Immune Escape Research Articles (Page 1)

Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer, and its progression is significantly influenced by the tumor microenvironment (TME). Tumor-derived exosomes (TEXs), an important component of the TME, significantly influence tumor growth by regulating immune responses, facilitating metastasis, and enhancing resistance to therapy. These extracellular vesicles (EVs) transport bioactive substances, such as proteins, lipids, and nucleic acids that promote interaction between cells in the TME. Recent research indicates that HCC-derived exosomes can inhibit immune cell activity, specifically in T cells, thus creating an immunosuppressive TME that facilitates tumor immune escape. They also augment metastatic capability by restructuring the extracellular matrix and promoting angiogenesis. Moreover, HCC-derived exosomes have been associated with developing resistance to drug therapy by transferring molecules such as apoptotic signals and oncogenic microRNAs, circRNAs and lncRNA. Understanding how HCC-derived exosomes affect immune modulation, metastasis, and drug resistance could yield innovative therapeutic targets to enhance therapy outcomes. This review focuses on recent research on the diverse functions of TEXs in HCC progression.

Lactate at the crossroads of tumor metabolism and immune escape: a new frontier in cancer therapy.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, highlighting the critical need for the development of innovative and effective therapeutic strategies. Baicalein, a bioactive flavonoid derived from Scutellaria baicalensis, has emerged as a promising anticancer agent with multifaceted effects against colorectal cancer. This work summarizes into the molecular and immunomodulatory mechanisms underlying baicalein's anticancer activity. Baicalein inhibits proliferation, suppresses metastasis, induces apoptosis, and modulates key pathways like PI3K/Akt, MAPK, and TLR4/NF-κB. It enhances the tumor microenvironment by promoting immune cell infiltration, regulating cytokines, and activating CD4 + and CD8 + T cells, amplifying antitumor immunity. By targeting critical oncogenic and immune pathways, baicalein disrupts tumor progression while simultaneously enhancing immune recognition and suppressing tumor-promoting mechanisms in CRC. Additionally, baicalein influences redox homeostasis by modulating reactive oxygen species (ROS) generation and restoring oxidative balance, thereby impacting cancer cell survival and proliferation. Its anti-oxidative properties further mitigate tumor-promoting oxidative stress while sensitizing CRC cells to apoptosis. Baicalein have poor solubility and rapid metabolism limits its effectiveness against colorectal cancer, where nanotechnology-based drug delivery can overcome these challenges. By using nanoparticles (NP) and other nano-carriers to improve stability, targeting, and controlled release, baicalein's anticancer potency and safety can be significantly enhanced for future CRC therapies. Thus, baicalein-NP conjugates can strengthen the immune defense and blocks cancer-promoting signals in colorectal cancer.

Modular design of a self-amplifying mRNA vaccine for multivalent immunization against Neisseria meningitidis B.

Chromatin regulators (CRs) play a critical role in tumorigenesis, drug response, and prognosis, with dysregulation of chromatin regulator genes (CRGs) potentially disrupting the tumor immune microenvironment (TME) and influencing immune responses in cervical cancer. However, the prognostic and therapeutic implications of integrating CRGs and TME parameters in cervical cancer remain poorly understood. This study used prognostic CRGs and TME cell signatures identified through Cox regression and Kaplan-Meier survival analyses to construct the CRG and TME score. The CRG score for each cell was calculated by integrating single-cell and spatial transcriptome, which were subsequently integrated to develop a CRG-TME classifier for prognostic prediction. The prognosis, somatic mutations, immune characteristics, therapeutic benefits, and drug sensitivity were then analyzed across CRG-TME defined subgroups. Both CRG score and TME score demonstrated prognostic value, and the high CRG score group showed distinct alterations in TME signaling dynamics and increased intensity of intercellular communication. Patients in CRGlow/TMEhigh subgroup exhibited enhanced prognosis and therapeutic responses compared to other subgroups, attributable to variations in tumor somatic mutations, immune-related molecules, cancer signaling pathways and drug sensitivity. Additionally, the clinical sample verification and in vitro experiments demonstrated that the key prognostic gene TSPYL2 was downregulated in cervical cancer tissues and overexpression of TSPYL2 inhibited the malignant progression of cervical cancer cells via regulating MAPK pathway and immune escape. This study develops a novel CRG-TME classifier to predict prognosis and therapy response in cervical cancer and unveils the inhibitory effect and underlying mechanism of TSPYL2 on cervical cancer progression.

The phospholipid scramblases Xkr8 and TMEM16F externalize phosphatidylserine (PS) by distinct mechanisms. Xkr8 is activated by caspase-mediated proteolytic cleavage and, in synergy with the inactivation of P4-ATPase flippases, results in the irreversible externalization of PS on apoptotic cells and an "eat-me" signal for efferocytosis. In contrast, TMEM16F is a calcium-activated scramblase that reversibly externalizes PS on viable cells via the transient increase in intracellular calcium in live cells. The tumor microenvironment (TME) is abundant with exposed PS, resulting from prolonged oncogenic and metabolic stresses and high apoptotic indexes of tumors. Such chronic PS externalization in the TME has been linked to host immune evasion from interactions of PS with inhibitory PS receptors, such as TAM and TIM family receptors. Here, in an effort to better understand the contributions of apoptotic vs live cell PS-externalization to tumorigenesis and immune evasion, we employed an EO771 orthotopic breast cancer model and genetically ablated Xkr8 and TMEM16F using CRISPR/Cas9. While neither the knockout of Xkr8 nor TMEM16F showed defects in cell intrinsic properties related to proliferation, tumor-sphere formation, and growth factor signaling, both knockouts suppressed tumorigenicity in immune-competent mice, but not in NOD/SCID or RAG-knockout immune-deficient strains. Mechanistically, Xkr8-KO tumors suppressed macrophage-mediated efferocytosis, and TMEM16F-KO suppressed ER stress/calcium-induced PS externalization. Our data support an emerging idea in immune-oncology that constitutive PS externalization, mediated by scramblase dysregulation on tumor cells, supports immune evasion in the tumor microenvironment. This links apoptosis/efferocytosis and oncogenic stress involving calcium dysregulation, contributing to PS-mediated immune escape and cancer progression.

The integration of chimeric antigen receptor (CAR) therapies with precision medicine holds potential to impact the treatment landscape for acute myeloid leukemia (AML). Genetic mutations play a role in the efficacy of CAR-T and CAR-NK cells, influencing their crucial role in determining the effectiveness of these cells, as well as their proliferation, persistence, resistance, and safety. This review examines how mutations in FLT3, DNMT3A, NPM1, TP53, TET2, gene fusions involving RUNX1 and KMT2A and other key genes modulate CAR-based immunotherapies, highlighting both vulnerabilities and resistance mechanisms. Recent findings demonstrate that mutations in genes such as DNMT3A and NPM1 enhance antigen expression, thereby improving CAR targeting. In contrast, mutations in TP53 drive immune escape and resistance to therapy. Understanding these mutation-specific effects is essential for tailoring CAR therapies to individual patients, optimizing efficacy while minimizing toxicity. By leveraging genomic profiling and personalized engineering approaches, CAR therapies can be refined to overcome resistance and enhance precision in AML treatment. Future research should focus on integrating multiomic data to develop mutation-adapted CAR strategies, ensuring that patients receive the most effective and personalized immunotherapy.

Gynecological cancer remains one of the leading causes of mortality worldwide. Recent advances in genomic and molecular sequencing have significantly enhanced our understanding of the biological pathways that drive tumor progression and resistance to therapy. Targeted therapies, including monoclonal antibodies (mAbs), have revolutionized cancer treatment by selectively interfering with oncogenic proteins expressed on cancer cells. However, the long-term clinical benefit is often limited due to the emergence of drug resistance, frequently mediated by compensatory signaling pathways or immune escape mechanisms. To overcome these limitations, bispecific antibodies (bsAbs) represent an innovative class of therapeutic agents that have shown promising results across various medical fields. They have been developed to engage two distinct targets simultaneously, such as tumor antigens, immune effectors, or immunomodulatory checkpoints, thereby enhancing anti-tumor activity and reducing the risk of resistance. There are 17 bsAbs approved for clinical use in various countries, with numerous others currently in active development and over 600 bsAbs undergoing clinical trials worldwide. Among these, 11 have received FDA approval for the treatment of hematologic malignancies as well as solid tumors, including uveal melanoma, metastatic non-small cell lung cancer, small cell lung cancer, and biliary tract cancers. Although some studies have explored bsAbs in gynecological cancers, this area remains underdeveloped compared to other oncology fields. Most ongoing studies in this area are still in their early phases (phase I or phase II), and there is a need for optimization in terms of antibody design, efficacy, and safety profiles. Therefore, the purpose of this review is to present a comprehensive summary of the current research on bsAbs in gynecological cancers, with a focus on endometrial, cervical, and ovarian cancers. We will highlight ongoing clinical trials, discuss the mechanisms of action of these agents, and explore their potential benefits in enhancing treatment outcomes.

Objective AT-rich interaction domain 1A (ARID1A), is frequently mutated in cancer, leading to loss-of-function and posing challenges to therapeutic targeting. This study aimed to systematically explore epigenetic regulation of ARID1A, specifically promoter hypermethylation, in gastric cancer (GC) and its functional/immunological consequences. Methods We employed multi-omics bioinformatics analyses (UALCAN, cBioPortal, MEXPRESS and UCSC Xena) combined with in vitro functional validation in GC cell lines, including pharmacological demethylation using 5-Aza-2’-deoxycytidine (5-aza-CdR) and mechanistic interrogation via AKT agonism (SC79). Results Promoter hypermethylation was identified as a key mechanism silencing ARID1A transcriptional, showing a significant negative correlation between methylation β -values and mRNA expression (Spearman’s ρ = − 0.29, p = 2.06 × 10 −8 ). 5-aza-CdR treatment restored ARID1A expression ( p < 0.001), suppressed malignant phenotypes (proliferation, invasion, and apoptosis resistance), and revealed that ARID1A lose activates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (elevated p-AKT, p-mTOR) and upregulates PD-L1. Rescue experiments with SC79 reversed 5-aza-CdR’s effects, confirming the ARID1A-PI3K/AKT/mTOR-PD-L1 axis. Integrative analysis linked ARID1A hypermethylation to elevated immune/ESTIMATE scores ( p < 0.05). Conclusion ARID1A promoter hypermethylation drives an epigenetic-immune checkpoint cascade in GC. Combined with its association with immune signatures and PD-L1 upregulation, ARID1A hypermethylation emerges as a candidate biomarker for predicting immune checkpoint blockade (ICB) responsiveness and patient stratification in GC. Future studies should evaluate 5-aza-CdR-ICB-AKT inhibitor regimens in advanced models to guide clinical translation.

Post-translational modification is an important mechanism for regulating protein function and cell signaling networks. Among these modifications, ISGylation is a ubiquitin-like modification regulated by ISG15. In this review, we explore the role of ISGylation in a variety of related phenotypes in the tumor context, including apoptosis regulation, autophagy regulation, immune escape, metabolic reprogramming, cancer stem cell maintenance, and DNA damage repair. ISGylation plays a dual role in apoptosis, promoting either pro-survival or pro-death pathways depending on contexts. It also regulates autophagy by promoting tumor adaptation or by regulating immune responses. Moreover, ISGylation contributes to the immune escape mechanism by regulating the stability of PD-L1 and immune cell infiltration. In addition, ISGylation is involved in metabolic reprogramming, supporting tumor growth and therapeutic resistance by regulating key metabolic pathways. It also plays a key role in maintaining the properties of cancer stem cells by stabilizing essential metabolic and signaling proteins. In sum, this review examines the functions and mechanisms of ISG15 and ISGylation in various tumor-associated phenotypes, enhancing our understanding of their role in tumorigenesis and disease progression.

Immune system control is a principal hurdle in cancer evolution. The temporal dynamics of immune evasion remain incompletely characterized, and how immune-mediated selection interrelates with epigenome alteration is unclear. Here we infer the genome- and epigenome-driven evolutionary dynamics of tumor-immune coevolution within primary colorectal cancers (CRCs). We utilize a multiregion multiomic dataset of matched genome, transcriptome and chromatin accessibility profiling from 495 single glands (from 29 CRCs) supplemented with high-resolution spatially resolved neoantigen sequencing data and multiplexed imaging of the tumor microenvironment from 82 microbiopsies within 11 CRCs. Somatic chromatin accessibility alterations contribute to accessibility loss of antigen-presenting genes and silencing of neoantigens. Immune escape and exclusion occur at the outset of CRC formation, and later intratumoral differences in immuno-editing are negligible or exclusive to sites of invasion. Collectively, immune evasion in CRC follows a 'Big Bang' evolutionary pattern, whereby it is acquired close to transformation and defines subsequent cancer-immune evolution.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, with therapeutic resistance posing the primary barrier to durable outcomes. Beyond genetic and epigenetic alterations, amino acid transporter-driven metabolic reprogramming—mediated by LAT1 (SLC7A5), ASCT2 (SLC1A5), and xCT (SLC7A11)—supports tumor proliferation, redox homeostasis, and immune escape. Their preferential expression in NSCLC highlights their potential as therapeutic targets and predictive biomarkers. In parallel, α-particle therapy has gained attention for its capacity to eradicate resistant clones through densely clustered, irreparable DNA double-strand breaks. Astatine-211 (211At) combines a clinically relevant half-life, high linear energy transfer, and predictable decay scheme, positioning it as a unique candidate among α-emitters. Preclinical studies of 211At-labeled transporter ligands, particularly LAT1-targeted conjugates, demonstrate potent tumor suppression and synergy with targeted therapy, chemotherapy, radiotherapy, immunotherapy, and ferroptosis inducers. Advances in radiochemistry, delivery systems (antibodies, peptides, and nanocarriers), and PET tracers such as [18F]FAMT and [18F]FSPG collectively support a theranostic framework for patient stratification and adaptive dosing. By linking transporter biology with α-particle delivery, 211At-based theranostics offer a mechanistically orthogonal strategy to overcome resistance and heterogeneity in NSCLC. Successful translation will depend on precise dosimetry, scaffold stabilization, and biomarker-guided trial design, enabling progression toward first-in-human studies and future integration into multimodal NSCLC therapy.

BackgroundCervical cancer remains a major threat to women’s health worldwide. Discoidin domain receptor 1 (DDR1) drives immune evasion in a variety of cancers, but its expression pattern, clinical significance, and immunoregulatory mechanisms in cervical cancer have not been clarified.MethodsDDR1 expression profiles were resolved based on TCGA and GEPIA2 databases; DDR1-related pathways were enriched by GO/KEGG/GSEA; immunohistochemistry was performed in 40 cases of cervical cancer and 20 cases of normal tissues to assess the association of the DDR1 protein with clinicopathological features and survival prognosis for clinical validation. In addition, the biological role of DDR1 in cervical cancer was detected by Western blot, CCK8 and transwell.ResultsDDR1 was significantly overexpressed in cervical cancer and correlated with advanced FIGO stage and poor overall survival; DDR1 can promote the proliferation and migration of cervical cancer cells, and at the same time affect immune escape by reshaping the tumor microenvironment and metabolic reprogramming.ConclusionDDR1 is able to remodel the immunosuppressive microenvironment. Targeting DDR1 may overcome immune escape and provide a new therapeutic strategy for cervical cancer.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-025-15099-4.

Introduction Human leukocyte antigen G (HLA-G) can induce tumor immune escape, facilitating tumor progression. Extracellular vesicles (EVs) are also involved in tumor progression, due to its activity on metastatic niche preparation and immune system modulation. However, the role of EVs bearing HLA-G, on its surface or cargo, is still few explored. Methods In this cross-sectional study, participants with benign (nevi) and malignant melanocytic lesions were recruited. Plasma large EVs (LEVs, ~100-900nm) were isolated by differential centrifugation and analyzed by nanoscale flow cytometry, nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Plasma soluble HLA-G (sHLA-G) and intravesicular HLA-G (int-HLA-G) were measured by ELISA. Results We included 68 patients (37 melanoma and 31 nevi), presenting a mean age of 57.9 ± 15.7 years-old and 67.6% were female. No differences were seen for particle count and size by NTA (p>0.05), or for total LEVs between benign and malignant lesions (p=0.8); however, sHLA-G levels were significantly higher in melanoma (p=0.02). Among patients with benign lesions, previous neoplasm was related to higher LEVs-HLA-G+ count (p=0.001) and int-HLA-G levels (p=0.03). Nevertheless, LEVs-HLA-G+ seems to be related to melanoma subtypes, especially with acral lentiginous melanoma. Moreover, sHLA-G was elevated in melanoma with head and neck localization (p=0.001). A preliminary in vitro assay showed that HLA-G may increase IL-6 secretion by leukocytes in the same way that plasma-derived LEVs from melanoma patients. Discussion These results may suggest that sHLA-G may be a promising biomarker to predict malignant melanocytic lesions; however, it is important to consider previous neoplasms. Also, its application may be relevant for specific histological subtypes and lesion sites.

Chronic hepatitis B virus (HBV) and Occult HBV infection (OBI) remain a health burden in sub-Saharan Africa. This study investigated HBV prevalence, circulating genotypes, and associated risk factors with HBV exposure among HIV-positive adults on antiretroviral therapy and pregnant women in southwestern Cameroon. A total of 233 HIV patients and 190 third-trimester pregnant women were screened for HBV DNA, viral load, serological markers (HBsAg, anti-HBc, and anti-HBs), and HBV genotypes were determined by partial sequencing of the S gene. HBV DNA was detected in 10% of HIV-positive patients and 4% of pregnant women, with an overall prevalence of 7%. OBI accounted for 9% and 3%, respectively. Anti-HBc seroprevalence was high (75% in HIV, 46% in pregnant women), while self-reported vaccination coverage was low (1% and 11%). Genotypes A, B, D, and E were identified, with genotype B reported for the first time in Cameroon. Immune escape mutations and the adefovir resistance mutation rtA181V were detected. Self-reported alcohol use was associated with HBV exposure in HIV patients (aOR = 2.08; p = 0.028) and inversely associated with tertiary education in pregnant women (aOR = 0.18; p = 0.038). This study highlights a significant burden of HBV and OBI among vulnerable populations in Cameroon.

The transfer of molecular cargo in exosomes plays a crucial role in cancer progression, influencing metabolic processes, angiogenesis, immune interactions, and invasive capabilities. This review synthesizes current evidence on how exosomes modulate tumor metabolism and drive drug resistance, and outlines therapeutic opportunities. We searched PubMed, Scopus, Web of Science, and Google Scholar for English-language studies using terms related to exosomes/extracellular vesicles, glycolysis, oxidative phosphorylation (OXPHOS), lipid metabolism, and drug resistance/chemoresistance, and integrated the literature qualitatively. Evidence indicates that exosomes reprogram tumor and stromal metabolism by delivering enzymes and non-coding RNAs that boost glycolysis and dampen OXPHOS, activate cancer-associated fibroblasts and extracellular matrix (ECM) remodeling, and modulate ferroptosis. They stimulate angiogenesis (e.g., via vascular endothelial growth factor (VEGF)/Wnt pathways) and promote immune escape through programmed death-ligand 1 (PD-L1), transforming growth factor beta (TGF-β), and macrophage reprogramming. Exosomal integrins and proteases contribute to epithelial-mesenchymal transition (EMT), organotropism, and pre-metastatic niche formation. Critically, exosomes propagate chemoresistance by exporting drugs and spreading determinants-including P-gp/BCRP/MRP-1, anti-apoptotic proteins, and regulatory RNAs-to previously sensitive cells; adipose-derived vesicles and lipid cargos further reinforce metabolic plasticity and therapy resistance. Given their stability, nanoscale dimensions, and ability to cross the blood-brain barrier, exosomes are promising vectors for targeted delivery; engineered vesicles can enhance chemotherapy responsiveness and counteract resistance, particularly alongside immunotherapy. In summary, interventions that disrupt exosome biogenesis, cargo loading, or uptake-paired with engineered exosomes for precision delivery-could mitigate drug resistance, metastasis, and immune evasion and advance more effective cancer treatment.

BackgroundProcollagen-lysine 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is important for extracellular matrix formation and is involved in a variety of diseases, including cancer; however, its role in gastric cancer (GC) remains elusive. Therefore, this study aimed to explore the mechanistic importance of PLOD1 as a regulator of GC.MethodsWe examined the potential function and prognostic efficiency of PLOD1 in GC using a variety of bioinformatics methods. In vitro, we assessed the ability of PLOD1 to regulate GC by CCK-8 assay, Transwell assay, and Elisa assay analysis. Furthermore, we evaluated the effect of PLOD1 on the immune escape of GC cells by CCK-8 assay, flow cytometry, and Elisa assay.ResultsAnalysis of PLOD1 expression in gastric cancer and other cancers in public databases as well as survival showed that low expression of PLOD1 has better survival, while the AUC area under the ROC curve of this gene showed that this gene has better prognostic value. Meanwhile, the results of correlation analysis between PLOD1 and 60 immune checkpoints showed that the gene was positively correlated with immune checkpoint genes, and one of the genes with the largest correlation was CD276, and the pearson’s correlation between PLOD1 and cancer immune cycle was also calculated, and the relationship between PLOD1 and the immune microenvironment was evaluated, and the enrichment of the immune infiltration analysis into a larger number of immune cells among which the importance of PLOD1 was determined. Differential gene analysis was then performed on the gastric cancer dataset, using the differential genes to perform WGCNA network co-expression analysis with the PLOD1 gene, and then pathway enrichment analysis was performed on these differential genes, enriching for cancer-related pathways and cell cycle signaling pathways. Two key genes were then obtained in the analysis with glycolysis, while drug sensitivity analysis was performed, yielding multiple potential drugs such as AZD7545, BRD-K03911514 and BRD-K14844214. Furthermore, in vitro experiments further demonstrated that PLOD1 increased the proliferation and migration ability of GC cells by promoting immune escape.ConclusionsThe results of this study suggest that PLOD1 is an important regulator of GC progression and participates in the immune escape process of GC, which is expected to be a potential target for GC treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-03774-8.

Genome instability, tumour-promoting inflammation, and immune escape are three distinct hallmarks of cancer. However, accumulating scientific and clinical evidence over the past decade have uncovered a multifaceted interplay of complex dynamic network of interactions between genome instability, the DNA damage response (DDR), and tumour immunogenicity. Fuelled by the clinical successes of immune checkpoint blockers (ICB), growing interest for immuno-oncology and recent cancer biology discoveries have allowed a better understanding of the underlying biology and clinical opportunities brought by this interplay-which is yet, still only in its infancy. The cooperative nature of tumour cell-intrinsic and -extrinsic mechanisms involved suggests that harnessing genomic instability in cancer does not only hamper cancer cells fitness but also stimulate the anti-tumour immune response, thereby paving the way to the development of DDR-based immunomodulatory therapeutic strategies applicable to a variety of molecular and histological cancer types. Here, we review the various aspects of this crosstalk between genome instability and tumour immunogenicity, including feedforward and feedback mechanisms affecting either side of this interplay, as well as the specific consequences of chromosomal instability. We further discuss emerging DDR-based predictive biomarkers of response to ICB therapies, and finally examine the latest clinical developments of therapeutic combinations that exploit the DDR-immunity interplay in immuno-oncology.

BackgroundT cell dysfunction in the tumor microenvironment (TME) is a major obstacle to effective immunotherapy in triple-negative breast cancer (TNBC). The molecular mechanisms underlying T cell exclusion remain poorly understood.PurposeThis study identifies RANBP1 as an oncogenic factor in TNBC and investigates its role in modulating T cell infiltration and tumor progression.MethodsSingle-cell and bulk RNA sequencing were used to assess immune cell infiltration associated with RANBP1 expression. RANBP1 protein levels were evaluated in 87 TNBC tumor and adjacent normal tissues by immunohistochemistry. Kaplan–Meier analysis was used to assess overall survival. In vitro and in vivo assays were performed to explore the RANBP1/miR-769-5p/PRUNE2 pathway.ResultsscRNA-seq identified 10 cell types in the TNBC TME. High RANBP1 expression correlated with increased tumor cells, B cells, macrophages, and epithelial cells, and reduced T cells. Cell–cell communication was enhanced in the high-RANBP1 group. TCGA and GSE65194 data confirmed decreased CD4⁺ T cells and Tregs in high-RANBP1 tumors. RANBP1 was significantly upregulated in TNBC and associated with poor prognosis. Functional studies showed that RANBP1 promotes TNBC cell proliferation and migration. Mechanistically, RANBP1 upregulates oncogenic miR-769-5p, which suppresses PRUNE2, a tumor suppressor that normally inhibits TNBC progression.ConclusionsRANBP1 shapes an immunosuppressive microenvironment in TNBC by reducing T cell infiltration through the miR-769-5p/PRUNE2 axis. These findings reveal a novel immune escape mechanism and suggest that targeting RANBP1 may enhance immunotherapy efficacy in TNBC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-03872-7.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and core component of the polycomb repressive complex 2 (PRC2), is an important player in cancer progression through its powerful effects on chromatin remodeling and gene silencing. In addition to its classical role in regulating the cell cycle and tumor proliferation, numerous publications have identified the broad role of EZH2 in modulating the tumor immune microenvironment (TIME), leading to immune evasion and resistance to immunotherapy. EZH2 has been shown to silence immune surveillance genes by binding to H3K27me3 histone, leading to epigenetic silencing in lymphomas and thereby reducing tumor immunogenicity, which facilitates immune escape. EZH2 also modulates the recruitment and activity of immunosuppressive cells by epigenetically modifying cytokine and chemokine networks. Importantly, EZH2 upregulates PD-L1 expression either directly or indirectly through its pro-oncogenic activation of STAT3 signaling, which induces T cell exhaustion and ultimately resistance to checkpoint inhibitors in cancers such as breast cancer and glioblastoma. Furthermore, EZH2 also influences the regulation of immune-related microRNAs, including the suppression of the miR-144/451a cluster, which encourages immunosuppressive macrophage polarization. Pharmacological EZH2 inhibition has been shown to be an arm of a synergistic therapy, combining immune checkpoint blockade therapies, which can reinstate antigen presentation and T cell infiltration, highlighting EZH2 as an essential epigenetic modulator of tumor-immune interactions. It remains a viable target for therapy to overcome immune resistance and improve cancer immunotherapy outcomes.