Glycosylation, the covalent attachment of glycans to proteins, lipids, and RNAs, is fundamental in regulating diverse biological processes. Glycosylation patterns are aberrantly altered in the tumor microenvironment and closely associated with tumor immune escape. However, the molecular mechanisms by which glycosylation regulates tumor immune escape are poorly understood. We show that Cluster of Differentiation 47 (CD47), an innate immune checkpoint protein, is highly modified with core fucosylated N-linked glycans. Core fucosylation of CD47 mediated by fucosyltransferase 8 (FUT8) at asparagine 111 (N111) reduces CD47 ubiquitination and degradation. Blockade of N111 glycosylation represses CD47 expression and promotes macrophage phagocytosis of tumor cells. Furthermore, elimination of N111 glycosylation promotes the infiltration of CD103+ dendritic cells (DCs), leading to the increased recruitment of natural killer (NK) cells and inhibition of tumor growth in a murine hepatocellular carcinoma (HCC) model. Combined treatment with core fucosylation inhibitors and an anti-CD47 antibody synergistically promotes therapeutic efficacy in the HCC model. Finally, FUT8 levels in human HCC specimens are positively correlated with CD47 expressions and negatively correlated with the infiltration of CD103+ DC and NK cells. Collectively, this study reveals a mechanism underlying CD47 upregulation in tumor cells and highlights the potential of targeting the FUT8-SMURF1-CD47 axis as a therapeutic strategy to improve anti-tumor immune responses.

Mechanosensitive signaling pathways in immune cells drive exhaustion and ultimately facilitate tumor immune escape. In situ mechanical modulation strategies, leveraging the tumor's mechanical features, may provide a distinctive perspective for immunotherapy. We repurpose conventional silica nanocarriers from mere "drug delivery vehicles" into "Piezo1 mechanotransduction modulators" by precisely tuning their mechanical properties to directly intervene in tumor-associated macrophages (TAMs) mechanosignaling. Our study revealed that Piezo1 acts as a mechano-immunological switch in tumors: its downregulation in large tumors promotes M2-like TAMs polarization, whereas its upregulation in small tumors drives M1-mediated antitumor immunity. This directly couples mechanical cues to immune reprogramming during cancer progression. To target this pathway, we engineered mesoporous silica nanoparticles (mSNs) with tunable stiffness (253-1084.5 MPa), which were loaded with the Piezo1 agonist Yoda1 and TAMs-targeting peptide CRV (YmSNs@CRV) to precisely modulate TAMs mechanosignaling. Results demonstrated that softer 20% mSN achieved dual regulation of both macrophage phenotypic reprogramming and exosome-mediated communication via Piezo1 activation. Specifically, softer 20% mSNs enhanced pro-inflammatory markers (CD80), increased cytokine secretion, and promoted exosome production 5-fold more effectively than stiffer 80% mSNs. Proteomic analysis revealed that exosomes from 20% mSN-treated macrophages activated the TCR signaling, amplifying immune responses. In vivo, 20% YmSNs@CRV improved tumor penetration, repolarized TAMs toward an antitumor phenotype, and boosted cytotoxic T cell infiltration, significantly inhibiting tumor growth. This study integrates the mechanical characteristics of tumor tissues and proposes an "in situ mechanical dual-regulation" strategy, which combines mechano-regulated TAMs reprogramming with exosome-triggered immune responses, introducing a distinctive mechano-immunotherapeutic paradigm.

Small molecule inhibitors of the co-receptor neuropilin-1ni.

PD-L1-targeted novel molecule design: recent advances in immunomodulatory technologies and emerging insights in Cancer therapy.

Accurate and sensitive determination of sialic acid using three-dimensional Raman imaging based on a background-free SERS strategy.

Background: A major challenge in cancer treatment is the ability of tumor cells to adapt to immunotherapy through immune escape, often mediated by the PD-1/PD-L1 pathway. To investigate this, we adapted an ordinary differential equation model of combination therapy, incorporating the dynamics of the immune checkpoint inhibitor Avelumab and the immunostimulant NHS-muIL12. Methods: Using literature-derived parameter values, we refitted a single parameter across therapies, which showed that PD-L1 expression increased with immunotherapy, while Avelumab blocked its functional signaling, preventing PD-L1 from suppressing T-cell activity. Incorporating therapy-dependent, dynamically regulated PD-L1 expression enabled a biologically grounded mechanism to reproduce experimental observations, leading us to formulate PD-L1 tumor expression as a dynamic variable (ϵ) and providing a mechanistic basis for both therapeutic synergy and treatment failure. Results: We validated this mechanistic framework by showing that the distinct outcomes observed in two independent cancer datasets (EMT-6 and MC38) can be captured by the same model structure, differing only in the parameterization of tumor-specific parameters and PD-L1 regulatory dynamics. Our results indicate that tumor resistance is linked to dose-dependent upregulation of PD-L1 following NHS-muIL12 treatment, explaining treatment failure, while PD-1/PD-L1 blockade in combination therapy enables effective antitumor immune responses. Conclusions: This work provides a validated mechanistic framework for adaptive resistance in combination immunotherapy. Quantified parameter differences between responder and non-responder phenotypes enable clearer biological interpretation and support the development of predictive tools for optimizing treatment strategies.

Genes belonging to the adenylate cyclase (ADCY) family regulate various biological processes, including tumor metabolism, metastasis, angiogenesis, and immune escape. However, the functions of these genes in multiple cancers unclear. This study analyzed the expression, prognostic value, correlation, mutation, and methylation patterns of ten genes belonging to the ADCY family across multiple cancers using multi-omics data. Additionally, the correlation between ADCY5 and immune cells, as well as the function of ADCY5 in multiple cancers were examined using single-cell data and spatial transcriptomic data. Ten ADCY family genes were differentially expressed in most tumors and normal tissues, and their aberrant expression in multiple cancers significantly reduced patient survival. The expression level of ADCY5 was significantly correlated with the immune microenvironment. We also identified and validated the potential of ADCY5 as a potential biomarker for gastric cancer. Our pan-cancer analysis nominates the ADCY family as a source of potential cancer biomarkers. We specifically validated ADCY5 in gastric cancer, establishing it as a promising prognostic biomarker with clinical and functional relevance, with significant implications for optimizing immunotherapy strategies and prognostic assessment in this malignancy.

Enhancer of Zeste Homolog 2 (EZH2) is an important methyltransferase, which is overexpressed in a variety of tumors and is involved in promoting tumor growth and immune escape. Both EZH2 and C–X–C chemokine receptor type 4 (CXCR4) exhibit high-level expression in the germinal centers of lymph nodes. However, it remains unclear whether there exists a synergistic relationship between these two molecules. Our study found that approximately 90.7% of cases of diffuse large B-cell lymphoma (DLBCL) exhibited medium-to-high intensity expression of both EZH2 and CXCR4. CXCR4 and C–X–C motif chemokine ligand 12 (CXCL12) are a pair of receptor-ligands, which are related to tumor invasion and migration and immune cell infiltration in the tumor background. Our study found that the expression intensity of EZH2 and CXCR4 in CXCL12 + group DLBCL and the level of Treg cell infiltration were higher than those in CXCL12- group. In CXCL12 + DLBCL, EZH2 might regulate the infiltration level of Treg cells through CXCR4/CXCL12. In the in vitro experiment of co-culture of human Peripheral Blood Mononuclear Cells (PBMCs) and DLBCL cell lines, we also observed that under the chemotactic effect of CXCL12, the proportion of Treg cells in the oe-EZH2 group was higher than that in the oe-NC group. In DLBCL tumor cells of the oe-EZH2 group, the expression of CXCR4 could be upregulated CXCR4 through the downregulation of miR-9. Subsequently, the upregulated CXCR4 binds to the exogenous CXCL12, thereby increasing the differentiation ratio of Treg cells in PBMCs. In the subcutaneous transplanted tumor model of C–NKG mice with human T cell immune function, the sh-EZH2 group had less Treg cell infiltration in the tumor and lower tumor cell activity compared with the sh-NC group. In summary, our study found that the EZH2/miR-9/CXCR4 pathway participates in the occurrence and development of DLBCL. Specifically, high-expression EZH2 recruits the infiltration of Treg cells within the chemotactic DLBCL microenvironment via the upregulated CXCR4/CXCL12 axis. This research provides novel evidence for elucidating the immune escape mechanism of DLBCL. EZH2 and its associated signaling cascades hold the potential to serve as promising targets for the immunotherapy of DLBCL.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10238-025-01924-4.

Immunotherapy has shown a modest clinical benefit in advanced hepatocellular carcinoma (HCC), probably due to tumor immunosuppressive functions. Although Notch1 signaling has been implicated in tumor immune escape, its underlying mechanism is unclear. Here, Notch1 signaling is established as a determinant of immunotherapy efficacy in HCC. Studies showedthat high Notch1 expression correlates with poor progression-free survival and worse immunotherapeutic response in recurrent HCC patients, while Notch1 overexpression promotes cancer cell escape by inhibiting CD8+ T cell activation. Mechanistically, Notch1 overexpression upregulates the expression of transcriptional factor YY1 (Yin-Yang 1), which in turn represses ICAM1 expression to prohibit CD8+ T cell-derived granzyme-driven cancer cell pyroptosis and cytotoxicity. Finally, co-administration of a PD-L1 antibody with PEI-siYY1 represses HCC tumor growth without causing severe adverse effects, as observed with the Notch1 inhibitor DAPT. The results establish that targeting Notch1-YY1-ICAM1 signaling axis may enhance immunotherapy efficacy by activating CD8+ T cell-driven cancer cell pyroptosis, providing a safe and effective treatment strategy for HCC patients.

The onset of pancreatic cancer is insidious, and the early symptoms are similar to those of common gastrointestinal diseases, which leads to easy neglect and misdiagnosis, which greatly affects the accuracy of survival prediction. Cell migration is the hallmark of malignant tumor and the key step of metastasis. Migrasome are involved in embryonic development, immune response, angiogenesis, inflammatory response, wound healing, and cancer metastasis in vivo. Considering the unknown association between migrasome and lncRNAs in pancreatic cancer, the purpose of this study was to identify migrasome-related lncRNAs (MRLs) and explore their prognostic value. In this study, we first analyzed the Pancreatic adenocarcinoma (PAAD) data in The Cancer Genome Atlas(TCGA) database and identified the correlation between MRLs and pancreatic cancer prognosis and immune infiltrating landscape. Secondly, four MRLs (MED14OS, AC141930.2, Z97832.2, LINC01091) were selected to construct a risk model as a prognostic feature. Kaplan-Meier survival analysis, Cox regression analysis, Nomogram and Time - dependent Receiver Operating Characteristic (ROC) Curve were then used to verify the accuracy of the model. And then, the Prognostic Risk Model were used in clinical to validate the accuracy. Finally, the correlation of immune score, tumor immune cell infiltration, tumor mutation load, tumor immune escape, and drug sensitivity of the risk model was systematically analyzed. The risk-prognosis model of MRLs was constructed. Survival analysis showed that the survival rate of high-risk subtypes was lower than that of low-risk subtypes. MRL features were an independent prognostic predictor, and the area under the subject working curve (AUC) for 1-year, 3-year, and 5-year were 0.667, 0.780, and 0.865, respectively. Prognosis MRLs is related to immune infiltrating landscape and can reflect the immune status, immune response, tumor mutation burden and drug sensitivity of pancreatic cancer patients. At the same time, this model can distinguish clinical patients well. The results of this study construct a predictive model of pancreatic cancer associated with migrasome, and clarify the relevance of this model to immunotherapy and so on. It provides a new idea for improving immunotherapy and drug therapy.

The role of heat shock proteins in tumorigenesis and their potential as targets for anti-tumor therapy.

TRIML2 promotes malignant progression of head and neck squamous cell carcinoma via canonical Wnt signaling and tumor immune escape

Cannabinoids have emerged as promising agents in cancer research due to their antitumor properties. While their effects on tumor growth and survival are well documented, their influence on immune checkpoint regulation remains poorly understood. Here, we investigated the effects of cannabidiol (CBD) and a high-CBD extract (CBD-HCE) on HLA-G expression in human choriocarcinoma JEG-3 cells, a non-classical HLA class I molecule linked to tumor immune escape. Safe concentrations of CBD and CBD-HCE were determined by MTT assays. Apoptosis (Caspase-3), proliferation (Ki-67), and migration (wound healing and MMP-9 immunostaining) were assessed, and HLA-G expression was quantified by RT-qPCR and immunocytochemistry. Both CBD and CBD-HCE reduced cell proliferation and migration, increased apoptosis, and significantly downregulated HLA-G expression at both the mRNA and protein levels. This inhibitory effect was dose- and time-dependent, and fully reversible after treatment withdrawal, indicating a dynamic and CBD-dependent modulation. These results provide the first experimental evidence of HLA-G downregulation by CBD and CBD-HCE, highlighting a novel immunomodulatory mechanism with potential therapeutic implications. By simultaneously impairing tumor viability and reversing immune evasion, CBD-based compounds may enhance antitumor immunity and potentiate immunotherapy efficacy. Further research involving additional tumor cell lines, in vivo models, and immune-relevant systems are necessary to validate and expand upon these findings.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-23554-2.

Recent years have seen a marked increase in studies focusing on the mechanistic role of Aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms in tumors, yet this field lacks systematic bibliometric analysis. By analyzing publication years, countries/regions, research institutions, disciplinary domains, authorship networks, journal distributions, and keyword networks, this study reveals that global research interest in ALDH2 and tumors continues to rise. China, the United States, and Japan form the core contributing triangle, with institutions such as Aichi Cancer Center and Stanford University leading cutting-edge exploration. The research landscape concentrates on oncology, biochemistry and molecular biology, and cell biology, while interdisciplinary immunology provides innovative perspectives. Key future directions include elucidating the regulatory networks of ALDH2 polymorphisms in the metabolism-cancer axis and their associations with gastrointestinal and hematologic malignancies, alongside mechanistic studies encompassing oxidative stress modulation, ferroptosis regulation, DNA adduct formation, apoptotic cascades, DNA methylation, senescence-associated secretory phenotypes and tumor immune escape microenvironment dynamics.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-03512-0.

Abstract BACKGROUND Glioblastoma (GBM) is the most lethal primary brain tumor, characterized by rapid progression, treatment resistance, and an immunosuppressive tumor microenvironment (TME). The cGAS-STING pathway is a key sensor of cytosolic DNA that plays a critical role in innate immunity by inducing type I interferons and pro-inflammatory cytokines. In GBM, STING expression is frequently downregulated in GBM, resulting in impaired immune activation and facilitating tumor immune escape. Restoring STING activity is a promising immunotherapeutic strategy to stimulate innate immune recruitment and reprogram the TME. METHODS We evaluated cGAS-STING signaling in a panel of murine GBM stem cell lines (005, NF53, C3, RIG) that closely recapitulate patient GBM heterogeneity while allowing immunocompetent in vivo experimentation. STING was activated using synthetic agonists (e.g., ADU-S100), alone or in combination with autophagy inhibitors or G47Δ oncolytic herpes simplex virus (oHSV) therapy. RESULTS RNA sequencing and western blot analyses revealed diverse basal expression profiles of cGAS-STING components across mGSCs: C3 and RIG expressed higher levels of cGAS, while 005 and NF53 showed greater STING expression. Despite this variability, all lines responded robustly to STING agonists, with transient IRF3 phosphorylation and significant upregulation of type I interferons (e.g., IFN-β) and inflammatory chemokines (e.g., CXCL10, CCL5). Notably, STING activation reduced oHSV replication, while viral exposure dampened STING-induced signaling, suggesting viral interference with host immunity. Conversely, pharmacological inhibition of autophagy enhanced STING-driven cytokine responses, revealing a synergistic avenue for immune activation. CONCLUSION Our data highlight the therapeutic promise of cGAS-STING modulation in GBM. While oHSV therapy may antagonize STING signaling, combining STING activation with autophagy inhibition can potentiate innate immune responses. Ongoing in vivo studies aim to define how these therapies reshape the TME and improve treatment efficacy. Targeting the cGAS-STING axis represents a promising strategy to overcome immune suppression in GBM and enhance immunotherapy outcomes.

IntroductionHuman 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.MethodsIn 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.ResultsWe 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.DiscussionThese 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.

Low expression of TMSB10 in bone marrow in MDS patients with T cell large granular lymphocytic proliferation is associated with improved immune tolerance status of T cells and disease prognosis: Clinical data and single-cell sequencing analysis

Combinations of high risk cytogenetic events in multiple myeloma drive distinct immune remodeling patterns and worse outcomes

Programmed death-ligand 1 (PD-L1) is a key immune checkpoint protein that facilitates tumor immune escape and correlates with response to immune checkpoint inhibitor therapy. However, noninvasive, real-time assessment of dynamic PD-L1 expression remains challenging due to tumor heterogeneity and limitations of tissue biopsies. In this study, we rationally designed and evaluated a novel 68Ga-labeled peptide-based radiotracer, 68Ga-DOTA-P6, for PET imaging of PD-L1. The PD-L1-targeting peptide P6 was identified via a high-throughput OBOC peptide library and validated using SPR and cellular fluorescence assays. The radiotracer demonstrated high radiochemical purity (>95%) and excellent stability in saline, PBS, and fetal bovine serum (>90% intact after 2 h). In vivo micro-PET/CT imaging in H1975 and MDA-MB-231 tumor-bearing mice revealed rapid, PD-L1-dependent tumor accumulation. Co-injection of unlabeled P6 reduced tumor uptake by 69%, confirming specificity. Biodistribution studies showed highest accumulation in kidneys and significant tumor uptake. Immunohistochemistry confirmed PD-L1 overexpression in H1975 tumors, with a strong correlation between SUVmax and PD-L1 levels (r = 0.8060, p < 0.001). Together, these findings demonstrate the promise of 68Ga-DOTA-P6 for noninvasive imaging of PD-L1 expression and potential prediction of immunotherapy response.

SLC7A11 suppresses ferroptosis via arginine metabolism and promotes tumor immune escape in acute lymphoblastic leukemia