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PubMed2025

Malaria: Factors affecting disease severity, immune evasion mechanisms, and reversal of immune inhibition to enhance vaccine efficacy.

Malaria is a complex parasitic disease caused by species of Plasmodium parasites. Infection with the parasites can lead to a spectrum of symptoms and disease severity, influenced by various parasite, host, and environmental factors. There have been some successes in developing vaccines against the disease recently, but the vaccine efficacies require improvement. Some issues associated with the difficulties in developing a sterile vaccine include high antigenic diversity, switching expression of the immune targets, and inhibition of immune pathways. Current vaccine research focuses on identifying conserved and protective epitopes, developing multivalent vaccines (including the whole parasite), and using more powerful adjuvants. However, overcoming the systematic immune inhibition and immune cell dysfunction/exhaustion may be required before high titers of protective antibodies can be achieved. Increased expression of surface molecules such as CD86 and MHC II on antigen-presenting cells and blocking immune checkpoint pathways (interactions of PD-1 and PD-L1; CTLA-4 and CD80) using small molecules could be a promising approach for enhancing vaccine efficacy. This assay reviews the factors affecting the disease severity, the genetics of host-parasite interaction, immune evasion mechanisms, and approaches potentially to improve host immune response for vaccine development.

Humans↗

PubMed2026

Hypoimmune platforms: from rejection to immune evasion and regulatory implications.

The growing gap between organ demand and clinical availability has renewed interest in immune-evasive graft strategies, yet rejection and lifelong immunosuppression remain major barriers to durable success. Advances in genome editing enable immune-evasive cell platforms designed to avoid immune recognition while replacing missing function in allogeneic settings. This review summarizes current strategies for engineering immune-evasive grafts that simultaneously suppress adaptive and innate immune responses. We discuss how coordinated modulation of antigen presentation and immune checkpoint pathways can protect transplanted allogeneic cells and tissues from T, NK, and macrophage-mediated rejection. We also present the emerging concept of integrating hypoimmune engineering with genetically modified porcine donors, where extensive genome editing has reduced, but not eliminated, xenogeneic immune barriers. Combining donor genome modification with immune-evasive graft design represents a promising conceptual advance toward xenograft survival, though whether full elimination of systemic immunosuppression is achievable remains to be established clinically. We further examine how the regulatory landscape for these products is evolving across major jurisdictions, and how differences in approval pathways, manufacturing standards, and long-term surveillance requirements shape the path to clinical translation. Finally, we outline the safety considerations and remaining limitations in immune evasion that must be addressed to enable clinical implementation.

Graft Rejection↗

PubMed2026

Machine learning and multi-omics clustering to map cellular rewiring and immune evasion in ccRCC.

Immune checkpoint blockade (ICB) efficacy in clear cell renal cell carcinoma (ccRCC) is limited by tumor microenvironment (TME) heterogeneity. Because traditional bulk-derived models lack spatial resolution, we developed an integrated framework connecting macroscopic survival risks to microscopic TME structures. We applied ten algorithms to establish multi-omics subtypes and evaluated 101 machine-learning combinations across three independent cohorts to generate a Consensus Machine Learning-driven Signature (CMLS). The signature's spatial and cellular origins were decoded using spatial transcriptomics (ST) and a 140,000-cell scRNA-seq atlas. Expression of key genes was experimentally validated via RT-qPCR in 17 paired ccRCC clinical tissues. We identified two molecular subtypes with distinct clinical and epigenetic profiles. SuperPC optimization yielded a 24-gene CMLS serving as an independent prognostic factor. scRNA-seq and ST deconvolution revealed these signals predominantly originate from cancer-associated fibroblasts (CAFs) and malignant epithelial cells, which collaborate to drive spatial immune exclusion. RT-qPCR confirmed significant overexpression of five core CMLS genes in ccRCC versus adjacent normal tissues. Low CMLS scores correlated with enhanced ICB responsiveness, whereas high-CMLS tumors demonstrated specific vulnerability to dasatinib and dabrafenib. The CMLS translates spatial immune-exclusion dynamics into a quantifiable metric, outperforming tumor mutational burden in predicting ICB benefits, providing a robust tool for patient stratification in ccRCC.

Humans↗

PubMed2026

Multi-omics and spatial transcriptomics reveal that S100A10 drives CD8+ T-cell exhaustion and immune evasion in hepatocellular carcinoma through cPLA2-5-LOX-mediated arachidonic acid metabolism and ferroptosis.

Immune evasion in hepatocellular carcinoma (HCC) represents a major biological barrier limiting the efficacy of immunotherapy, yet its molecular basis remains incompletely understood. Increasing evidence indicates that tumor metabolic reprogramming and ferroptosis-related signaling play critical roles in shaping an immunosuppressive tumor microenvironment (TME); however, the specific regulatory factors involved remain unclear. This study aims to systematically elucidate the functional role of S100 calcium-binding protein A10 (S100A10) in immune evasion in HCC, with a particular focus on the molecular mechanisms by which S100A10 regulates CD8+ T-cell exhaustion through arachidonic acid (AA) metabolism and ferroptosis, as well as its potential therapeutic implications. To this end, data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort are integrated to analyze the expression patterns of S100A10, its prognostic value, and its association with the immune microenvironment. S100A10 overexpression and knockout models are established in HCCLM3 and MHCC97L cell lines, and S100A10-mediated metabolic pathway reprogramming is characterized using transcriptomic profiling, untargeted metabolomics, and ferroptosis-related functional assays. In parallel, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics are employed to delineate the cell-type specificity and spatial distribution of S100A10. Furthermore, human CD8+ T-cell co-culture systems and orthotopic mouse HCC models are used to evaluate the impact of S100A10 on immune function and responsiveness to anti-programmed cell death protein 1 (anti-PD-1) therapy. The results demonstrate that S100A10 is significantly upregulated in HCC and is closely associated with poor prognosis and an immunosuppressive state. Mechanistically, S100A10 activates cytosolic phospholipase A2-arachidonate 5-lipoxygenase (cPLA2-5-LOX)-mediated AA oxidative metabolism, leading to the accumulation of lipid peroxidation products and ferroptosis-associated signals, thereby driving CD8+ T-cell exhaustion and promoting immune evasion. Significantly, inhibition of S100A10 reshapes the tumor immune microenvironment (TIME) and enhances the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify S100A10 as a critical regulator of metabolic-immune coupling in HCC and provide a theoretical basis for combinatorial strategies targeting metabolism and immunotherapy.

Arachidonic acid metabolism↗

PubMed2026

Convergent evolution of immune evasion in ESKAPE pathogens: A cross-pathogen architecture of conserved host-defense checkpoints.

Antimicrobial resistance in ESKAPE pathogens is primarily attributed to resistance genes, yet persistent infections despite appropriate therapy implicate immune evasion as an independent driver of treatment failure. Although immune-evasion mechanisms have been extensively characterized in individual pathogens, their shared architecture across the ESKAPE group remains insufficiently integrated. This review synthesizes current evidence to show that phylogenetically diverse ESKAPE pathogens have convergently evolved conserved strategies to evade host immunity under comparable selective pressures. A cross-pathogen immune-evasion framework emerges, encompassing impaired pathogen recognition, complement inhibition, phagocyte dysfunction, immunometabolic reprogramming, biofilm-mediated protection, and persistence-promoting inflammation, together with pathogen-specific virulence mechanisms. These processes intersect with adaptive immune dysfunction and emerging concepts, including quorum-sensing-mediated immunomodulation, trained immunity, and the itaconate-succinate immunometabolic axis, forming an interconnected persistence network rather than isolated virulence traits. This systems-level perspective identifies conserved host-directed therapeutic targets that may complement conventional antimicrobial therapy across species. However, host-directed therapies, immunotherapeutics, and vaccines remain largely preclinical or have shown inconsistent clinical efficacy. Mechanistic evidence is strongest for Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, whereas substantial knowledge gaps persist for Enterococcus faecium, Acinetobacter baumannii, and Enterobacter spp. Overcoming persistent ESKAPE infections will require targeting conserved host-pathogen interactions alongside pathogen-specific antimicrobial resistance mechanisms.

Convergent immune evasion↗

PubMed2026

Pan-cancer single-cell atlas of immunotherapy response identifies ZNF385A as a regulator of immune evasion in small cell lung cancer.

Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of solid tumors, response rates in patients with small cell lung cancer (SCLC) remain limited, and acquired resistance is highly prevalent. The underlying mechanisms of this immunotherapy resistance remain to be fully elucidated. Clinically, SCLC typically manifests as an "immune-cold" tumor, characterized by a low abundance of CD8+ T cell infiltration and the rare formation of tertiary lymphoid structures (TLS). While DNA damage repair (DDR) is closely linked to innate immune responses, how DDR networks orchestrate the SCLC immune microenvironment remains obscure. In this study, we integrated single-cell transcriptomic data (comprising 344,447 high-quality cells) from six cancer types (BCC, CRC, HCC, HNSCC, iCCA, and SCLC). Our comparative analysis revealed a fundamental depletion of TLS-associated cellular subpopulations (e.g., CXCL13+ CD8+ T cells, HLA-DRB5+ B cells, and CXCL9+ dendritic cells) in SCLC, which was significantly correlated with aberrant DDR activity. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified ZNF385A as the core hub gene within the DDR-associated module. ZNF385A is highly expressed in SCLC and is associated with poorer prognosis. In vitro, ZNF385A depletion suppressed SCLC cell proliferation and induced apoptosis, accompanied by R-loop accumulation and activation of cGAS-STING signaling, indicating a potential link between ZNF385A, genomic stability and tumor-intrinsic innate immune signaling. Collectively, these findings identify ZNF385A as a potential regulator associated with TLS deficiency and immune evasion in SCLC.

Immunotherapy resistance↗

PubMed2021

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.

Aged↗

PubMed2026

Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion.

Viruses are intracellular parasites that reprogram the host proteome to promote replication and evade immune recognition. We applied a virome-wide library of ~10,000 open reading frames to discover viral ubiquitin ligases, mapping their mechanisms of degradation and host substrates using targeted CRISPR screens and proteomics. These viral effectors could be classified as canonical ligases that mimic host E3s, hijackers that redirect host E3s, and noncanonical ligases that rewire cullin-RING ligase machinery. These diverse strategies of virus-mediated degradation converged on immune-related substrates, including JAK1 and CUL1β-TrCP, underscoring immune evasion as a major driver of viral ubiquitin ligase evolution. Our findings elucidate viral strategies for exploiting the ubiquitin-proteasome system with potential for therapeutic targeting.

Humans↗

PubMed2026

SLA2 is Associated With Immune evasion and Exhaustion of CD8+ T Cells in Gastric Cancer.

The Src-like adaptor 2 (SLA2) functions as a negative regulator of T cell receptor signalling. However, its involvement in the tumour microenvironment (TME) of gastric cancer (GC) remains unexplored. In this study, we found that SLA2 expression was significantly elevated in GC tissues, and a high level of SLA2 was associated with poor prognosis in GC patients. Bioinformatics analyses revealed a close association between SLA2 and TME in GC. Single-cell RNA sequencing analysis indicated that SLA2 was significantly enriched in CD8+ T cells in GC tissues. Functional validation demonstrated that SLA2 overexpression contributed to the exhaustion of CD8+ T cells by suppressing their proliferation, upregulating the expression of exhaustion markers, reducing the secretion of effector cytokines (IFN-γ and TNF-α) and impairing cytotoxic function. SLA2 knockdown in in vitro-generated exhausted CD8 T cells significantly alleviated T cell exhaustion. Mechanistically, we found that inverse promoter methylation and active histone marks (H3K27ac, H3K4me3 and H3K4me1) may regulate SLA2 expression. Our findings suggest that SLA2 may modulate the TME and promote immune evasion via CD8+ T cell exhaustion in GC.

Humans↗

PubMed2026

A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.

Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1-4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

Journal Article↗

PubMed2025

High MGMT expression identifies aggressive colorectal cancer with distinct genomic features and immune evasion properties.

INTRODUCTION: The epigenetic silencing of O6-methylguanine DNA methyltransferase (MGMT) is associated with reduced DNA repair capacity, carcinogenesis and increased sensitivity to alkylating chemotherapy. However, the biological role and clinical significance of MGMT overexpression in cancer remains poorly understood. METHODS: Using multiplexed quantitative immunofluorescence we measured the localized levels of MGMT protein, γH2AX and CD8+ T cells in multiple retrospective colorectal cancer (CRC) cohorts. Genomic and transcriptomic features of selected cases were also studied with whole exome DNA sequencing and genome-wide methylation analysis. MGMT-methylated human CRC cells SW620 were transfected with an MGMT-containing plasmid and co-cultured with allogeneic peripheral blood mononuclear cells. RESULTS: A subset of CRCs showed MGMT protein upregulation associated with lower γH2AX, reduced CD8+ tumor infiltrating lymphocytes (TILs), mismatch repair proficient (pMMR) status and shorter survival. CD8+ TILs were more distant from MGMT-expressing cells than MGMT-negative cells and the MGMT promoter methylation status did not highly correlate with MGMT protein levels in CRC. In genomic/transcriptomic analysis, high MGMT expression was associated with a lower nonsynonymous somatic mutational burden, higher transition-to-transversion mutation ratio, increased deleterious TP53 variants and distinct transcriptomic profiles. The exogenous expression of MGMT in SW620 CRC cells reduced the number of spontaneous nonsynonymous mutations, reproduced mutational features of MGMT-high CRC and limited the in vitro T-cell-mediated killing of malignant cells induced by proinflammatory cytokines in tumor/immune cell co-cultures. CONCLUSIONS: MGMT overexpression identifies a previously undescribed subset of CRCs with distinct biological and clinical properties including reduced mutagenesis, adaptive immune evasion, predominantly pMMR phenotype and aggressive clinical course. Direct, quantitative assessment of MGMT protein expression using spatially resolved analysis is more reliable than inference of MGMT expression by promoter methylation status in CRC.

Humans↗

PubMed2026

Oral melanoma in the immunotherapy era: Immune evasion, resistance, and therapeutic opportunities.

Oral melanoma (OM) is a rare and highly aggressive mucosal malignancy associated with poor survival and limited evidence to guide immunotherapy. This narrative review synthesizes current knowledge on OM immunobiology and its therapeutic implications. OM differs from cutaneous melanoma in its origin in sun-protected sites, genomic architecture, and heterogeneous immune microenvironments, features that can contribute to attenuated responses to immune checkpoint inhibitors. Anti-PD-1-based therapy has demonstrated clinical activity in mucosal melanoma, and selected OM cases have shown meaningful responses, including in multimodal and perioperative settings. However, OM-specific prospective data remain sparse, and the available evidence is largely derived from pooled mucosal melanoma cohorts or case reports. Emerging combination strategies, such as antiangiogenic agents, radiotherapy, and perioperative immunotherapy, remain insufficiently validated. This review critically reappraises the available evidence, identifies key knowledge gaps, and outlines future directions for biomarker-driven, OM-specific translational research.

Humans↗

PubMed2024

Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression.

Gene therapy aims to add, replace or turn off genes to help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene therapy products. With the increasing interest in gene therapy, feasible gene delivery vectors are necessary for inserting new genes into cells. There are different kinds of gene delivery vectors including viral vectors like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, and non-viral vectors like naked DNA, lipid vectors, polymer nanoparticles, exosomes et al, with viruses being the most commonly used. Among them, the most concerned vector is adeno-associated virus (AAV) because of its safety, natural ability to efficiently deliver gene into cells and sustained transgene expression in multiple tissues. In addition, the AAV genome can be engineered to generate recombinant AAV (rAAV) containing transgene sequences of interest and has been proven to be a safe gene vector. Recently, rAAV vectors have been approved for the treatment of various rare diseases. Despite these approvals, some major limitations of rAAV remain, namely nonspecific tissue targeting and host immune response. Additional problems include neutralizing antibodies that block transgene delivery, a finite transgene packaging capacity, high viral titer used for per dose and high cost. To deal with these challenges, several techniques have been developed. Based on differences in engineering methods, this review proposes three strategies: gene engineering-based capsid modification (capsid modification), capsid surface tethering through chemical conjugation (surface tethering), and other formulations loaded with AAV (virus load). In addition, the major advantages and limitations encountered in rAAV engineering strategies are summarized.

Dependovirus↗

PubMed2026

Amplification-Driven S100A11 Overexpression in Hepatocellular Carcinoma Is Associated with Metabolic Reprogramming, ECM Remodelling, and Immune Evasion: A Pan-Cancer Genomic Study.

BACKGROUND: S100A11, a calcium-binding S100 family protein, is increasingly implicated in carcinogenesis, yet its molecular regulation and clinical relevance across cancers remain unclear. Hepatocellular carcinoma (HCC) carries a dismal prognosis, in part due to a lack of reliable biomarkers for risk stratification of established disease. METHODS: We conducted a pan-cancer analysis of S100A11 genomic alterations across 31 studies (10,767 samples) obtained from TCGA, encompassing copy number alterations, somatic mutations, and DNA methylation. HCC-specific analyses evaluated S100A11 expression, its potential as a diagnostic/prognostic marker, co-expression networks, and pathway enrichment using TCGA-LIHC data, with univariate and multivariate Cox regression to assess survival associations. RESULTS: S100A11 alterations were predominantly driven by copy number amplification, with the highest frequencies in hepatobiliary cancers, lung and breast cancers. Copy number amplification showed a consistent inverse relationship with promoter methylation, indicating amplification-driven transcriptional activation. In HCC, S100A11 was markedly overexpressed compared with normal liver tissue, with strong diagnostic discriminatory capacity. High S100A11 expression was significantly associated with inferior overall survival (log-rank p = 0.032; HR = 1.46, 95% CI 1.03-2.06) and remained an independent predictor of overall survival after adjustment for age, sex, and AJCC pathologic stage (HR = 1.27, 95% CI 1.01-1.60, p = 0.038). Co-expression and pathway analyses demonstrated an association between S100A11 and metabolic reprogramming, extracellular matrix remodelling, and immune dysregulation. CONCLUSIONS: These findings identify S100A11 as a candidate diagnostic and prognostic biomarker in HCC whose overexpression is associated with metabolic reprogramming, ECM remodelling, and immune dysregulation, warranting experimental validation of a mechanistic role.

ECM↗

PubMed2026

Upsurge of pneumococcal clade I-α/CC180 serotype 3 and its association with a LytA mutation linked to immune evasion and disease potential: an observational and experimental study.

BACKGROUND: Streptococcus pneumoniae serotype 3 is one of the most prevalent serotypes that cause invasive pneumococcal disease (IPD) in children and adults worldwide. Serotype 3 is associated with vaccine failures and breakthrough episodes in children vaccinated with 13-valent pneumococcal conjugate vaccine (PCV13). In this study, we aimed to investigate potential genetic mechanisms that could explain the increase in cases of serotype 3 IPD in Spain. METHODS: We analysed the epidemiology of serotype 3 causing IPD in Spain, during 2009-23, in different age groups. Molecular characterisation was performed by whole-genome sequencing. Host-pathogen interactions of the different lineages were evaluated in terms of interaction with lung epithelial cells, biofilm formation, and capsular polysaccharide production, using opsonophagocytosis assays and mouse models of pneumonia. We used Poisson regression models to compare incidence and chi-square test calculations to identify clonal variations across vaccine periods. FINDINGS: Genomic analyses confirmed the predominance of clade I-α/clonal complex (CC) 180 in Spain, which shows increased resistance to complement-mediated immunity and phagocytosis and enhanced potential to infect lung cells. In all isolates of this lineage, we observed a single amino acid substitution (166His→Tyr) in the crucial virulence factor LytA, which increased its enzymatic activity. On evaluating the phagocytosis of mutants without LytA of the two major lineages of serotype 3 (CC180 and CC260), LytA was responsible for the increased phagocytosis-evasion pattern of clade I-α/CC180. Evaluation of individuals with IPD caused by different serotype 3 genotypes confirmed a significant (p<0·05) association between cardiac and respiratory comorbidities and infection by sequence type 180/CC180, which showed the importance of CC180 in IPD. INTERPRETATION: Our findings confirm that PCV13 reduced IPD cases caused by the susceptible CC260 lineage until CC260 was replaced by the clade I-α/CC180 lineage, which has a higher potential to cause IPD and divert the host immune system. A key mutation on LytA protein was associated with this hypervirulent phenotype. Emerging lineages jeopardise the effectiveness of pneumococcal conjugate vaccines. FUNDING: Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, and PubMLST.

Animals↗

PubMed2026

SYT8 Drives Colorectal Cancer Progression and Immune Evasion via the SETD1A-H3K4me3 Axis.

By integrating transcriptomic data from The Cancer Genome Atlas, Gene Expression Omnibus, and a self-established colorectal cancer (CRC) cohort, it was identified that synaptotagmin 8 (SYT8) is significantly up-regulated in tumors and is predictive of poor prognosis. Single-cell RNA sequencing, immunohistochemistry, and immunofluorescence experiments demonstrate that SYT8 expression is largely confined to tumor cells, predominantly in the nucleus. Functional assays reveal that depletion of SYT8 impairs, whereas its overexpression enhances, CRC cell proliferation and invasion. Transcriptomic profiling indicates an enrichment of cell cycle and epithelial-mesenchymal transition signatures. Mechanistically, co-immunoprecipitation/mass spectrometry identifies SET domain containing 1A (SETD1A) as a direct SYT8-interacting partner. The SYT8-SETD1A axis forms a positive-feedback loop that increases histone H3 lysine 4 trimethylation (H3K4me3) levels and drives the transcription of protumorigenic genes. Immune profiling further indicates that high SYT8 expression correlates with increased regulatory T-cell infiltration, suggesting an immunosuppressive microenvironment and potential resistance to immunotherapy. Collectively, SYT8 promotes CRC progression through the SETD1A/H3K4me3-mediated activation of the cell cycle, induction of epithelial-mesenchymal transition, and remodeling of the immune microenvironment. Therefore, SYT8 is established as a prognostic biomarker and serves as a therapeutic target in colorectal cancer.

Humans↗

PubMed2025

EZH2-driven immune evasion at disease presentation defines a targetable high-risk subset of acute leukemia exemplified by t(16;21) FUS::ERG AML.

The past 25 years of clinical trials have produced few improvements in pediatric AML (pAML) outcomes. This is acutely evident in patients with t(16;21)(p11;q22), yielding FUS::ERG. Patients with FUS::ERG-positive AML relapse quickly and do not respond to transplantation. Major histocompatibility complex (MHC) class I & II receptors and costimulatory molecules are absent at diagnosis in FUS::ERG-positive AML, mirroring the phenotype and outcomes of post-transplant relapse. We show that this is driven by overexpression of EZH2, in vitro and in multiple clinical cohorts. While FUS::ERG AML is the most extreme example, this phenotype is shared by lethal CBFA2T3::GLIS2-driven AML, and patients with RUNX1::RUNX1T1 have significantly worse outcomes when EZH2 overexpression co-occurs. The FDA-approved EZH2 inhibitor tazemetostat reverses this phenotype, re-establishes MHC presentation, and elicits immune effector cell-mediated elimination. EZH2 inhibitors may provide the first targeted therapeutic frontline option for AML patients with FUS::ERG, with the potential for broader frontline immunostimulatory benefits.

Journal Article↗

PubMed2026

Integrative single-cell and genomic analysis reveals NMB as a driver of metastatic adaptation in esophageal squamous cell carcinoma via metabolic rewiring and immune evasion.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has high mortality, and metastasis is the leading cause of patient death. Neuromedin B (NMB) promotes tumor development in various cancers, yet its role in ESCC metastasis remains unclear. METHODS: We integrated single-cell transcriptomic data from matched primary and metastatic ESCC lesions (GSE309392) with bulk transcriptomic cohorts from TCGA and GSE53624. In silico gene perturbation, ligand-receptor communication analysis, and single-cell prognostic model construction were performed, followed by functional validation through siRNA-mediated NMB knockdown in TE-1 and KYSE30 cell lines. RESULTS: NMB was identified as a key gene enriched in metastatic ESCC lesions, and its high expression was associated with coordinated upregulation of oxidative phosphorylation pathway genes and aldo-keto reductase family antioxidant enzymes (AKR1C1, AKR1C2, AKR1B10). Genomic analysis revealed that NMB-high tumors carried a higher clonal mutation burden and a markedly increased frequency of NFE2L2 activating mutations (23% vs. 8%, P = 0.04). In silico knockout and correlation analysis identified AKR1C1 as a downstream effector of NMB. NMB expression was negatively correlated with CD8+ T cell and activated NK cell infiltration. CellChat analysis revealed communication between NMB-positive cells and monocytes via the TGM2-ADGRG1 axis, and specifically detected IFNG signaling. In the single-cell prognostic model, NMB-positive cells accounted for 50% of the high-risk group but only 20% of the low-risk group. TCGA-based survival analysis demonstrated that high NMB expression was associated with shorter overall survival (HR = 2.98, P = 0.03). In vitro NMB-targeted RNA interference markedly inhibited proliferation, colony formation, and migration in TE-1 and KYSE30 cells. CMap screening identified the endothelin-PDE5-cGMP axis as a potential therapeutic target. CONCLUSION: NMB serves as a key driver of metastatic adaptation in ESCC, conferring a survival advantage to tumor cells during metastatic colonization through genomic evolution and immune remodeling, with metabolic adaptation as a downstream consequence of genomic alterations.

NMB↗