular carcinoma (HCC) progression by public database analysis. It was found that E2F4 promoted the proliferation and invasiveness of HCC cells via SUMOylation using Soft agar and Transwell migration assays. Mechanistically, it was demonstrated that E2F4 upregulated the transcript and protein expression levels of baculoviral IAP repeat containing 5, cell division cycle associated 8 and DNA topoisomerase II α using western blotting. Furthermore, the interaction between E2F4 with lin‑9 DREAM multi‑vulva class B core complex component (LIN9) was explored by co‑immunoprecipitation, immunofluorescence co‑localization and bimolecular fluorescence complementation assays. Moreover, it was demonstrated that E2F4 promoted the progression of HCC cells via LIN9. Rescue experiments revealed that LIN9 facilitated the SUMOylation and proliferation of HCC cells, which was prevented by knocking down E2F4 expression. In conclusion, the findings of the present study indicated that E2F4 plays a major role in the proliferation of HCC cells and may be a potential therapeutic target in the future.

In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms.

Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo.

Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI.

Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics.

The interferon regulatory factors (IRFs) family comprises 11 members that are involved in various biological processes such as antiviral defense, cell proliferation regulation, differentiation, and apoptosis. Recent studies have highlighted the roles of IRF1-9 in a range of liver diseases, including hepatic ischemia-reperfusion injury (IRI), alcohol-induced liver injury, Con A-induced liver injury, nonalcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). IRF1 is involved in the progression of hepatic IRI through signaling pathways such as PIAS1/NFATc1/HDAC1/IRF1/p38 MAPK and IRF1/JNK. The regulation of downstream IL-12, IL-15, p21, p38, HMGB1, JNK, Beclin1, β-catenin, caspase 3, caspase 8, IFN-γ, IFN-β and other genes are involved in the progression of hepatic IRI, and in the development of HCC through the regulation of PD-L1, IL-6, IL-8, CXCL1, CXCL10, and CXCR3. In addition, IRF3-PPP2R1B and IRF4-FSTL1-DIP2A/CD14 pathways are involved in the development of NAFLD. Other members of the IRF family also play moderately important functions in different liver diseases. Therefore, given the significance of IRFs in liver diseases and the lack of a comprehensive compilation of their molecular mechanisms in different liver diseases, this review is dedicated to exploring the molecular mechanisms of IRFs in various liver diseases.

Interferon regulatory factor 1 (IRF-1) is a member of the IRF family. It is the first transcription factor to be identified that could bind to the interferon-stimulated response element (ISRE) on the target gene and displays crucial roles in the interferon-induced signals and pathways. IRF-1, as an important medium, has all of the advantages of full cell cycle regulation, cell death signaling transduction, and reinforcing immune surveillance, which are well documented. Current studies indicate that IRF-1 is of vital importance to the occurrence and evolution of multifarious liver diseases, including but not limited to inhibiting the replication of the hepatitis virus (A/B/C/E), alleviating the progression of liver fibrosis, and aggravating hepatic ischemia-reperfusion injury (HIRI). The tumor suppression of IRF-1 is related to the clinical characteristics of liver cancer patients, which makes it a potential indicator for predicting the prognosis and recurrence of liver cancer; additionally, the latest studies have revealed other effects of IRF-1 such as protection against alcoholic/non-alcoholic fatty liver disease (AFLD/NAFLD), cholangiocarcinoma suppression, and uncommon traits in other liver diseases that had previously received little attention. Intriguingly, several compounds and drugs have featured a protective function in specific liver disease models in which there is significant involvement of the IRF-1 signal. In this paper, we hope to propose a prospective research basis upon which to help decipher translational medicine applications of IRF-1 in liver disease treatment.

Despite the successful application of programmed cell death ligand 1 (PD-L1)-blocking strategies in some types of cancers and well-established prognostic indicators in pancreatic ductal adenocarcinoma (PDAC), the biological and clinical implications of the methylation status of PD-L1/PD-L2 in PDAC remain largely unknown. Therefore, this study aimed to explore the biological role of PD-L1/PD-L2 methylation and its association with clinicopathological features, clinical outcomes, and the immune microenvironment by analyzing the data on PD-L1/PD-L2 methylation and mRNA expression in PDAC cohorts obtained from the Cancer Genome Atlas and International Cancer Genome Consortium. The correlation between PD-L1 promoter methylation and PD-L1 expression and survival was further validated in an independent validation cohort (Peking Union Medical College Hospital [PUMCH] cohort) using pyrosequencing and immunohistochemistry. These results demonstrated that hypomethylation of the PD-L1 promoter was strongly associated with upregulated PD-L1 expression and shorter overall survival in PDAC. Multivariate Cox regression analyses revealed that the PD-L1 promoter methylation was an independent prognostic factor. PD-L1 promoter hypomethylation and high expression were related to aggressive clinical phenotypes. Moreover, both PD-L1 and PD-L2 methylation correlated with immune cell infiltration and the expression of immune checkpoint genes. PD-L1 promoter methylation status was further validated as an independent prognostic biomarker in patients with PDAC using the PUMCH cohort. The prognostic significance of PD-L1 promoter methylation was more discriminative in tumors with perineural/lymphovascular invasion and distant metastasis than in those without perineural/lymphovascular invasion and distant metastasis. In summary, the methylation status of the PD-L1 promoter is a promising biomarker for survival outcomes, immune infiltration, and the potential immune benefits of immunotherapy in PDAC.

Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer-associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction-dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS-cGAMP-STING signaling loop, leading to increased production of interferon-β (IFNβ) by MSCs. IFNβ reversely enhances the type I IFN (IFN-I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA-I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN-I signaling, HLA-I expression, and NK tolerance in human tumor samples. Thus, the NK-resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.

Immune checkpoints (ICPs) can promote tumor growth and prevent immunity-induced cancer cell apoptosis. Fortunately, targeting ICPs, such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4), has achieved great success in the past few years and has gradually become an effective treatment for cancers, including hepatocellular carcinoma (HCC). However, many patients do not respond to ICP therapy due to acquired resistance and recurrence. Therefore, clarifying the specific mechanisms of ICP in the development of HCC is very important for enhancing the efficacy of anti-PD-1 and anti-CTLA-4 therapy. In particular, antigen presentation and interferon-γ (IFN-γ) signaling were reported to be involved in the development of resistance. In this review, we have explained the role and regulatory mechanisms of ICP therapy in HCC pathology. Moreover, we have also elaborated on combinations of ICP inhibitors and other treatments to enhance the antitumor effect. Collectively, recent advances in the pharmacological targeting of ICPs provide insights for the development of a novel alternative treatment for HCC.

IRF1 is a transcription factor well known for its role in IFN signaling. Although IRF1 was initially identified for its involvement in inflammatory processes, there is now evidence that it provides a function in carcinogenesis as well. IRF1 has been shown to affect several important antitumor mechanisms, such as induction of apoptosis, cell cycle arrest, remodeling of tumor immune microenvironment, suppression of telomerase activity, suppression of angiogenesis and others. Nevertheless, the opposite effects of IRF1 on tumor growth have also been demonstrated. In particular, the "immune checkpoint" molecule PD-L1, which is responsible for tumor immune evasion, has IRF1 as a major transcriptional regulator. These and several other properties of IRF1, including its proposed association with response and resistance to immunotherapy and several chemotherapeutic drugs, make it a promising object for further research. Numerous mechanisms of IRF1 regulation in cancer have been identified, including genetic, epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms, although their significance for tumor progression remains to be explored. This review will focus on the established tumor-suppressive and tumor-promoting functions of IRF1, as well as the molecular mechanisms of IRF1 regulation identified in various cancers.

Clinical treatment and preclinical studies have highlighted the role of immune checkpoint blockade in cancer treatment. Research has been devoted to developing immune checkpoint inhibitors in combination with other drugs to achieve better efficacy or reduce adverse effects. Phytochemicals sourced from vegetables and fruits have demonstrated antiproliferative, proapoptotic, anti-migratory, and antiangiogenic effects against several cancers. Phytochemicals also modulate the tumor microenvironment such as T cells, regulatory T cells, and cytokines. Recently, several phytochemicals have been reported to modulate immune checkpoint proteins in in vivo or in vitro models. Phytochemicals decreased programmed cell death ligand-1 expression and synergized programmed cell death receptor 1 (PD-1) monoclonal antibody to suppress tumor growth. Combined administration of phytochemicals and PD-1 monoclonal antibody enhanced the tumor growth inhibition as well as CD4+ /CD8+ T-cell infiltration. In this review, we discuss immune checkpoint molecules as potential therapeutic targets of cancers. We further assess the impact of phytochemicals including carotenoids, polyphenols, saponins, and organosulfur compounds on cancer PD-1/programmed cell death ligand-1 immune checkpoint molecules and document their combination effects with immune checkpoint inhibitors on various malignancies.

IRF family genes have been shown to be crucial in tumorigenesis and tumour immunity. However, information about the role of IRF in the systematic assessment of pan-cancer and in predicting the efficacy of tumour therapy is still unknown. In this work, we performed a systematic analysis of IRF family genes in 33 tumour samples, including expression profiles, genomics and clinical characteristics. We then applied Single-Sample Gene-Set Enrichment Analysis (ssGSEA) to calculate IRF-scores and analysed the impact of IRF-scores on tumour progression, immune infiltration and treatment efficacy. Our results showed that genomic alterations, including SNPs, CNVs and DNA methylation, can lead to dysregulation of IRFs expression in tumours and participate in regulating multiple tumorigenesis. IRF-score expression differed significantly between 12 normal and tumour samples and the impact on tumour prognosis and immune infiltration depended on tumour type. IRF expression was correlated to drug sensitivity and to the expression of immune checkpoints and immune cell infiltration, suggesting that dysregulation of IRF family expression may be a critical factor affecting tumour drug response. Our study comprehensively characterizes the genomic and clinical profile of IRFs in pan-cancer and highlights their reliability and potential value as predictive markers of oncology drug efficacy. This may provide new ideas for future personalized oncology treatment.

tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in HCC.

single-cell RNA-sequencing data and bulk RNA-sequencing data were derived from open source databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Through this analysis, we elucidated the interactions between MICA+ tumor cells and MMP9+ macrophages, primarily mediated via the PROS1-AXL axis in advanced HCC. Subsequently, we employed a range of experimental techniques including lentivirus infection, recombinant protein stimulation, and AXL inhibition experiments to validate these interactions and unravel the underlying mechanisms.

we presented a single-cell atlas of advanced HCC, highlighting the expression patterns of MICA and MMP9 in tumor cells and macrophages, respectively. Activation of the interferon gamma (IFN-γ) signaling pathway was observed in MICA+ tumor cells and MMP9+ macrophages. We identified the existence of an interaction between MICA+ tumor cells and MMP9+ macrophages mediated via the PROS1-AXL axis. Additionally, we found MMP9+ macrophages had a positive correlation with M2-like macrophages. Subsequently, experiments validated that DNA damage not only induced MICA expression in tumor cells via IRF1, but also upregulated PROS1 levels in HCC cells, stimulating macrophages to secrete MMP9. Consequently, MMP9 led to the proteolysis of MICA.

MICA+ HCC cells secreted PROS1, which upregulated MMP9 expression in macrophages through AXL receptors. The increased MMP9 activity resulted in the proteolytic shedding of MICA, leading to the release of soluble MICA (sMICA) and the subsequent facilitation of tumor immune escape.

Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint blockade as a breakthrough in cancer immunotherapy has shown unprecedented positive outcomes in the clinic. However, the overall effectiveness of PD-L1 antibody is less than expected. An increasing number of studies have demonstrated that PD-L1 is widely distributed and expressed not only on the cell membrane but also on the inside of the cells as well as on the extracellular vesicles secreted by tumour cells. Both endogenous and exogenous PD-L1 play significant roles in influencing the therapeutic effect of anti-tumour immunity. Herein, we mainly focused on the distribution and function of PD-L1 and further summarized the potential targeted therapeutic strategies. More importantly, in addition to taking the overall expression abundance of PD-L1 as a predictive indicator for selecting corresponding PD-1/PD-L1 monoclonal antibodies (mAbs), we also proposed that personalized combination therapies based on the different distribution of PD-L1 are worth attention to achieve more efficient and effective therapeutic outcomes in cancer patients. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.

Cancer progression is a multifaceted process that entails several stages and demands the persistent expression or activation of transcription factors (TFs) to facilitate growth and survival. TFs are a cluster of proteins with DNA-binding domains that attach to promoter or enhancer DNA strands to start the transcription of genes by collaborating with RNA polymerase and other supporting proteins. They are generally acknowledged as the major regulatory molecules that coordinate biological homeostasis and the appropriate functioning of cellular components, subsequently contributing to human physiology. TFs proteins are crucial for controlling transcription during the embryonic stage and development, and the stability of different cell types depends on how they function in different cell types. The development and progression of cancer cells and tumors might be triggered by any anomaly in transcription factor function. It has long been acknowledged that cancer development is accompanied by the dysregulated activity of TF alterations which might result in faulty gene expression. Recent studies have suggested that dysregulated transcription factors play a major role in developing various human malignancies by altering and rewiring metabolic processes, modifying the immune response, and triggering oncogenic signaling cascades. This review emphasizes the interplay between TFs involved in metabolic and epigenetic reprogramming, evading immune attacks, cellular senescence, and the maintenance of cancer stemness in cancerous cells. The insights presented herein will facilitate the development of innovative therapeutic modalities to tackle the dysregulated transcription factors underlying cancer.

Germline alleles near genes that encode certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer but in opposite directions. This motivates a systematic search for additional germline alleles which demonstrate this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetic evidence.

Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. To ensure detection of alleles with opposite effects on cancer and autoimmune/autoinflammatory disease, the signs on the beta coefficients in the autoimmune/autoinflammatory GWAS were reversed prior to meta-analyses.

Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with Pmeta<5x10-8 associated with at least one of the cancer types at Pcancer<10-3 and one of the autoimmune/autoinflammatory diseases at Pauto<10-3. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping each lead variant to its nearest gene as its putative functional target and focusing on genes with established immunological effects implicated 32 of the nearest genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (IRF1, IKZF1, SPI1, SH2B3, LAT) were each strongly correlated (Spearman's ρ>0.5) with at least one intra-tumor T/myeloid cell infiltration marker (CD4, CD8A, CD11B, CD45) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via expression quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable.

We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3, and LAT as possible targets for cancer immunotherapy.

The application of immunotherapy in tumor, especially immune checkpoint inhibitors (ICIs), has played an important role in the treatment of advanced unresectable liver cancer. However, the efficacy of ICIs varies greatly among different patients, which has aroused people's attention to the regulatory mechanism of programmed death ligand-1 (PD-L1) in the immune escape of liver cancer. PD-L1 is regulated by multiple levels and signaling pathways in hepatocellular carcinoma (HCC), including gene variation, epigenetic inheritance, transcriptional regulation, post-transcriptional regulation, and post-translational modification. More studies have also found that the high expression of PD-L1 may be the main factor affecting the immunotherapy of liver cancer. However, what is the difference of PD-L1 expressed by different types of cells in the microenvironment of HCC, and which type of cells expressed PD-L1 determines the effect of tumor immunotherapy remains unclear. Therefore, clarifying the regulatory mechanism of PD-L1 in liver cancer can provide more basis for liver cancer immunotherapy and combined immune treatment strategy. In addition to its well-known role in immune regulation, PD-L1 also plays a role in regulating cancer cell proliferation and promoting drug resistance of tumor cells, which will be reviewed in this paper. In addition, we also summarized the natural products and drugs that regulated the expression of PD-L1 in HCC.

The immune checkpoint protein PD-L1 plays critical roles in both immune system homeostasis and tumor progression. Impaired PD-1/PD-L1 function promotes autoimmunity and PD-L1 expression within tumors promotes immune evasion. If and how changes in metabolism or defined metabolites regulate PD-L1 expression is not fully understood. Here, using a metabolomics activity screening-based approach, we have determined that hydroxyproline (Hyp) significantly and directly enhances adaptive (i.e., IFN-γ-induced) PD-L1 expression in multiple relevant myeloid and cancer cell types. Mechanistic studies reveal that Hyp acts as an inhibitor of autophagic flux, which allows it to regulate this negative feedback mechanism, thereby contributing to its overall effect on PD-L1 expression. Due to its prevalence in fibrotic tumors, these findings suggest that hydroxyproline could contribute to the establishment of an immunosuppressive tumor microenvironment and that Hyp metabolism could be targeted to pharmacologically control PD-L1 expression for the treatment of cancer or autoimmune diseases.

Immune checkpoint blockade (ICB) offers a new opportunity for treatment for gastric cancer (G.C.). Understanding the upstream regulation of immune checkpoints is crucial to further improve the efficacy of ICB therapy. Herein, using the CRISPR-Cas9-based genome-wide screening, we identified TRIM28 as one of the most significant regulators of PD-L1, a checkpoint protein, in G.C. cells. Mechanistically, TRIM28 directly binds to and stabilizes PD-L1 by inhibiting PD-L1 ubiquitination and promoting PD-L1 SUMOylation. Furthermore, TRIM28 facilitates K63 polyubiquitination of TBK1, activating TBK1-IRF1 and TBK1-mTOR pathways, resulting in enhanced PD-L1 transcription. It was found that TRIM28 was positively correlated with PD-L1 in G.C. cells. Moreover, high TRIM28 expression suggests poor survival in a cohort of 466 patients with G.C., and this observation is consistent while analyzing data from publicly available databases. Ectopic TRIM28 expression facilitated tumor growth, increased PD-L1 expression, and suppressed T cell activation in mice. Administration of the PD-L1 or TBK1 inhibitor significantly alleviated the TRIM28-induced tumor progression. Furthermore, combining the TBK1 inhibitor with CTLA4 immune checkpoint blockade has synergistic effects on G.C., and provides a novel strategy for G.C. therapy.

Liver cancer is one of the most lethal cancers in the world, mainly owing to the lack of effective means for early monitoring and treatment. Accordingly, there is considerable research interest in various clinically applicable methods for addressing these unmet needs. At present, the most commonly used biomarker for the early diagnosis of liver cancer is alpha-fetoprotein (AFP), but AFP is sensitive to interference from other factors and cannot really be used as the basis for determining liver cancer. Treatment options in addition to liver surgery (resection, transplantation) include radiation therapy, chemotherapy, and targeted therapy. However, even more expensive targeted drug therapies have a limited impact on the clinical outcome of liver cancer. One of the big reasons is the rapid emergence of drug resistance. Therefore, in addition to finding effective biomarkers for early diagnosis, an important focus of current discussions is on how to effectively adjust and select drug strategies and guidelines for the treatment of liver cancer patients. In this review, we bring this thought process to the drug resistance problem faced by different treatment strategies, approaching it from the perspective of gene expression and molecular biology and the possibility of finding effective solutions.

Interleukin (IL)-10 is a main player in peripheral immune tolerance, the physiological mechanism preventing immune reactions to self/harmless antigens. Here, we investigate IL-10-induced molecular mechanisms generating tolerogenic dendritic cells (tolDC) from monocytes. Using genomic studies, we show that IL-10 induces a pattern of accessible enhancers exploited by aryl hydrocarbon receptor (AHR) to promote expression of a set of core genes. We demonstrate that AHR activity occurs downstream of IL-10 signaling in myeloid cells and is required for the induction of tolerogenic activities in DC. Analyses of circulating DCs show that IL-10/AHR genomic signature is active in vivo in health. In multiple sclerosis patients, we instead observe significantly altered signature correlating with functional defects and reduced frequencies of IL-10-induced-tolDC in vitro and in vivo. Our studies identify molecular mechanisms controlling tolerogenic activities in human myeloid cells and may help in designing therapies to re-establish immune tolerance.

Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.

Cancer immunity is regulated by several mechanisms that include co-stimulatory and/or co-inhibitory molecules known as immune checkpoints expressed by the immune cells. In colorectal cancer (CRC), CTLA-4, LAG3, TIM-3 and PD-1 are the major co-inhibitory checkpoints involved in tumor development and progression. On the other hand, the deregulation of transcription factors and cancer stem cells activity plays a major role in the development of drug resistance and in the spread of metastatic disease in CRC. In this review, we describe how the modulation of such transcription factors affects the response of CRC to therapies. We also focus on the role of cancer stem cells in tumor metastasis and chemoresistance and discuss both preclinical and clinical approaches for targeting stem cells to prevent their tumorigenic effect. Finally, we provide an update on the clinical applications of immune checkpoint inhibitors in CRC and discuss the regulatory effects of transcription factors on the expression of the immune inhibitory checkpoints with specific focus on the PD-1 and PD-L1 molecules.

Understanding the mechanisms regulating PD-L1 expression in hepatocellular carcinoma (HCC) is important to improve the response rate to PD-1/PD-L1 blockade therapy. Here, we show that DKK1 expression is positively associated with PD-L1 expression and inversely correlated with CD8⁺ T cell infiltration in human HCC tumor specimens. In a subcutaneous xenograft tumor model, overexpression of DKK1 significantly promotes tumor growth, tumoral PD-L1 expression, but reduces tumoral CD8⁺ T cell infiltration; whereas knockdown of DKK1 has opposite effects. Moreover, enforced expression of DKK1 dramatically promotes PD-L1 expression, Akt activation, β-catenin phosphorylation and total protein expression in HCC cells. By contrast, knockdown of DKK1 inhibits all, relative to controls. In addition, CKAP4 depletion, Akt inhibition, or β-catenin depletion remarkably abrogates DKK1 overexpression-induced transcriptional expression of PD-L1 in HCC cells. Reconstituted expression of the active Akt1 largely increased PD-L1 transcriptional expression in HCC cells. Similarly, expression of WT β-catenin, but not the phosphorylation-defective β-catenin S552A mutant, significantly promotes PD-L1 expression. Correlation analysis of human HCC tumor specimens further revealed that DKK1 and PD-L1 expression were positively correlated with p-β-catenin expression. Together, our findings revealed that DKK1 promotes PD-L1 expression through the activation of Akt/β-catenin signaling, providing a potential strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade therapy in HCC patients.

CHK1 is considered a key cell cycle checkpoint kinase in DNA damage response (DDR) pathway to communicate with several signaling pathways involved in the tumor microenvironment (TME) in numerous cancers. However, the mechanism of CHK1 signaling regulating TME in hepatocellular carcinoma (HCC) remains unclear.

CHK1 expression in HCC tissue was determined by IHC staining assay. DNA damage and apoptosis in HCC cells induced by cisplatin or CHK1 inhibition were detected by WB and flow cytometry. The interaction of CHK1 and IRF1 was analyzed by single-cell RNA-sequence, WB, and immunoprecipitation assay. The mechanism of IRF1 regulating MICA was investigated by ChIP-qPCR.

CHK1 expression is upregulated in human HCC tumors compared to the background liver. High CHK1 mRNA level predicts advanced tumor stage and worse prognosis. Cisplatin and CHK1 inhibition augment cellular DNA damage and apoptosis. Overexpressed CHK1 suppresses IRF1 expression through proteolysis. Furthermore, single-cell RNA-sequence analyses confirmed that MICA expression positively correlated with IRF1 in HCC cells. Immunoprecipitation assay showed the binding between CHK1 and IRF1. Cisplatin and CHK1 inhibition upregulate MICA expression through IRF1-mediated transcriptional effects. A novel specific cis-acting IRF response element was identified at -1756 bp in the MICA promoter region that bound IRF1 to induce MICA gene transcription. MICA may increase NK cell and CD8+T cell infiltration in HCC.

DNA damage regulates the interaction of CHK1 and IRF1 to activate anti-tumor immunity via the IRF1-MICA pathway in HCC.

Tumors meet their energy, biosynthesis, and redox demands through metabolic reprogramming. This metabolic abnormality results in elevated levels of metabolites, particularly lactate, in the tumor microenvironment. Immune cell reprogramming and cellular plasticity mediated by lactate and lactylation increase immunosuppression in the tumor microenvironment and are emerging as key factors in regulating tumor development, metastasis, and the effectiveness of immunotherapies such as immune checkpoint inhibitors. Reprogramming of glucose metabolism and the "Warburg effect" in hepatocellular carcinoma (HCC) lead to the massive production and accumulation of lactate, so lactate modification in tumor tissue is likely to be abnormal as well. This article reviews the immune regulation of abnormal lactate metabolism and lactate modification in hepatocellular carcinoma and the therapeutic strategy of targeting lactate-immunotherapy, which will help to better guide the medication and treatment of patients with hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a main cause of malignancy-related death all over the world with a poor prognosis. The current research is focused on developing novel prognostic and diagnostic models of Hepatocellular carcinoma from the perspective of hepatitis B virus (HBV)-related genes, and predicting its prognostic characteristics and potential reliable biomarkers for Hepatocellular carcinoma diagnosis. Methods: As per the information related to Hepatocellular carcinoma expression profile and the clinical data in multiple public databases, we utilized limma for assessing the differentially expressed genes (DEGs) in HBV vs non- hepatitis B virus groups, and the gene set was enriched, analyzed and annotated by WebGestaltR package. Then, STRING was employed to investigate the protein interactions. A risk model for evaluating Hepatocellular carcinoma prognosis was built with Lasso Cox regression analysis. The effect patients receiving immunotherapy was predicted using Tumor Immune Dysfunction and Exclusion (TIDE). Additionally, pRRophetic was used to investigate the drug sensitivity. Lastly, the Support Vector Machine (SVM) approach was utilized for building the diagnostic model. Results: The Hepatocellular Carcinoma Molecular Atlas 18 (HCCDB18) data set was utilized for the identification of 1344 HBV-related differentially expressed genes, mainly associated with cell division activities. Five functional modules were established and then we built a prognostic model in accordance with the protein-protein interaction (PPI) network. Five HBV-related genes affecting prognosis were identified for constructing a prognostic model. Then, the samples were assigned into RS-high and -low groups as per their relevant prognostic risk score (RS). High-risk group showed worse prognosis, higher mutation rate of TP53, lower sensitivity to immunotherapy but higher response to chemotherapeutic drugs than low-risk group. Finally, the hepatitis B virus diagnostic model of Hepatocellular carcinoma was established. Conclusion: In conclusion, the prognostic and diagnostic models of hepatitis B virus gene-related Hepatocellular carcinoma were constructed. ABCB6, IPO7, TIMM9, FZD7, and ACAT1, the five HBV-related genes that affect the prognosis, can work as reliable biomarkers for the diagnosis of Hepatocellular carcinoma, giving a new insight for improving the prognosis, diagnosis, and treatment outcomes of HBV-type Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the most prevalent subtype of liver cancer, is the second main reason for cancer-related deaths worldwide. In recent decades, sufficient evidence supported that immunotherapy was a safe and effective treatment option for HCC. However, tolerance and frequent recurrence and metastasis occurred in patients after immunotherapy due to the complicated crosstalk in the tumor immunosuppressive microenvironment (TIME) in HCC. Therefore, elucidating the TIME in HCC and finding novel modulators to target TIME for attenuating immune suppression is critical to optimize immunotherapy. Recently, studies have shown the potentially immunoregulatory activities of natural compounds, characterized by multiple targets and pathways and low toxicity. In this review, we concluded the unique role of TIME in HCC. Moreover, we summarized evidence that supports the hypothesis of natural compounds to target TIME to improve immunotherapy. Furthermore, we discussed the comprehensive mechanisms of these natural compounds in the immunotherapy of HCC. Accordingly, we present a well-grounded review of the naturally occurring compounds in cancer immunotherapy, expecting to shed new light on discovering novel anti-HCC immunomodulatory drugs from natural sources.

Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8+ T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8+ T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.

Hepatocellular carcinoma (HCC), one of the most common tumours worldwide, is one of the main causes of mortality in cancer patients. There are still numerous problems hindering its early diagnosis, which lead to late patients receiving treatment, and these problems need to be solved urgently. The tumour microecosystem is a complex network system comprising seven parts: the hypoxia niche, immune microenvironment, metabolic microenvironment, acidic niche, innervated niche, mechanical microenvironment, and microbial microenvironment. Intercellular communication is divided into direct contact and indirect communication. Direct contact communication includes gap junctions, tunneling nanotubes, and receptor-ligand interactions, whereas indirect communication includes exosomes, apoptotic vesicles, and soluble factors. Mechanical communication and cytoplasmic exchange are further means of intercellular communication. Intercellular communication mediates the crosstalk between the tumour microecosystem and the host as well as that between cells and cell-free components in the tumour microecosystem, causing changes in the tumour hallmarks of the HCC microecosystem such as changes in tumour proliferation, invasion, apoptosis, angiogenesis, metastasis, inflammatory response, gene mutation, immune escape, metabolic reprogramming, and therapeutic resistance. Here, we review the role of the above-mentioned intercellular communication in the HCC microecosystem and discuss the advantages of targeted intercellular communication in the clinical diagnosis and treatment of HCC. Finally, the current problems and prospects are discussed.

Hepatocellular carcinoma (HCC) is still a main health concern around the world, with a rising incidence and high mortality rate. The tumor-promoting components of the tumor microenvironment (TME) play a vital role in the development and metastasis of HCC. TME-targeted therapies have recently drawn increasing interest in the treatment of HCC. However, the short medication retention time in TME limits the efficiency of TME modulating strategies. The nanoparticles can be elaborately designed as needed to specifically target the tumor-promoting components in TME. In this regard, the use of nanomedicine to modulate TME components by delivering drugs with protection and prolonged circulation time in a spatiotemporal manner has shown promising potential. In this review, we briefly introduce the obstacles of TME and highlight the updated information on nanoparticles that modulate these obstacles. Furthermore, the present challenges and future prospects of TME modulating nanomedicines will be briefly discussed.