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PubMed2025

Effect of extracellular vesicles in remodeling the tumor microenvironment by DNMT1 downregulation for enhanced cancer immunotherapy.

BACKGROUND: The efficacy of immunotherapy is often hindered by the suppression of immune responses via the tumor microenvironment (TME). The presence of cancer cells forces other proximal non-cancerous cells to support tumor growth and persistence. A clear example of this cancerous-to-non-cancerous communication is represented by the accumulation of myeloid-derived suppressor cells (MDSCs) within the TME. Several studies have convergently shown that the overexpression of DNA-methyl-transferase-1 (DNMT1) in these cells results in protection from necroptosis and enhanced accumulation in vivo. Conversely, targeting DNMT1 through hypo-methylating agents has shown promising therapeutic potential by not only reducing the levels of MDSCs but also enhancing cancer immunogenicity and the efficacy of immune checkpoint inhibitors (ICI). METHODS: Murine 4T1 (triple-negative breast cancer (TNBC)) and CT26 (colon carcinoma) cell lines were cultured under standard conditions and used to generate tumor models in BALB/c mice. An oncolytic adenovirus expressing a DNMT1-targeting short hairpin RNA (OAd.shDNMT1) was engineered and validated for DNMT1 knockdown and genome-wide methylation reduction. Small extracellular vesicles (sEVs) were isolated from virus-infected cancer cells and characterized for RNA content and uptake by MDSCs. MDSC differentiation and suppressive function were assessed in vitro using flow cytometry and co-culture assays with murine splenocytes. In vivo, tumor-bearing mice received intratumoral OAd.shDNMT1, systemic decitabine, or immune checkpoint inhibitors (anti-Programmed cell Death protein-1), and tumor growth, immune infiltration, and systemic MDSC levels were evaluated. RESULTS: In this study, we report that, by using virally infected TNBC murine cells as a source for shDNMT1-loaded sEVs, OAd.shDNMT1 successfully reduced MDSC levels in vitro and in vivo. Furthermore, the co-administration with ICI resulted in a significant tumor growth reduction in mice bearing poorly immunogenic TNBC 4T1 cells. Also, our treatment promoted antitumor immunity, prolonged survival, and complete tumor eradication in modestly immunogenic colon CT26 cancer cells. CONCLUSION: This multifaceted strategy, based on OV-mediated immune stimulation and reduction of MDSC levels via sEVs, may improve clinical outcomes and the success of immuno-based regimens for patients facing MDSC-rich and highly aggressive cancer subtypes.

Animals↗

PubMed2025

HMGA2 links morphological evolution and microenvironment dynamics to systemic therapy response in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits significant heterogeneity due to morphological changes and tumor microenvironment dynamics, influencing systemic therapy responses. While the role of high-mobility group AT-hook 2 (HMGA2) in tumor progression has been implicated in other cancers, its significance in ccRCC remains unclear. This study investigates the role of HMGA2 in these processes and its clinical impact. METHODS: Spatial transcriptomics (ST) was performed on primary ccRCC samples to investigate expression trajectories associated with HMGA2 expression and morphological evolution. In metastatic ccRCC cohorts treated with systemic therapy, immunohistochemistry and bulk RNA sequencing data were analyzed to evaluate molecular and clinical features in relation to HMGA2. Single-cell RNA sequencing (scRNA-seq) data were used to explore immune cell populations and their interactions. Based on these findings, multiplex immunohistochemistry (mIHC) assessed spatial distribution, cell-cell interactions, and pathological responses of key immune populations. RESULTS: HMGA2 expression was associated with aggressive morphological patterns, such as solid sheets and rhabdoid/sarcomatoid. ST revealed a progressive increase in HMGA2 expression along the morphological trajectory, marked by a shift from clear to eosinophilic cytoplasm, with eccentric nuclei and prominent nucleoli, and loss of vascular architecture. HMGA2-high tumors exhibited aggressive phenotypes driven by cell cycle, epithelial-mesenchymal transition, and inflammatory signaling pathways. Clinically, patients with high HMGA2 had worse progression-free survival but responded better to immune checkpoint inhibitor combination (Combo-ICI) therapy than to tyrosine kinase inhibitor monotherapy. To assess the immune landscape, scRNA-seq data revealed that HMGA2-high tumors were enriched with progenitor exhausted CD8+ T cells (Tpex), along with increased frequencies of conventional dendritic cell type 1 (cDC1) and inflammatory cDC type 2, which were found to interact with Tpex via ICAM-1. mIHC confirmed that Tpex were enriched among Combo-ICI responders in HMGA2-high tumors, with higher densities and closer proximity to ICAM-1+ cDC1. CONCLUSIONS: These findings suggest that dynamic HMGA2 expression contributes to morphological evolution and modulates immune responses through enhanced Tpex-cDCs engagement, serving as a potential marker for systemic therapy response in ccRCC. However, additional experimental studies are required to validate these mechanisms.

Humans↗

PubMed2025

Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.

Humans↗

PubMed2026

Multinucleated Giant Cells in Human Pancreatic Cancer Are a Distinct Macrophage Population Undergoing a DNA Damage Response and Associated with an Aggressive Tumor Microenvironment.

Macrophages (Mϕ) constitute a dominant and functionally diverse immune population within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), yet how Mϕ heterogeneity contributes to the tumor remains poorly defined. In an institutional cohort of 145 PDAC specimens, we identified a population of multinucleated giant cells (MGC) of Mϕ origin, an entity previously described in chronic inflammation but rarely in cancer. CD68+ MGCs were present in 28% of tumors, enriched in squamous, nonglandular regions, and more frequent after neoadjuvant chemotherapy. By integrating spatial transcriptomics and quantitative imaging, we defined the features of these cells, which, compared with MGCs in nonneoplastic inflammatory lesions, lacked canonical polarization markers (HLA-DR and CD163) and displayed a distinctive transcriptional program characterized by upregulation of the POLR2K, TUBA8, COX5B, and VDAC1 genes, which encode proteins involved in DNA repair, oxidative stress, and MYC signaling. Spatial analyses revealed activation of hypoxia and extracellular matrix-remodeling pathways in MGC-associated niches, and experimental hypoxia promoted MGC formation in vitro. Consistent with these data, we found that in the The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) dataset a Mϕ MGC gene signature was enriched in the squamous PDAC subtype and correlated with poorer overall survival (P = 0.018). Morphometric and immunofluorescence analyses further showed increased 53BP1+Ki67+ nuclei and nuclear atypia in MGCs, indicating ongoing proliferation despite DNA damage. Together, these data identify MGCs of Mϕ origin as an immune cell state shaped by hypoxia and stress signaling, associated with aggressive tumor phenotypes, and potentially exploitable as an immune classifier in PDAC.

Humans↗

PubMed2026

Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment by dampening cytokine secretion.

Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.

Animals↗

PubMed2024

Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment.

CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.

CD8-Positive T-Lymphocytes↗

PubMed2024

Integrated bioinformatics analysis and experimental validation reveal the relationship between ALOX5AP and the prognosis and immune microenvironment in glioma.

BACKGROUND: Treatment of gliomas, the most prevalent primary malignant neoplasm of the central nervous system, is challenging. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) is crucial for converting arachidonic acid into leukotrienes and is associated with poor prognosis in multiple cancers. Nevertheless, its relationship with the prognosis and the immune microenvironment of gliomas remains incompletely understood. METHODS: The differential expression of ALOX5AP was evaluated based on public Databases. Kaplan-Meier, multivariate Cox proportional hazards regression analysis, time-dependent receiver operating characteristic, and nomogram were used to estimate the prognostic value of ALOX5AP. The relationship between ALOX5AP and immune infiltration was calculated using ESTIMATE and CIBERSORT algorithms. Relationships between ALOX5AP and human leukocyte antigen molecules, immune checkpoints, tumor mutation burden, TIDE score, and immunophenoscore were calculated to evaluate glioma immunotherapy response. Single gene GSEA and co-expression network-based GO and KEGG enrichment analysis were performed to explore the potential function of ALOX5AP. ALOX5AP expression was verified using multiplex immunofluorescence staining and its prognostic effects were confirmed using a glioma tissue microarray. RESULT: ALOX5AP was highly expressed in gliomas, and the expression level was related to World Health Organization (WHO) grade, age, sex, IDH mutation status, 1p19q co-deletion status, MGMTp methylation status, and poor prognosis. Single-cell RNA sequencing showed that ALOX5AP was expressed in macrophages, monocytes, and T cells but not in tumor cells. ALOX5AP expression positively correlated with M2 macrophage infiltration and poor immunotherapy response. Immunofluorescence staining demonstrated that ALOX5AP was upregulated in WHO higher-grade gliomas, localizing to M2 macrophages. Glioma tissue microarray confirmed the adverse effect of ALOX5AP in the prognosis of glioma. CONCLUSION: ALOX5AP is highly expressed in M2 macrophages and may act as a potential biomarker for predicting prognosis and immunotherapy response in patients with glioma.

Humans↗

PubMed2025

Radiogenomic MRI biomarkers for noninvasive prediction of GPC3 expression and tumor microenvironment in hepatocellular carcinoma.

BACKGROUND: Glypican-3 (GPC3) is frequently overexpressed in hepatocellular carcinoma (HCC) and plays a key role in immune and metabolic remodeling of the tumor microenvironment. Reliable noninvasive biomarkers for predicting GPC3 status could improve patient stratification and support precision immunotherapy. METHODS: This multicenter retrospective study included 274 patients with pathologically confirmed hepatocellular carcinoma from three institutions, 34 external cases with MRI from The Cancer Imaging Archive, and 363 transcriptomic profiles from The Cancer Genome Atlas. Contrast-enhanced T1-weighted imaging and diffusion-weighted imaging were analyzed. Tumor and peritumoral regions were segmented manually and radiomic features extracted using PyRadiomics. Feature selection was performed with correlation filtering and least absolute shrinkage and selection operator regression. Machine learning classifiers including logistic regression, random forest, support vector machine, k-nearest neighbor, and decision tree were trained with 10-fold cross-validation and tested on independent external cohorts. A radiomics score was calculated for each patient. Radiogenomic analysis correlated radiomics scores with transcriptomic data using weighted gene co-expression network analysis. Hub genes and enriched pathways were identified, and immune infiltration and predicted immunotherapy response were assessed using computational methods. RESULTS: The random forest model using contrast-enhanced T1-weighted imaging achieved an area under the curve of 0.966 in training and 0.935 in internal validation. The integrated contrast-enhanced T1-weighted imaging plus diffusion-weighted imaging model reached an internal validation area under the curve of 0.979. In external testing, the best performance was obtained with a support vector machine model (area under the curve 0.756). Radiomics scores were significantly correlated with GPC3 expression (R = 0.78, p < 0.05). Transcriptomic analysis identified a 10-gene signature enriched in hypoxia and lipid metabolism pathways that stratified patients into prognostic subgroups (concordance index 0.720, hazard ratio 4.07, p < 0.0001). High-risk patients had greater immune infiltration and a lower predicted immune evasion score, suggesting a potential benefit from immunotherapy. CONCLUSIONS: MRI-based radiomics models can noninvasively predict GPC3 expression in hepatocellular carcinoma. Radiomics scores reflect underlying hypoxia and lipid metabolism pathways and stratify patients by prognosis and predicted immunotherapy response. These findings support radiogenomics as a translational approach to imaging-guided precision treatment in hepatocellular carcinoma.

Humans↗

PubMed2025

Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis.

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.

Tumor Microenvironment↗

PubMed2026

Pan-cancer characterization of HMGA1 reveals its oncogenic role in tumor microenvironment and stemness: functional validation in pancreatic cancer migration and invasion.

BACKGROUND: HMGA1 is a chromatin-associated oncogenic factor implicated in tumor progression, epithelial-mesenchymal transition (EMT), stemness, and metastasis. However, its pan-cancer expression and prognostic patterns, epigenetic activation, and relationship with malignant-cell stemness/plasticity and tumor microenvironment (TME) remodeling in pancreatic adenocarcinoma (PAAD) remain incompletely defined. This study aimed to systematically characterize HMGA1 across cancers and clarify its clinical and biological relevance in PAAD. METHODS: Pan-cancer transcriptomic, clinical, genetic, methylation, immune, and stemness data were integrated from multiple public databases. PAAD single-cell RNA sequencing data were analyzed to localize HMGA1 expression, infer malignant-cell pseudotime, calculate a stemness module score, and assess ligand-receptor communication using CellChat. Public HMGA1-knockdown RNA sequencing data were reanalyzed to evaluate transcriptional remodeling. The Cancer Genome Atlas (TCGA)-PAAD expression and methylation data were used to assess TME-remodeling, immune-suppression, stemness/plasticity, cytokine/chemokine, checkpoint, and promoter-methylation features. HMGA1 expression and function were further examined using immunohistochemistry (IHC), quantitative real-time polymerase chain reaction, Western blotting, wound-healing assays, and Transwell migration and invasion assays. RESULTS: HMGA1 was upregulated in most tumor types, and high expression was associated with unfavorable survival in multiple cancers, including PAAD. In PAAD, HMGA1 was enriched in malignant epithelial cells and positively correlated with pseudotime (Spearman's rho =0.594), while the stemness module score increased along pseudotime (rho =0.748). HMGA1-high malignant cells showed markedly stronger CellChat-inferred outgoing communication, predominantly involving extracellular matrix (ECM)-receptor, adhesion-related, and selected immunomodulatory ligand-receptor axes. HMGA1 knockdown was associated with broad remodeling of EMT, TGF-β, Hedgehog, IL6/JAK/STAT3, KRAS, and cancer stem cell/stemness-related programs rather than uniform suppression of these programs. HMGA1 promoter methylation was inversely correlated with HMGA1 expression (rho =-0.633) and the TME-remodeling score (rho =-0.347). HMGA1 was associated with selected mediators, including PPIA, PLAU, ANXA1, LGALS9, TGFB1, CD276, and CD47, but not with a generalized checkpoint-high phenotype. Functionally, HMGA1 knockdown significantly reduced pancreatic cancer (PC) cell migration and invasion. CONCLUSIONS: These findings support an association-based model in which promoter hypomethylation-associated HMGA1 activation is linked to malignant epithelial stemness/plasticity, ECM/adhesion-dominant TME remodeling, selected immunomodulatory programs, and aggressive PAAD phenotypes. Further mechanistic and clinical validation is required before HMGA1 can be used for therapeutic stratification or immunotherapy-response prediction.

HMGA1↗

PubMed2026

KLK6 is Associated with a Neutrophil-Dominant Immunosuppressive Microenvironment and Epigenetic Deregulation in Lung Adenocarcinoma.

INTRODUCTION: Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer and is associated with poor survival despite advances in targeted therapies. Kallikrein-related peptidase 6 (KLK6) has been implicated in several malignancies, but its expression pattern, clinical relevance, and biological function in LUAD remain incompletely characterized. This study aimed to evaluate KLK6 expression and its associations with prognosis, epigenetic regulation, immune infiltration, and migratory phenotypes in LUAD. METHODS: RNA-seq expression and clinical data were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases. KLK6 expression was analyzed in relation to clinicopathological parameters, survival outcomes, promoter methylation status (via UALCAN), and tumor-infiltrating immune cell abundance (via TIMER2.0). In vitro, KLK6 was knocked down using shRNA in A549 and H1299 LUAD cell lines. Cell migration was assessed by transwell assays, and the expression of Epithelial-Mesenchymal Transition (EMT)- and Wnt signaling-related markers was examined by qRT-PCR and Western blotting. RESULTS: KLK6 expression was significantly upregulated in LUAD tissues compared with normal lung tissues. High KLK6 expression was associated with poorer overall survival (HR = 1.52, P = 0.009) and disease-specific survival (HR = 1.55, P = 0.03). ROC analysis showed that KLK6 discriminated stage I LUAD from normal tissues with an AUC of 0.73. Promoter hypomethylation was observed in LUAD tumors and correlated with increased KLK6 expression. Immune infiltration analysis revealed that KLK6-high tumors exhibited reduced B-cell infiltration and increased neutrophil infiltration. Functional experiments demonstrated that KLK6 knockdown significantly suppressed cell migration, accompanied by increased E-cadherin and decreased N-cadherin, Vimentin, Wnt5a, and β-catenin expression. DISCUSSION: These findings suggest that KLK6 overexpression in LUAD is driven in part by promoter hypomethylation and is closely linked to a neutrophil-dominant immunosuppressive microenvironment. Furthermore, KLK6 appears to promote LUAD cell migration through EMT- and Wnt-related signaling pathways. Collectively, these multi-layered data position KLK6 as a potential driver of aggressive tumor behavior and a candidate biomarker for risk stratification. CONCLUSION: KLK6 is aberrantly overexpressed in LUAD and is associated with poor prognosis and enhanced migratory capacity. It may serve as a promising prognostic biomarker and a potential therapeutic target for LUAD.

KLK6↗

PubMed2024

Developing a machine learning-based prognosis and immunotherapeutic response signature in colorectal cancer: insights from ferroptosis, fatty acid dynamics, and the tumor microenvironment.

INSTRUCTION: Colorectal cancer (CRC) poses a challenge to public health and is characterized by a high incidence rate. This study explored the relationship between ferroptosis and fatty acid metabolism in the tumor microenvironment (TME) of patients with CRC to identify how these interactions impact the prognosis and effectiveness of immunotherapy, focusing on patient outcomes and the potential for predicting treatment response. METHODS: Using datasets from multiple cohorts, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we conducted an in-depth multi-omics study to uncover the relationship between ferroptosis regulators and fatty acid metabolism in CRC. Through unsupervised clustering, we discovered unique patterns that link ferroptosis and fatty acid metabolism, and further investigated them in the context of immune cell infiltration and pathway analysis. We developed the FeFAMscore, a prognostic model created using a combination of machine learning algorithms, and assessed its predictive power for patient outcomes and responsiveness to treatment. The FeFAMscore signature expression level was confirmed using RT-PCR, and ACAA2 progression in cancer was further verified. RESULTS: This study revealed significant correlations between ferroptosis regulators and fatty acid metabolism-related genes with respect to tumor progression. Three distinct patient clusters with varied prognoses and immune cell infiltration were identified. The FeFAMscore demonstrated superior prognostic accuracy over existing models, with a C-index of 0.689 in the training cohort and values ranging from 0.648 to 0.720 in four independent validation cohorts. It also responses to immunotherapy and chemotherapy, indicating a sensitive response of special therapies (e.g., anti-PD-1, anti-CTLA4, osimertinib) in high FeFAMscore patients. CONCLUSION: Ferroptosis regulators and fatty acid metabolism-related genes not only enhance immune activation, but also contribute to immune escape. Thus, the FeFAMscore, a novel prognostic tool, is promising for predicting both the prognosis and efficacy of immunotherapeutic strategies in patients with CRC.

Ferroptosis↗

PubMed2026

OLFML2B promotes hepatocellular carcinoma malignancy via the PI3K/AKT-EMT axis and correlates with an immunosuppressive tumor microenvironment.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality, highlighting the need for novel biomarkers and therapeutic targets. METHODS: The role of Olfactomedin-like 2B (OLFML2B) in HCC was investigated through multi-database analyses (The Cancer Genome Atlas, International Cancer Genome Consortium, Gene Expression Omnibus) and experimental validation. RESULTS: OLFML2B was significantly upregulated in HCC tissues, correlated with poor overall and disease-specific survival, clinicopathological features (tumor grade, stage, age, gender), and robust diagnostic performance (AUC > 0.7 across 14/15 datasets). Transcriptomic and single-cell analyses further revealed that high OLFML2B expression was associated with an immunosuppressive tumor microenvironment, characterized by increased infiltration of M2 macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as reduced abundance of cytotoxic T cells and NK cells. Knockdown of OLFML2B suppressed malignant phenotypes, including cell proliferation, migration, invasion, and angiogenesis, attenuated PI3K/AKT-EMT signaling, and enhanced sensitivity to sorafenib, cabozantinib, and regorafenib in Huh7 and HepG2 cells. Additionally, OLFML2B knockdown suppressed tumor growth and metastasis in zebrafish xenografts. DISCUSSION: Collectively, these findings indicate that OLFML2B is required for HCC progression and represents a prognostic biomarker and potential therapeutic target.

Humans↗

PubMed2026

[Laryngeal squamous cell carcinoma-derived exosomes promote neuronal axonal growth by remodeling the neural microenvironment].

Objective: Perineural invasion (PNI) is a critical determinant of poor prognosis in laryngeal squamous cell carcinoma (LSCC), but its underlying mechanisms remain unclear. This study aimed to investigate whether LSCC-derived exosomes induce axonal growth by delivering neuroactive molecules, thereby contributing to tumor perineural invasion. Methods: Clinical data from the laryngeal cancer cohort of The Cancer Genome Atlas Head and Neck Squamous Cell Carcinoma (TCGA-HNSC) dataset were analyzed. Propensity score matching (PSM) and Cox regression were used to evaluate the prognostic value of nerve density, and these findings were validated using 35 pairs of laryngeal cancer and adjacent normal tissue specimens collected at Yantai Yuhuangding Hospital between 2022 and 2026 to assess neural morphological changes. Exosomes were isolated from the human LSCC cell line AMC-HN-8, characterized by quality-control assays, and co-cultured with PC12 cells. A rescue experiment using GW4869, a specific inhibitor of neutral sphingomyelinase, was performed to confirm the exosome-dependent effect. Neurite outgrowth was evaluated by immunofluorescence, and the expression of axonal growth-related genes was measured by RT-qPCR. Targeted metabolomics was employed for the absolute quantification of neuroactive metabolites within the vesicles and for pathway enrichment analysis. Results: After PSM adjustment, high nerve density was identified as an independent poor prognostic factor in LSCC patients (HR=2.10, P=0.035), with particularly pronounced prognostic value in the early-stage node-negative (N0) subgroup (HR=4.07, P=0.001). Pathological sections showed high expression of the neural markers βIII-tubulin and PGP9.5 in LSCC tissues (βIII-tubulin: t=2.234, P<0.05; PGP9.5: t=2.575, P<0.05). Exosomes were successfully isolated from AMC-HN-8 cells and passed quality control. In vitro assays showed that LSCC-derived exosomes significantly promoted neurite extension and branching in PC12 cells (t=4.147, P<0.000 1) and upregulated core axonal growth genes, including GAP-43, NEFL, and NEFM (GAP-43: t=3.698, P<0.05; NEFL: t=5.113, P<0.01; NEFM: t=5.263, P<0.01); this effect was completely reversed by the exosome-release inhibitor GW4869 (t=3.535, P<0.001). Targeted metabolomics revealed a specific enrichment of 12 neurotransmitters and metabolites within LSCC exosomes, centered on glutamine (83.411 μmol/L, FC=1.88) and glutamate (18.461 μmol/L, FC=1.21), which were significantly enriched in signaling pathways such as "central carbon metabolism in cancer" and "glutamatergic synapse". Conclusion: Nerve density is a potential adverse prognostic factor in patients with LSCC. LSCC-derived exosomes can directly induce axonal growth in neuron-like cells, suggesting that tumor cells actively remodel the neural microenvironment and drive axonal growth through exosome-mediated long-range signaling.

Exosomes↗

PubMed2026

Association of MPO Expression with the Immune Microenvironment in Breast Cancer: Insights from Bioinformatics and Single-Cell Analyses.

Breast cancer remains a major cause of cancer-related mortality, and exploratory computational workflows can help prioritize immune-associated markers for further investigation. Here, we used the cancer genome atlas breast invasive carcinoma (TCGA-BRCA) bulk transcriptomic data and the public single-cell dataset GSE161529 to examine associations between myeloperoxidase (MPO) expression, clinical outcomes, immune infiltration, methylation, upstream-regulator annotations, single-cell expression patterns, virtual knockdown sensitivity outputs, drug-gene interaction retrieval, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) annotation. MPO expression was lower in breast cancer tissues than in adjacent non-tumor tissues. Higher MPO expression was associated with a longer progression-free interval, whereas its associations with overall survival and disease-specific survival were not statistically significant. Receiver operating characteristic (ROC) analysis suggested tumor-normal separation within the analyzed public dataset, but this should not be interpreted as clinical diagnostic validation. Immune deconvolution and enrichment analyses indicated that MPO expression mainly tracked with immune- and myeloid-related transcriptional features, rather than establishing tumor-intrinsic regulation of the immune microenvironment. At single-cell resolution, the MPO signal was sparse, with only 85 MPO-positive cells detected before k-nearest neighbor (KNN)-based neighborhood expansion. Detectable MPO signal and MPO-associated scores were interpreted cautiously because they may be influenced by sparse expression, cell-type annotation uncertainty, dropout, doublets, or ambient RNA. In silico virtual knockdown suggested candidate immune- and inflammatory-related transcriptional changes, but these results were considered exploratory and require validation. Drug-gene interaction database (DGIdb)-based drug-gene retrieval and ADMET annotation were used only as preliminary chemical annotations and were not interpreted as therapeutic evidence. Overall, this study provides a reproducible in silico workflow for generating hypotheses about MPO-associated immune/myeloid features in breast cancer, which require external cohort validation and experimental confirmation.

Humans↗

PubMed1994

Exudative neutrophils. Modulation of microbicidal function in the inflammatory microenvironment.

OBJECTIVE: To determine whether the inflammatory microenvironment primes neutrophils for increased microbicidal activity. DESIGN: In vitro studies of host defense were performed on surgical patients. SETTING: A tertiary care, university hospital. PATIENTS: A volunteer sample of hospitalized preoperative, noninfected surgical patients. INTERVENTION: Exudative neutrophils were collected from skin-blister chambers and functionally compared with circulating neutrophils. METHODS: Flow cytometry was used to evaluate directly neutrophil microbicidal activity (using fluoresceinated Candida albicans), formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide production (using 123 dihydrorhodamine), and surface expression of CD11b, CD16, and the fMLP receptor. In vitro tumor necrosis factor alpha was used to determine the possibility and extent of further priming in both circulating and exudative neutrophils. RESULTS: Exudative polymorphonuclear neutrophils have enhanced microbicidal activity, superoxide production, and expression of CD11b, CD16, and the fMLP receptor. Exogenous tumor necrosis factor was able to prime circulating neutrophils but did not further augment superoxide production in exudative neutrophils. CONCLUSION: The microbicidal activity of neutrophils is enhanced after exudation and is associated with neutrophil priming. The inability of exogenous tumor necrosis factor to further augment superoxide production after exudation suggests that this priming has been maximized.

Candida albicans↗

PubMed1999

Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development.

Recent studies have suggested the importance of hypoxia-inducible transcription factors in development, yet the questions of whether hypoxia actually exists in a developing embryo in vivo and, if so, what role it plays in development remain unanswered. In this study, we directly demonstrate that regions of hypoxia, most prominently the hindbrain, otic vesicle, and first branchial arch, exist in a gestational day (GD) 11 rat embryo grown in utero. We also show that varying the oxygen environment of an embryo affects its morphological development. Rat embryos which were grown at 45% oxygen from GD 9-11 showed gross morphological abnormalities, including defective cranial neural tube closure, incomplete otic vesicle invagination, and abnormal somite formation and embryo turning. These embryos, in addition, exhibited reduced cell death. On the other hand, embryos which were grown at 5% oxygen during the same period were stunted in overall growth, yet morphologically normal, and displayed prominent areas of apoptosis. In this study, we propose that embryonic development, like tumor development, requires two different but interactive sets of signals. One set exists in the genetic program for development; the other set arises from changes in the microenvironment of the embryo. Therefore, it is the interplay between these two sets of cues that drives normal embryonic development. The requirement for hypoxia to activate apoptotic cell death is but one example of such interactions.

Animals↗

PubMed1997

Immuno-electron microscopy of the thymic epithelial microenvironment.

Normal T cell development depends upon interactions between progenitor cells and the thymic microenvironment. Monoclonal antibodies (Mabs) have been used to define subtypes of thymic epithelium by light microscopy (clusters of thymic epithelial staining [CTES]). We have now used a range of these Mabs together with gold-coupled reagents in immuno-electron microscopy to study the fine cellular distribution of the molecules to which the antibodies bind. Anti-cytokeratin antibodies were used to identify all thymic epithelial cells, while the distribution of MHC class II molecules was revealed with Mabs to shared nonpolymorphic determinants. MR6, a CTES III Mab, shows strong surface labelling of cortical epithelial cells and thymic nurse cells and very weak surface staining of thymocytes, medullary macrophages, and interdigitating cells. Mab 8.18 (CTES V) also labels a cell surface molecule; this is present on Hassall's corpuscles and associated medullary epithelial cells. The molecules detected by Mabs MR6 and 8.18 are therefore located in a position where they are available to interact with external cellular and soluble signals within the thymus. In contrast, Mabs MR10 and MR19 (CTES II) recognise intracellular molecules within subcapsular, perivascular, and medullary epithelium. A similar distribution was seen with Mab 4beta, directed against the thymic hormone thymulin, although, in addition to the expected intracellular epithelial staining, large lymphoblasts in the subcapsular zone showed surface positivity, indicating the presence of thymulin bound to surface receptors on these early lymphoid cells. As expected, MHC class II molecules were expressed on some medullary and essentially all cortical epithelial cells. However, although most subcapsular epithelium was class II-negative, some cells did express these MHC molecules on their apical surface and on the surface of their cytoplasmic extensions into the cortex. Interestingly, some cortical epithelial cells surrounding capillaries were positive for both MR6 (CTES III) and for MR10, MR19, and 4beta (CTES II). Double-labelling experiments, using MR6 and MR19 simultaneously, revealed a double-positive perivascular epithelial cell population in the thymic cortex. The possibility that these cells represent a thymic epithelial progenitor population is discussed.

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