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Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1-/- tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.

UNLABELLED: Gonorrhea, caused by the bacterium Neisseria gonorrhoeae (Gc), is characterized by neutrophilic influx to infection sites. Gc has developed mechanisms to resist killing by neutrophils that include modifications to its surface lipooligosaccharide (LOS). One such LOS modification is sialylation: Gc sialylates its terminal LOS sugars with cytidine-5-monophosphate-N-acetylneuraminic acid, which is scavenged from the host using LOS sialyltransferase (Lst) since Gc cannot make its sialic acid. Sialylation enables sensitive strains of Gc to resist complement-mediated killing in a serum-dependent manner. However, little is known about the contribution of sialylation to complement-independent, direct Gc-neutrophil interactions. In the absence of complement, we found sialylated Gc expressing opacity-associated (Opa) proteins decreased the oxidative burst and granule exocytosis from primary human neutrophils. In addition, sialylated Opa+ Gc survived better than vehicle treated or Δlst Gc when challenged with neutrophils. However, Gc sialylation did not significantly affect Opa-dependent association with or internalization of Gc by neutrophils. Previous studies have implicated sialic acid-binding immunoglobulin-type lectins (Siglecs) in modulating neutrophil interactions with sialylated Gc. Blocking neutrophil Siglecs with antibodies that bind to their extracellular domains eliminated the ability of sialylated Opa+ Gc to suppress the oxidative burst and resist neutrophil killing. These findings highlight a new role for sialylation in Gc evasion of human innate immunity, with implications for the development of vaccines and therapeutics for gonorrhea. IMPORTANCE: Neisseria gonorrhoeae, the bacterium that causes gonorrhea, is an urgent global health concern due to increasing infection rates, widespread antibiotic resistance, and its ability to thwart protective immune responses. The mechanisms by which Gc subverts protective immune responses remain poorly characterized. One way N. gonorrhoeae evades human immunity is by adding sialic acid that is scavenged from the host onto its lipooligosaccharide, using the sialyltransferase Lst. Here, we found that sialylation enhances N. gonorrhoeae survival from neutrophil assault and inhibits neutrophil activation, independently of the complement system. Our results implicate bacterial binding of sialic acid-binding lectins (Siglecs) on the neutrophil surface, which dampens neutrophil antimicrobial responses. This work identifies a new role for sialylation in protecting N. gonorrhoeae from cellular innate immunity, which can be targeted to enhance the human immune response in gonorrhea.

Vaccination arguably remains the only long-term strategy to limit the spread of S. aureus infections and its related antibiotic resistance. To date, however, all staphylococcal vaccines tested in clinical trials have failed. In this review, we propose that the failure of S. aureus vaccines is intricately linked to prior host exposure to S. aureus and the pathogens capacity to evade adaptive immune defenses. We suggest that non-protective immune imprints created by previous exposure to S. aureus are preferentially recalled by SA vaccines, and IL-10 induced by S. aureus plays a unique role in shaping these non-protective anti-staphylococcal immune responses. We discuss how S. aureus modifies the host immune landscape, which thereby necessitates alternative approaches to develop successful staphylococcal vaccines.

Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies to manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated by an intricately immunosuppression entrenched within the tumor microenvironment (TME). Principal mechanisms underpinning tumor immune evasion from CBIs encompass loss of antigens, downregulation of antigen presentation, activation of immune checkpoint pathways, initiation of anti-apoptotic cascades, and induction of immune dysfunction and exhaustion. In this review, we delve into the intrinsic mechanisms underlying the capacity of tumor cells to resist CBIs and proffer prospective stratagems to navigate around these challenges.

Glioma progression is a complex process controlled by molecular factors that coordinate the crosstalk between tumor cells and components of the tumor microenvironment (TME). Among these, immune cells play a critical role in cancer survival and progression. The complex interplay between cancer cells and the immune TME influences the outcome of immunotherapy and other anti-cancer therapies. Here, we present an updated view of the pro- and anti-tumor activities of the main myeloid and lymphocyte cell populations in the glioma TME. We review the underlying mechanisms involved in crosstalk between cancer cells and immune cells that enable gliomas to evade the immune system and co-opt these cells for tumor growth. Lastly, we discuss the current and experimental therapeutic options being developed to revert the immunosuppressive activity of the glioma TME. Knowledge of the complex interplay that elapses between tumor and immune cells may help develop new combination treatments able to overcome tumor immune evasion mechanisms and enhance response to immunotherapies.

Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer, with the tumor microenvironment (TME) playing a pivotal role in modulating the immune response. CD47, a cell surface protein, has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy. However, the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood. This comprehensive review aims to provide an overview of CD47's multifaced role in TME regulation and immune evasion, elucidating its impact on various types of immunotherapy outcomes, including checkpoint inhibitors and CAR T-cell therapy. Notably, CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes, especially when combined with other immunotherapeutic approaches. The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47. Despite the demonstrated effectiveness of CD47-targeted therapies, there are potential problems, including unintended effects on healthy cells, hematological toxicities, and the development if resistance. Consequently, further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches, ultimately improving cancer treatment outcomes. Overall, this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.

Tumor cells possess complex immune evasion mechanisms to evade immune system attacks, primarily through metabolic reprogramming, which significantly alters the tumor microenvironment (TME) to modulate immune cell functions. When a tumor is sufficiently immunogenic, it can activate cytotoxic T-cells to target and destroy it. However, tumors adapt by manipulating their metabolic pathways, particularly glucose, amino acid, and lipid metabolism, to create an immunosuppressive TME that promotes immune escape. These metabolic alterations impact the function and differentiation of non-tumor cells within the TME, such as inhibiting effector T-cell activity while expanding regulatory T-cells and myeloid-derived suppressor cells. Additionally, these changes lead to an imbalance in cytokine and chemokine secretion, further enhancing the immunosuppressive landscape. Emerging research is increasingly focusing on the regulatory roles of non-tumor cells within the TME, evaluating how their reprogrammed glucose, amino acid, and lipid metabolism influence their functional changes and ultimately aid in tumor immune evasion. Despite our incomplete understanding of the intricate metabolic interactions between tumor and non-tumor cells, the connection between these elements presents significant challenges for cancer immunotherapy. This review highlights the impact of altered glucose, amino acid, and lipid metabolism in the TME on the metabolism and function of non-tumor cells, providing new insights that could facilitate the development of novel cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals. [ABSTRACT FROM AUTHOR]

Herpes simplex virus (HSV), an epidemic human pathogen threatening global public health, gains notoriety for its complex pathogenesis that encompasses lytic infection of mucosal cells, latent infection within neurons, and periodic reactivation. This intricate interplay, coupled with HSV's sophisticated immune evasion strategies, gives rise to various diseases, including genital lesions, neonatal encephalitis, and cancer. Despite more than 70 years of relentless research, an effective preventive or therapeutic vaccine against HSV has yet to emerge, primarily due to the limited understanding of virus-host interactions, which in turn impedes the identification of effective vaccine targets. However, HSV's unique pathological features, including its substantial genetic load capacity, high replicability, transmissibility, and neurotropism, render it a promising candidate for various applications, spanning oncolytic virotherapy, gene and immune therapies, and even as an imaging tracer in neuroscience. In this review, we comprehensively update recent breakthroughs in HSV pathogenesis and immune evasion, critically summarize the progress made in vaccine candidate development, and discuss the multifaceted applications of HSV as a biological tool. Importantly, we highlight both success and challenges, emphasizing the critical need for intensified research into HSV, with the aim of providing deeper insights that can not only advance HSV treatment strategies but also broaden its application horizons. [ABSTRACT FROM AUTHOR]

Mucosal immunity plays a crucial role in defending against coronaviruses, particularly at respiratory sites, serving as the first line of defense against viral invasion and replication. Coronaviruses have developed various immune evasion strategies at the mucosal immune system, hindering the recognition of infected cells and evading antibody responses. Understanding the immune mechanisms and responses is crucial for developing effective vaccines and therapeutics against coronaviruses. The role of mucosal immunity in COVID-19 is significant, influencing both local and systemic immune responses to the virus. Although most clinical studies focus on antibodies and cellular immunity in peripheral blood, mucosal immune responses in the respiratory tract play a key role in the early restriction of viral replication and the clearance of SARS-CoV-2. Identification of mucosal biomarkers associated with viral clearance will allow monitoring of infection-induced immunity. Mucosally delivered vaccines and those under clinical trials are being compared and contrasted to understand their effectiveness in inducing mucosal immunity against coronaviruses. A greater understanding of lung tissue-based immunity may lead to improved diagnostic and prognostic procedures and novel treatment strategies aimed at reducing the disease burden of community-acquired pneumonia, avoiding the systemic manifestations of infection and excess morbidity and mortality. This comprehensive review article outlines the current evidence about the role of mucosal immune responses in the clearance of SARS-CoV-2 infection, as well as potential mucosal mechanisms of protection against (re-)infection. It also proposes that there is a significant role for mucosal immunity and for secretory as well as circulating IgA antibodies in COVID-19, and that it is important to elucidate this in order to comprehend especially the asymptomatic and mild states of the infection, which appear to account for the majority of cases. Moreover, it is possible that mucosal immunity can be exploited for beneficial diagnostic, therapeutic, or prophylactic purposes. The findings from recent studies on mucosal immunity in COVID-19 can be used to develop effective vaccines and treatments that can effectively target both mucosal and systemic immune responses. [ABSTRACT FROM AUTHOR]

Arthritogenic alphaviruses pose a significant public health concern due to their ability to cause joint inflammation, with emerging evidence of potential neurological consequences. In this review, we examine the immunopathology and immune evasion strategies employed by these viruses, highlighting their complex mechanisms of pathogenesis and neurological implications. We delve into how these viruses manipulate host immune responses, modulate inflammatory pathways, and potentially establish persistent infections. Further, we explore their ability to breach the blood-brain barrier, triggering neurological complications, and how co-infections exacerbate neurological outcomes. This review synthesizes current research to provide a comprehensive overview of the immunopathological mechanisms driving arthritogenic alphavirus infections and their impact on neurological health. By highlighting knowledge gaps, it underscores the need for research to unravel the complexities of virus-host interactions. This deeper understanding is crucial for developing targeted therapies to address both joint and neurological manifestations of these infections. [ABSTRACT FROM AUTHOR]

Background: Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. Methods: The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. Results: APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. Conclusions: APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Myeloid sarcomas (MS) comprise rare extramedullary manifestations of myeloid neoplasms with poor patients' outcome. While the clinical relevance of the tumor microenvironment (TME) is well established in many malignancies, there exists limited information in MS. Methods: The expression of the human leukocyte antigen class I (HLA-I) antigens, HLA-I antigen processing and presenting machinery (APM) components and the composition of the TME of 45 MS and paired bone marrow (BM) samples from two independent cohorts were assessed by immunohistochemistry, multispectral imaging, and RNA sequencing (RNAseq). Results: A significant downregulation of the HLA-I heavy chain (HC; 67.5%) and ß2-microglobulin (ß2M; 64.8%), but an upregulation of HLA-G was found in MS compared to BM samples, which was confirmed in a publicly available dataset. Moreover, MS tumors showed a predominantly immune cell excluded TME with decreased numbers of tissue infiltrating lymphocytes (TILs) (9.5%) compared to paired BM (22.9%). RNAseq analysis of a subset of 10 MS patients with preserved and reduced HLA-I HC expression revealed 150 differentially expressed genes and a significantly reduced expression of inflammatory response genes was found in samples with preserved HLA-I expression. Furthermore, low HLA-I expression and low TIL numbers in the TME of MS cases were linked to an inferior patients' outcome. Discussion: This study demonstrated a high prevalence of immune escape strategies in the pathogenesis and extramedullary spread of MS, which was also found in patients without evidence of any BM pathology, which yields the rational for the development of novel individually tailored therapies for MS patients. [ABSTRACT FROM AUTHOR]

Immune evasion is a key phenomenon in understanding tumor recurrence, metastasis, and other critical steps in tumor progression. The tumor microenvironment (TME) is in constant flux due to the tumor's ability to release signals that affect it, while immune cells within it can impact cancer cell behavior. Cancer cells undergo several changes, which can change the enrichment of different immune cells and modulate the activity of existing immune cells in the tumor microenvironment. Cancer cells can evade immune surveillance by downregulating antigen presentation or expressing immune checkpoint molecules. High levels of tumor-infiltrating lymphocytes (TILs) correlate with better outcomes, and robust immune responses can control tumor growth. On the contrary, increased enrichment of Tregs, myeloid-derived suppressor cells, and M2-like anti-inflammatory macrophages can hinder effective immune surveillance and predict poor prognosis. Overall, understanding these immune evasion mechanisms guides therapeutic strategies. Researchers aim to modulate the TME to enhance immune surveillance and improve patient outcomes. In this review article, we strive to summarize the composition of the tumor immune microenvironment, factors affecting the tumor immune microenvironment (TIME), and different therapeutic modalities targeting the immune cells. This review is a first-hand reference to understand the basics of immune surveillance and immune evasion. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid‐binding Ig‐like lectin 10 (Siglec‐10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec‐10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec‐10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec‐10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec‐10 modulates immune responses and facilitates immune escape in cancer. Siglec‐10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec‐10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec‐10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics. [ABSTRACT FROM AUTHOR]

This review explores the intricate roles of metal ions—iron, copper, zinc, and selenium—in glioma pathogenesis and immune evasion. Dysregulated metal ion metabolism significantly contributes to glioma progression by inducing oxidative stress, promoting angiogenesis, and modulating immune cell functions. Iron accumulation enhances oxidative DNA damage, copper activates hypoxia-inducible factors to stimulate angiogenesis, zinc influences cell proliferation and apoptosis, and selenium modulates the tumor microenvironment through its antioxidant properties. These metal ions also facilitate immune escape by upregulating immune checkpoints and secreting immunosuppressive cytokines. Targeting metal ion pathways with therapeutic strategies such as chelating agents and metalloproteinase inhibitors, particularly in combination with conventional treatments like chemotherapy and immunotherapy, shows promise in improving treatment efficacy and overcoming resistance. Future research should leverage advanced bioinformatics and integrative methodologies to deepen the understanding of metal ion-immune interactions, ultimately identifying novel biomarkers and therapeutic targets to enhance glioma management and patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, characterized by high rates of angiogenesis and immune evasion. Paraspeckle genes, involved in gene regulation and RNA metabolism, have recently been linked to tumor progression. This study aims to elucidate the relationship between paraspeckle genes and HCC prognosis, focusing on SFPQ, DDX39B, and UBAP2. Methods: We analyzed HCC (LIHC) and prostate cancer (PRAD) samples from the TCGA database to explore the correlation between paraspeckle genes and angiogenesis. We conducted unsupervised clustering, risk scoring, and survival analysis to identify distinct patient groups and their clinical outcomes. Gene expression data were used to perform differential analysis and Gene Ontology (GO) enrichment. Results: Our analysis identified significant correlations between paraspeckle genes and angiogenesis across multiple cancer types. Elevated expression levels of SFPQ, DDX39B, and UBAP2 were associated with poor prognosis in HCC patients, and all of them has statistical significance. Unsupervised clustering of HCC samples based on paraspeckle gene expression revealed two distinct clusters, with high-risk patients exhibiting stronger immune suppression and tumor immune evasion. GO enrichment highlighted critical pathways related to angiogenesis and immune regulation. Additionally, a risk scoring model based on these genes effectively distinguished high-risk and low-risk patient groups, providing valuable prognostic insights. Conclusion: This study demonstrates that SFPQ, DDX39B, and UBAP2 are significantly associated with poor prognosis in HCC, likely due to their roles in promoting angiogenesis and immune suppression. These findings highlight the potential of paraspeckle genes as prognostic biomarkers and therapeutic targets, offering new avenues for personalized treatment strategies in HCC. Further research into their functional mechanisms and clinical applicability is crucial for advancing HCC treatment and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains one of the gravest global health challenges. Mycobacterium tuberculosis (M. tuberculosis), the causative agent, employs sophisticated immune evasion and pathogenesis strategies. Its capability to thrive within immune cells and incite robust inflammatory responses prolongs infection and dissemination. Mycobacterial advanced adaptations facilitate navigation through the human immune system and present a variable antigenic profile throughout different infection stages. Investigating these strategies unfolds targeted approaches to effective vaccine development against TB. This review delves into the most advanced and exhaustive insights into the immune evasion tactics and pathogenic processes of M. tuberculosis across various infection stages. The knowledge distilled from this analysis holds the promise of guiding the creation of innovative TB vaccines and translating theoretical groundwork into practical immunological defenses. [ABSTRACT FROM AUTHOR]

Immune evasion of Mycobacterium tuberculosis (Mtb) facilitates intracellular bacterial growth. The mechanisms of immune evasion, however, are still not fully understood. In this study, we reveal that tristetraprolin (TTP), one of the best characterized RNA‐binding proteins controlling the stability of targeted mRNAs, mediates innate immune evasion of mycobacteria. We found that TTP knockout mice displayed reduced bacterial burden in the early stage after Mtb aerosol challenge. Macrophages deficient in TTP also showed an inhibition in intracellular mycobacterial growth. Live mycobacteria induced TTP protein expression in macrophages, which was blocked by the mTOR inhibitor rapamycin. Rapamycin and AZD8055 specifically blocked 4EBP1 phosphorylation in infected macrophages and suppressed intracellular BCG growth. Rapamycin promoted TTP protein degradation through the ubiquitination pathway, whereas the proteasome inhibitor MG‐132 blocked rapamycin function and thus stabilized TTP protein. TTP induction suppressed the expression of iNOS/TNF‐α/IL‐12/IL‐23, and weakened protective immune responses in macrophages, whereas rapamycin enhanced the bactericidal effects through TTP inhibition. Moreover, blocking TTP binding increased the expression of TNF‐α and iNOS and suppressed intracellular mycobacterial growth. Overall, our study reveals a novel role for RNA‐binding protein TTP in Mtb immune evasion mechanisms and provides a potential target for host‐directed therapy against tuberculosis (TB). [ABSTRACT FROM AUTHOR]

Viruses are obligate intracellular pathogens as their replication depends on the metabolism of the host cell. The induction of cellular suicide, known as programmed cell death (PCD), has the potential to hinder viral replication and act as a first line of defense against viral pathogens. Apoptosis, necroptosis, and pyroptosis are three important PCD modalities. Different signaling pathways are involved in their execution, and they also differ in their ability to cause inflammation. Cytomegaloviruses (CMV), beta-herpesviruses with large double-stranded DNA genomes, encode a great variety of immune evasion genes, including several cell death suppressors. While CMV inhibitors of apoptosis and necroptosis have been known and studied for years, the first pyroptosis inhibitor has been identified and characterized only recently. Here, we describe how human and murine CMV interfere with apoptosis, necroptosis, and pyroptosis signaling pathways. We also discuss the importance of the different PCD forms and their viral inhibitors for the containment of viral replication and spread in vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockade has shown remarkable efficacy across various cancers but has failed to improve outcomes in patients with relapsed medulloblastoma (MB). While it is thought that the cold, immunosuppressive tumor microenvironment of MB accounts for this poor efficacy, the precise mechanisms contributing to immune suppression in this context remain unclear. In this study, we explore the immune landscape of MB using a previously unexplored syngeneic mouse model. Our study demonstrates that this model faithfully recapitulates the cold, immunosuppressive tumor microenvironment observed in human disease. Importantly, our research uncovers mechanisms employed by myeloid cells and tumor cells to evade immune detection while highlighting the therapeutic potential of targeting V-domain Ig Suppressor of T-cell Activation (VISTA), a novel inhibitory immune checkpoint, to enhance anti-tumor immunity. Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor–cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA–VSIG axis to enhance anti-tumor responses. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV), a member of the γ-herpesvirus family, is one of the most prevalent and persistent human viruses, infecting up to 90% of the adult population globally. EBV's life cycle includes primary infection, latency, and lytic reactivation, with the virus primarily infecting B cells and epithelial cells. This virus has evolved sophisticated strategies to evade both innate and adaptive immune responses, thereby maintaining a lifelong presence within the host. This persistence is facilitated by the expression of latent genes such as EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs), which play crucial roles in viral latency and oncogenesis. In addition to their well-known roles in several types of cancer, including nasopharyngeal carcinoma and B-cell lymphomas, recent studies have identified the pathogenic roles of EBV in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This review highlights the intricate interactions between EBV and the host immune system, underscoring the need for further research to develop effective therapeutic and preventive strategies against EBV-associated diseases. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) contributes to the incidence and prognosis of lung cancer. The presence of COPD significantly increases the risk of lung squamous cell carcinoma (LSCC). COPD may promote an immunosuppressive microenvironment in LSCC by regulating the expression of immune‐inhibitory factors in T cells, although the mechanisms remain unclear. In this study, we aimed to decipher the tumour microenvironment signature for LSCC with COPD at a single‐cell level. Methods: We performed single‐cell RNA sequencing on tumour tissues from LSCC with or without COPD, then investigated the features of the immune and tumour cells. We employed multiple techniques, including multispectral imaging, flow cytometry, tissue microarray analysis, survival analysis, co‐culture systems and in vitro and in vivo treatment experiments, to validate the findings obtained from single‐cell analyses. Results: LSCC with COPD showed increased proportions of tumour‐associated macrophages (TAMs) and higher levels of CD8+ T cell exhaustion molecules, which contributed to an immunosuppressive microenvironment. Further analysis revealed a critical cluster of CD74+ tumour cells that expressed both epithelial and immune cell signatures, exhibited a stronger capacity for tumorigenesis and predicted worse overall survival. Notably, migration inhibitory factor (MIF) secreted by TAMs from LSCC with COPD may promote the activation of CD74. MIF‐CD74 may interact with CD8+ T cells and impair their anti‐tumour activity by regulating the PI3K‐STAT3‐programmed cell death‐1 ligand 1 signalling pathway, facilitating tumour proliferation and immune evasion. Conclusions: Our comprehensive picture of the tumour ecosystem in LSCC with COPD provides deeper insights into relevant immune evasion mechanisms and potential targets for immunotherapy. Highlight: Our results demonstrated higher proportions of tumour‐associated macrophages (TAMs) and higher levels of exhaustion molecules in CD8+ T cells in the microenvironment of LSCC with COPD.CD74+tumour cells were associated with poor disease prognosis.Migration inhibitory factor (MIF)‐CD74 may interact with CD8+ T cells and impair their anti‐tumour activity by regulating the PI3K‐STAT3‐PD‐L1 signalling pathway, facilitating immune evasion. [ABSTRACT FROM AUTHOR]

Varicella zoster virus (VZV) reactivates from ganglionic sensory neurons to produce herpes zoster (shingles) in a unilateral dermatomal distribution, typically in the thoracic region. Reactivation not only heightens the risk of stroke and other neurological complications but also increases susceptibility to co-infections with various viral and bacterial pathogens at sites distant from the original infection. The mechanism by which VZV results in complications remote from the initial foci remains unclear. Small extracellular vesicles (sEVs) are membranous signaling structures that can deliver proteins and nucleic acids to modify the function of distal cells and tissues during normal physiological conditions. Although viruses have been documented to exploit the sEV machinery to propagate infection, the role of non-infectious sEVs released from VZV-infected neurons in viral spread and disease has not been studied. Using multi-omic approaches, we characterized the content of sEVs released from VZV-infected human sensory neurons (VZV sEVs). One viral protein was detected (immediate-early 62), as well as numerous immunosuppressive and vascular disease-associated host proteins and miRNAs that were absent in sEVs from uninfected neurons. Notably, VZV sEVs are non-infectious yet transcriptionally altered primary human cells, suppressing the antiviral type 1 interferon response and promoting neuroinvasion of a secondary pathogen in vivo. These results challenge our understanding of VZV infection, proposing that the virus may contribute to distant pathologies through non-infectious sEVs beyond the primary infection site. Furthermore, this study provides a previously undescribed immune-evasion mechanism induced by VZV that highlights the significance of non-infectious sEVs in early VZV pathogenesis. IMPORTANCE Varicella zoster virus (VZV) is a ubiquitous human virus that predominantly spreads by direct cell-cell contact and requires efficient and immediate host immune evasion strategies to spread. The mechanisms of immune evasion prior to virion entry have not been fully elucidated and represent a critical gap in our complete understanding of VZV pathogenesis. This study describes a previously unreported antiviral evasion strategy employed by VZV through the exploitation of the infected host cell’s small extracellular vesicle (sEV) machinery. These findings suggest that non-infectious VZV sEVs could travel throughout the body, affecting cells remote from the site of infection and challenging the current understanding of VZV clinical disease, which has focused on local effects and direct infection. The significance of these sEVs in early VZV pathogenesis highlights the importance of further investigating their role in viral spread and secondary disease development to reduce systemic complications following VZV infections. [ABSTRACT FROM AUTHOR]

Insufficient understanding about the immune evasion mechanism leads to the inability in predicting current immunotherapy effects in clear cell renal cell carcinoma (ccRCC) and sensitizing ccRCC to immunotherapy. RNA binding proteins (RBPs) can promote tumor progression and immune evasion. However, research on RBPs, particularly m6A reader YTHDF3, in ccRCC development and immune evasion is limited. In this study, we found that YTHDF3 level was downregulated in ccRCC and was an independent prognostic biomarker for ccRCC. Decreased YTHDF3 expression was correlated with the malignancy, immune evasion, and poor response to anti‐programmed death ligand 1 (PD‐L1)/CTLA‐4 in ccRCC. YTHDF3 overexpression restrained ccRCC cell malignancy, PD‐L1 expression, CD8+ T cell infiltration and activities in vivo, indicating its inhibitory role in ccRCC development and immune evasion. Mechanistically, YTHDF3 WT was found to have phase separation characteristics and suppress ccRCC malignancy and immune evasion. Whereas YTHDF3 mutant, which disrupted phase separation, abolished its function. YTHDF3 enhanced the degradation of its target mRNA HSPA13 by phase separation and recruiting DDX6, resulting in the downregulation of the downstream immune checkpoint PD‐L1. HSPA13 overexpression restored ccRCC malignancy and immune evasion suppressed by YTHDF3 overexpression. In all, our results identify a new model of YTHDF3 in regulating ccRCC progression and immune evasion through phase separation. [ABSTRACT FROM AUTHOR]

Multiple Endocrine Neoplasia 1 gene (MEN1), which is known to be a tumor suppressor gene in lung tissues, encodes a 610 amino acid protein menin. Previous research has proven that MEN1 deficiency promotes the malignant progression of lung cancer. However, the biological role of this gene in the immune microenvironment of lung cancer remains unclear. In this study, we found that programmed cell death‐ligand 1 (PD‐L1) is upregulated in lung‐specific KrasG12D mutation‐induced lung adenocarcinoma in mice, after Men1 deficiency. Simultaneously, CD8+ and CD3+ T cells are depleted, and their cytotoxic effects are suppressed. In vitro, PD‐L1 is inhibited by the overexpression of menin. Mechanistically, we found that MEN1 inactivation promotes the deubiquitinating activity of COP9 signalosome subunit 5 (CSN5) and subsequently increases the level of PD‐L1. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus, being one of the most common human pathogens, is responsible for infections in both hospital and community settings. Its virulence is attributed to its ability to evade the immune system by producing immune evasion (IE) proteins. The aim of this study was to detect the frequency of selected IE genes (spin, sbi, sea, sak, chp, scin, sep, ecb), belonging to the immune evasion cluster (IEC), and IEC types in 86 methicillin-susceptible S. aureus (MSSA) strains isolated from unrelated outpatients. In order to determine the diversity of analyzed strains, the phylogenetic relatedness was also determined. All strains were examined for the presence of IE genes using polymerase chain reaction assay. To analyze the clonal relatedness of S. aureus, pulsed-field gel electrophoresis (PFGE) was performed. All analyzed strains harbored the scn gene, followed by sbi (95.4%), ecb (91.7%), spin (89.5%), sak (83.7%), chp (67.4%), sep (67.4%) and sea (5.8%). Seventy-three (84.9%) S. aureus strains were classified into IEC types, of which, IEC type F was most commonly observed. IEC type A was not detected. PFGE results showed no association between clonal relatedness and the presence of IE genes/IEC types. In conclusion, the abundant and so diverse repertoire of genes determining invasion in analyzed strains may prove the fact that these strains are highly advanced and adapted to evade the host immune response. [ABSTRACT FROM AUTHOR]

CD8+ T cells are the primary mediators of anticancer immunity, and modulation of the CD8+ T cell response has been a central focus of immunotherapy to treat cancer. When CD8+ T cells specifically recognize antigenic peptides presented by the MHC-I on tumor cells, they become activated and kill the tumor cells. However, one pivotal mechanism through which tumor cells evade immune surveillance is to reduce their antigen presentation. To identify novel immunotherapeutic targets, we specifically focused on the role of MAL2 in immune evasion in endometrial cancer (EC) and the underlying mechanism. MAL2 was overexpressed in EC tissues and cells and its transcription was enhanced by RAD21. Knockdown of MAL2 or RAD21 inhibited malignant behavior and immune evasion of EC cells by repressing MHC-I expression and the cytotoxic effects of CD8+ cells. Conversely, MAL2 promoted immune evasion of EC cells and tumor growth in mice in the presence of RAD21 knockdown. These results indicate that RAD21 activation of MAL2 inhibits antigen processing and presentation of MHC-I, thereby inducing immune evasion of EC cells. We further suggest that RAD21 and MAL2 may serve as novel targets for EC immunotherapy. [ABSTRACT FROM AUTHOR]

The JN.1 variant of COVID‐19 has emerged as the dominant strain worldwide since the end of 2023. As a subclade of the BA.2.86 variant, JN.1 harbors a unique combination of mutations inherited from the BA.2.86 lineage, notably featuring the novel L455S mutation within its receptor‐binding motif. This mutation has been linked to increased transmissibility and enhanced immune evasion capabilities. During the rise of JN.1, evidence of resistance to various monoclonal antibodies and reduced cross‐neutralization effects of the XBB.1.5 vaccine have been observed. Although the public health threat posed by the JN.1 variant appears relatively low, concerns persist regarding its evolutionary trajectory under immune pressure. This review provides a comprehensive overview of the evolving JN.1 variant, highlighting the need for continuous monitoring and investigation of new variants that could lead to widespread infection. It assesses the efficacy of current vaccines and therapeutics against emerging variants, particularly focusing on immunocompromised populations. Additionally, this review summarizes potential vaccine advancements and clinical treatments for COVID‐19, offering insights to optimize prevention and treatment strategies. This review thoroughly evaluates the JN.1 variant's impact on public health and its implications for future vaccine and therapeutic development, contributing to ongoing efforts to mitigate the risk of virus transmission and disease severity. [ABSTRACT FROM AUTHOR]

Pericytes, recognized as mural cells, have long been described as components involved in blood vessel formation, playing a mere supporting role for endothelial cells (ECs). Emerging evidence strongly suggests their multifaceted roles in tissues and organs. Indeed, pericytes exhibit a remarkable ability to anticipate endothelial cell behavior and adapt their functions based on the specific cells they interact with. Pericytes can be activated by pro-inflammatory stimuli and crosstalk with immune cells, actively participating in their transmigration into blood vessels. Moreover, they can influence the immune response, often sustaining an immunosuppressive phenotype in most of the cancer types studied. In this review, we concentrate on the intricate crosstalk between pericytes and immune cells in cancer, highlighting the primary evidence regarding pericyte involvement in primary tumor mass dynamics, their contributions to tumor reprogramming for invasion and migration of malignant cells, and their role in the formation of pre-metastatic niches. Finally, we explored recent and emerging pharmacological approaches aimed at vascular normalization, including novel strategies to enhance the efficacy of immunotherapy through combined use with anti-angiogenic drugs. [ABSTRACT FROM AUTHOR]

Background: Trichinella spiralis (T. spiralis) is a parasitic helminth that causes a globally prevalent neglected zoonotic disease, and worms at different developmental stages (muscle larvae, adult worms, newborn larvae) induce immune attack at different infection sites, causing serious harm to host health. Several innate immune cells release extracellular traps (ETs) to entrap and kill most pathogens that invade the body. In response, some unicellular pathogens have evolved a strategy to escape capture by ETs through the secretion of nucleases, but few related studies have investigated multicellular helminths. Results: In the present study, we observed that ETs from neutrophils capture adult worms of T. spiralis, while ETs from macrophages trap muscle larvae and newborn larvae, and ETs had a killing effect on parasites in vitro. To defend against this immune attack, T. spiralis secretes plancitoxin-1, a DNase II-like protein, to degrade ETs and escape capture, which is essential for the survival of T. spiralis in the host. Conclusions: In summary, these findings demonstrate that T. spiralis escapes ET-mediated capture by secreting deoxyribonuclease as a potential conserved immune evasion mechanism, and plancitoxin-1 could be used as a potential vaccine candidate. [ABSTRACT FROM AUTHOR]

During tumorigenesis and progression, the immune checkpoint programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) play critical roles in suppressing T cell-mediated anticancer immune responses, leading to T-cell exhaustion and subsequent tumor evasion. Therefore, anti-PD-L1/PD-1 therapy has been an attractive strategy for treating cancer over the past decade. However, the overall efficacy of this approach remains suboptimal, revealing an urgent need for novel insights. Interestingly, increasing evidence indicates that both PD-L1 on tumor cells and PD-1 on tumor-specific T cells undergo extensive N-linked glycosylation, which is essential for the stability and interaction of these proteins, and this modification promotes tumor evasion. In various preclinical models, targeting the N-linked glycosylation of PD-L1/PD-1 was shown to significantly increase the efficacy of PD-L1/PD-1 blockade therapy. Furthermore, deglycosylation of PD-L1 strengthens the signal intensity in PD-L1 immunohistochemistry (IHC) assays, improving the diagnostic and therapeutic relevance of this protein. In this review, we provide an overview of the regulatory mechanisms underlying the N-linked glycosylation of PD-L1/PD-1 as well as the crucial role of N-linked glycosylation in PD-L1/PD-1-mediated immune evasion. In addition, we highlight the promising implications of targeting the N-linked glycosylation of PD-L1/PD-1 in the clinical diagnosis and treatment of cancer. Our review identifies knowledge gaps and sheds new light on the cancer research field. [ABSTRACT FROM AUTHOR]

In the decades since the discovery, Type I interferon (IFN-I) has been intensively studied for their antiviral activity. However, increasing evidences suggest that it may also play an important role in the infection of Toxoplasma gondii, a model organism for intracellular parasites. Recent studies demonstrated that the induction of IFN-I by the parasite depends on cell type, strain genotype, and mouse strain. IFN-I can inhibit the proliferation of T. gondii, but few studies showed that it is beneficial to the growth of the parasite. Meanwhile, T. gondii also can secrete proteins that impact the pathway of IFN-I production and downstream induced interferon-stimulated genes (ISGs) regulation, thereby escaping immune destruction by the host. This article reviews the major findings and progress in the production, function, and regulation of IFN-I during T. gondii infection, to thoroughly understand the innate immune mechanism of T. gondii infection, which provides a new target for subsequent intervention and treatment. [ABSTRACT FROM AUTHOR]

The Epstein–Barr virus (EBV) has a very high prevalence (>90% in adults), establishes a lifelong latency after primary infection, and exerts an oncogenic potential. This dsDNA virus encodes for various molecules, including microRNAs (miRs), which can be detected in the latent and lytic phases with different expression levels and affect, among others, immune evasion and malignant transformation. In this study, the different EBV miRs are quantified in EBV-positive lymphomas, and the impact on the host cell transcriptome of the most abundant EBV miRs will be analyzed using comparative RNA sequencing analyses. The EBV miRs ebv-miR-BART1, -BART4, -BART17, and -BHRF1-1 were most highly expressed, and their selective overexpression in EBV-negative human cells resulted in a large number of statistically significantly down- and up-regulated host cell genes. Functional analyses showed that these dysregulated target genes are involved in important cellular processes, including growth factor pathways such as WNT, EGF, FGF, and PDGF, as well as cellular processes such as apoptosis regulation and inflammation. Individual differences were observed between these four analyzed EBV miRs. In particular, ebv-miR-BHRF1-1 appears to be more important for malignant transformation and immune evasion than the other EBV miRs. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a mature‐type B cell malignancy correlated with significant changes and defects in both the innate and adaptive arms of the immune system, together with a high dependency on the tumor microenvironment. Overall, the tumor microenvironment (TME) in CLL provides a supportive niche for leukemic cells to grow and survive, and interactions between CLL cells and the TME can contribute to disease progression and treatment resistance. Therefore, the increasing knowledge of the complicated interaction between immune cells and tumor cells, which is responsible for immune evasion and cancer progression, has provided an opportunity for the development of new therapeutic approaches. In this review, we outline tumor microenvironment‐driven contributions to the licensing of immune escape mechanisms in CLL patients. [ABSTRACT FROM AUTHOR]

MYC has been implicated in the pathogenesis of a wide range of human tumors and has been described for many years as a transcription factor that regulates genes with pleiotropic functions to promote tumorigenic growth. However, despite extensive efforts to identify specific target genes of MYC that alone could be responsible for promoting tumorigenesis, the field is yet to reach a consensus whether this is the crucial function of MYC. Recent work shifts the view on MYC's function from being a gene‐specific transcription factor to an essential stress resilience factor. In highly proliferating cells, MYC preserves cell integrity by promoting DNA repair at core promoters, protecting stalled replication forks, and/or preventing transcription‐replication conflicts. Furthermore, an increasing body of evidence demonstrates that MYC not only promotes tumorigenesis by driving cell‐autonomous growth, but also enables tumors to evade the host's immune system. In this review, we summarize our current understanding of how MYC impairs antitumor immunity and why this function is evolutionarily hard‐wired to the biology of the MYC protein family. We show why the cell‐autonomous and immune evasive functions of MYC are mutually dependent and discuss ways to target MYC proteins in cancer therapy. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune evasion that contribute to poor prognosis. Cancer‐associated fibroblasts (CAFs) play a pivotal role in orchestrating the PDAC tumour microenvironment. We investigated the role of CAF‐derived extracellular vesicle (EV)‐packaged long non‐coding RNAs (lncRNAs) in immune evasion and explored gene therapy using engineered EVs loading small interfering RNAs (siRNAs) as a potential therapeutic strategy. Our findings highlight the significance of EV‐packaged lncRNA RP11‐161H23.5 from CAF in promoting PDAC immune evasion by downregulating HLA‐A expression, a key component of antigen presentation. Mechanistically, RP11‐161H23.5 forms a complex with CNOT4, a subunit of the mRNA deadenylase CCR4‐NOT complex, enhancing the degradation of HLA‐A mRNA by shortening its poly(A) tail. This immune evasion mechanism compromises the anti‐tumour immune response. To combat this, we propose an innovative approach utilising engineered EVs as natural and biocompatible nanocarriers for siRNA‐based gene therapy and this strategy holds promise for enhancing the effectiveness of immunotherapy in PDAC. Overall, our study sheds light on the critical role of CAF‐derived EV‐packaged lncRNA RP11‐161H23.5/CNOT4/HLA‐A axis in PDAC immune evasion and presents a novel avenue for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) presents a significant global health challenge due to its high incidence, poor prognosis, and limited treatment options. As a pivotal regulator of protein stability, E3 ubiquitin ligase plays a crucial role in tumorigenesis and development. This review provides an overview of the latest research on the involvement of E3 ubiquitin ligase in hepatocellular carcinoma and elucidates its significance in hepatocellular carcinoma cell proliferation, invasion, and evasion from immune surveillance. Special attention is given to the functions of RING, HECT, and RBR E3 ubiquitin ligases and their association with hepatocellular carcinoma progression. By dissecting the molecular mechanisms and regulatory networks governed by E3 ubiquitin ligase, several potential therapeutic strategies are proposed: including the development of specific inhibitors targeting E3 ligases; augmentation of their tumor suppressor activity through drug or gene therapy; utilization of E3 ubiquitin ligase to modulate immune checkpoint proteins for improved efficacy of immunotherapy; combination strategies integrating traditional therapies with E3 ubiquitin ligase inhibitors; as well as biomarker development based on E3 ubiquitin ligase activity. Furthermore, this review discusses the prospect of overcoming drug resistance in hepatocellular carcinoma treatment through these novel approaches. Overall, this review establishes a theoretical foundation and offers fresh insights into harnessing the potential of E3 ubiquitin ligase for treating hepatocellular carcinoma while highlighting future research directions that pave the way for clinical translation studies and new drug discoveries. [ABSTRACT FROM AUTHOR]

Introduction: Human Herpesvirus 6B (HHV-6B) impedes host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Downregulation of MHC-I disengages inhibitory receptors on natural killer (NK) cells, resulting in activation and killing of the target cell if NK cell activating receptors such as NKG2D have engaged stress ligands upregulated on the target cells. Previous work has shown that HHV-6B downregulates three MHC-like stress ligands MICB, ULBP1, and ULBP3, which are recognized by NKG2D. The U20 glycoprotein of the related virus HHV-6A has been implicated in the downregulation of ULBP1, but the precise mechanism remains undetermined. Methods: We set out to investigate the role of HHV-6B U20 in modulating NK cell activity. We used HHV-6B U20 expressed as a recombinant protein or transduced into target cells, as well as HHV-6B infection, to investigate binding interactions with NK cell ligands and receptors and to assess effects on NK cell activation. Small-angle X-ray scattering was used to align molecular models derived from machine-learning approaches. Results: We demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity. Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels, either at the cell surface or in toto. HHV-6B infection and soluble U20 have the same effect. Transduction of U20 blocks NK cell activation in response to cell-surface ULBP1. Structuralmodeling of the U20 - ULBP1 complex indicates some similarities to the m152-RAE1g complex. [ABSTRACT FROM AUTHOR]

As the main pathogen associated with enzootic pneumonia (EP), Mycoplasma hyopneumoniae (Mhp) is globally prevalent and inflicts huge financial losses on the worldwide swine industry each year. However, the pathogenicity of Mhp has not been fully explained to date. Mhp invasion usually leads to long-term chronic infection and persistent lung colonization, suggesting that Mhp has developed effective immune evasion strategies. In this review, we offer more detailed information than was previously available about its immune evasion mechanisms through a systematic summary of the extant findings. Genetic mutation and post-translational protein processing confer Mhp the ability to alter its surface antigens. With the help of adhesins, Mhp can achieve cell invasion. And Mhp can modulate the host immune system through the induction of inflammation, incomplete autophagy, apoptosis, and the suppression of immune cell or immune effector activity. Furthermore, we offer the latest views on how we may treat Mhp infections and develop novel vaccines. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between CSCs and the tumor microenvironment (TME) is observed, with the TME providing a supportive niche for CSC survival and self-renewal, while CSCs, in turn, influence the polarization and persistence of the TME, promoting an immunosuppressive state. Consequently, these interactions hinder the efficacy of current cancer therapies, necessitating the exploration of novel therapeutic approaches to modulate the TME and target CSCs. In this review, we highlight the intricate strategies employed by CSCs to evade immune surveillance and develop resistance to therapies. Furthermore, we examine the dynamic interplay between CSCs and the TME, shedding light on how this interaction impacts cancer progression. Moreover, we provide an overview of advanced therapeutic strategies that specifically target CSCs and the TME, which hold promise for future clinical and translational studies in cancer treatment.

Abstract Tumor cells possess complex immune evasion mechanisms to evade immune system attacks, primarily through metabolic reprogramming, which significantly alters the tumor microenvironment (TME) to modulate immune cell functions. When a tumor is sufficiently immunogenic, it can activate cytotoxic T-cells to target and destroy it. However, tumors adapt by manipulating their metabolic pathways, particularly glucose, amino acid, and lipid metabolism, to create an immunosuppressive TME that promotes immune escape. These metabolic alterations impact the function and differentiation of non-tumor cells within the TME, such as inhibiting effector T-cell activity while expanding regulatory T-cells and myeloid-derived suppressor cells. Additionally, these changes lead to an imbalance in cytokine and chemokine secretion, further enhancing the immunosuppressive landscape. Emerging research is increasingly focusing on the regulatory roles of non-tumor cells within the TME, evaluating how their reprogrammed glucose, amino acid, and lipid metabolism influence their functional changes and ultimately aid in tumor immune evasion. Despite our incomplete understanding of the intricate metabolic interactions between tumor and non-tumor cells, the connection between these elements presents significant challenges for cancer immunotherapy. This review highlights the impact of altered glucose, amino acid, and lipid metabolism in the TME on the metabolism and function of non-tumor cells, providing new insights that could facilitate the development of novel cancer immunotherapies.

Abstract Herpes simplex virus (HSV), an epidemic human pathogen threatening global public health, gains notoriety for its complex pathogenesis that encompasses lytic infection of mucosal cells, latent infection within neurons, and periodic reactivation. This intricate interplay, coupled with HSV's sophisticated immune evasion strategies, gives rise to various diseases, including genital lesions, neonatal encephalitis, and cancer. Despite more than 70 years of relentless research, an effective preventive or therapeutic vaccine against HSV has yet to emerge, primarily due to the limited understanding of virus-host interactions, which in turn impedes the identification of effective vaccine targets. However, HSV's unique pathological features, including its substantial genetic load capacity, high replicability, transmissibility, and neurotropism, render it a promising candidate for various applications, spanning oncolytic virotherapy, gene and immune therapies, and even as an imaging tracer in neuroscience. In this review, we comprehensively update recent breakthroughs in HSV pathogenesis and immune evasion, critically summarize the progress made in vaccine candidate development, and discuss the multifaceted applications of HSV as a biological tool. Importantly, we highlight both success and challenges, emphasizing the critical need for intensified research into HSV, with the aim of providing deeper insights that can not only advance HSV treatment strategies but also broaden its application horizons.

Abstract Small extracellular vesicles (sEVs) have the ability to transfer genetic material between cells, but their role in mediating HBV infection and regulating M1 macrophages to promote immune evasion remains unclear. In this study, we utilized PMA + LPS + IFN-γ to induce THP-1 into M1 macrophages. We then extracted sEVs from HepG2.2.15 cell and treated the M1 macrophages with these sEVs. QPCR detection revealed the presence of HBV-DNA in the M1 macrophages. Additionally, RT-qPCR and WB analysis demonstrated a significantly decreased in the expression of TLR4, NLRP3, pro-caspase-1, caspase-1p20, IL-1β and IL-18 in the M1 macrophages (P

Abstract Background Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. Methods The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. Results APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. Conclusions APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.

Abstract Background Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, characterized by high rates of angiogenesis and immune evasion. Paraspeckle genes, involved in gene regulation and RNA metabolism, have recently been linked to tumor progression. This study aims to elucidate the relationship between paraspeckle genes and HCC prognosis, focusing on SFPQ, DDX39B, and UBAP2. Methods We analyzed HCC (LIHC) and prostate cancer (PRAD) samples from the TCGA database to explore the correlation between paraspeckle genes and angiogenesis. We conducted unsupervised clustering, risk scoring, and survival analysis to identify distinct patient groups and their clinical outcomes. Gene expression data were used to perform differential analysis and Gene Ontology (GO) enrichment. Results Our analysis identified significant correlations between paraspeckle genes and angiogenesis across multiple cancer types. Elevated expression levels of SFPQ, DDX39B, and UBAP2 were associated with poor prognosis in HCC patients, and all of them has statistical significance. Unsupervised clustering of HCC samples based on paraspeckle gene expression revealed two distinct clusters, with high-risk patients exhibiting stronger immune suppression and tumor immune evasion. GO enrichment highlighted critical pathways related to angiogenesis and immune regulation. Additionally, a risk scoring model based on these genes effectively distinguished high-risk and low-risk patient groups, providing valuable prognostic insights. Conclusion This study demonstrates that SFPQ, DDX39B, and UBAP2 are significantly associated with poor prognosis in HCC, likely due to their roles in promoting angiogenesis and immune suppression. These findings highlight the potential of paraspeckle genes as prognostic biomarkers and therapeutic targets, offering new avenues for personalized treatment strategies in HCC. Further research into their functional mechanisms and clinical applicability is crucial for advancing HCC treatment and improving patient outcomes.

Abstract This review explores the intricate roles of metal ions—iron, copper, zinc, and selenium—in glioma pathogenesis and immune evasion. Dysregulated metal ion metabolism significantly contributes to glioma progression by inducing oxidative stress, promoting angiogenesis, and modulating immune cell functions. Iron accumulation enhances oxidative DNA damage, copper activates hypoxia-inducible factors to stimulate angiogenesis, zinc influences cell proliferation and apoptosis, and selenium modulates the tumor microenvironment through its antioxidant properties. These metal ions also facilitate immune escape by upregulating immune checkpoints and secreting immunosuppressive cytokines. Targeting metal ion pathways with therapeutic strategies such as chelating agents and metalloproteinase inhibitors, particularly in combination with conventional treatments like chemotherapy and immunotherapy, shows promise in improving treatment efficacy and overcoming resistance. Future research should leverage advanced bioinformatics and integrative methodologies to deepen the understanding of metal ion-immune interactions, ultimately identifying novel biomarkers and therapeutic targets to enhance glioma management and patient outcomes.

Abstract Immune evasion of Mycobacterium tuberculosis (Mtb) facilitates intracellular bacterial growth. The mechanisms of immune evasion, however, are still not fully understood. In this study, we reveal that tristetraprolin (TTP), one of the best characterized RNA‐binding proteins controlling the stability of targeted mRNAs, mediates innate immune evasion of mycobacteria. We found that TTP knockout mice displayed reduced bacterial burden in the early stage after Mtb aerosol challenge. Macrophages deficient in TTP also showed an inhibition in intracellular mycobacterial growth. Live mycobacteria induced TTP protein expression in macrophages, which was blocked by the mTOR inhibitor rapamycin. Rapamycin and AZD8055 specifically blocked 4EBP1 phosphorylation in infected macrophages and suppressed intracellular BCG growth. Rapamycin promoted TTP protein degradation through the ubiquitination pathway, whereas the proteasome inhibitor MG‐132 blocked rapamycin function and thus stabilized TTP protein. TTP induction suppressed the expression of iNOS/TNF‐α/IL‐12/IL‐23, and weakened protective immune responses in macrophages, whereas rapamycin enhanced the bactericidal effects through TTP inhibition. Moreover, blocking TTP binding increased the expression of TNF‐α and iNOS and suppressed intracellular mycobacterial growth. Overall, our study reveals a novel role for RNA‐binding protein TTP in Mtb immune evasion mechanisms and provides a potential target for host‐directed therapy against tuberculosis (TB).

Abstract During tumorigenesis and progression, the immune checkpoint programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) play critical roles in suppressing T cell-mediated anticancer immune responses, leading to T-cell exhaustion and subsequent tumor evasion. Therefore, anti-PD-L1/PD-1 therapy has been an attractive strategy for treating cancer over the past decade. However, the overall efficacy of this approach remains suboptimal, revealing an urgent need for novel insights. Interestingly, increasing evidence indicates that both PD-L1 on tumor cells and PD-1 on tumor-specific T cells undergo extensive N-linked glycosylation, which is essential for the stability and interaction of these proteins, and this modification promotes tumor evasion. In various preclinical models, targeting the N-linked glycosylation of PD-L1/PD-1 was shown to significantly increase the efficacy of PD-L1/PD-1 blockade therapy. Furthermore, deglycosylation of PD-L1 strengthens the signal intensity in PD-L1 immunohistochemistry (IHC) assays, improving the diagnostic and therapeutic relevance of this protein. In this review, we provide an overview of the regulatory mechanisms underlying the N-linked glycosylation of PD-L1/PD-1 as well as the crucial role of N-linked glycosylation in PD-L1/PD-1-mediated immune evasion. In addition, we highlight the promising implications of targeting the N-linked glycosylation of PD-L1/PD-1 in the clinical diagnosis and treatment of cancer. Our review identifies knowledge gaps and sheds new light on the cancer research field.

Abstract Background Trichinella spiralis (T. spiralis) is a parasitic helminth that causes a globally prevalent neglected zoonotic disease, and worms at different developmental stages (muscle larvae, adult worms, newborn larvae) induce immune attack at different infection sites, causing serious harm to host health. Several innate immune cells release extracellular traps (ETs) to entrap and kill most pathogens that invade the body. In response, some unicellular pathogens have evolved a strategy to escape capture by ETs through the secretion of nucleases, but few related studies have investigated multicellular helminths. Results In the present study, we observed that ETs from neutrophils capture adult worms of T. spiralis, while ETs from macrophages trap muscle larvae and newborn larvae, and ETs had a killing effect on parasites in vitro. To defend against this immune attack, T. spiralis secretes plancitoxin-1, a DNase II-like protein, to degrade ETs and escape capture, which is essential for the survival of T. spiralis in the host. Conclusions In summary, these findings demonstrate that T. spiralis escapes ET-mediated capture by secreting deoxyribonuclease as a potential conserved immune evasion mechanism, and plancitoxin-1 could be used as a potential vaccine candidate.