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Results for “Tumor Immune Microenvironment”

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PubMed2026

Spatial biology reveals altered macrophage states in immunosuppressed non-melanoma skin cancer.

Immunosuppressed patients with non-melanoma skin cancer experience worse clinical outcomes, yet the tumor immune microenvironment associated with systemic immunosuppression remains incompletely defined. Using integrated single-cell, spatial transcriptomic, multiplex immunofluorescence, and spatial epigenomic profiling across immunocompetent and immunosuppressed tumors, we found that overall immune-cell composition was largely preserved despite differences in immune-cell distribution, spatial organization, and T cell clonality. Immunosuppressed tumors demonstrated reduced intratumoral macrophage densities, decreased T cell clonal diversity, altered antigen-presenting cell and T cell spatial interactions, and distinct fibroblast- and macrophage-associated spatial niches. Multi-cohort validation across complementary spatial and single-cell platforms identified consistent alterations in innate-adaptive immune organization in immunosuppressed tumors. Together, these findings define spatial and functional remodeling of the tumor immune microenvironment under systemic immunosuppression and provide a framework for future therapeutic investigation in high-risk patients.

Humans↗

PubMed2024

A comprehensive meta-analysis of tissue resident memory T cells and their roles in shaping immune microenvironment and patient prognosis in non-small cell lung cancer.

Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint and stimulatory genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification.

Humans↗

PubMed2026

Distinct spatial immune microenvironment features of different EGFR mutation subtypes in early-stage lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (LUAD), yet their influence on the spatial tumor immune microenvironment (TIME) in early-stage disease remains unclear. We characterized the spatial TIME in 144 treatment-naïve, early-stage LUADs using integrated genomic sequencing and multiplex immunohistochemistry (mIHC). Although EGFR-mutant tumors overall displayed reduced CD8 + T-cell infiltration compared with EGFR-wild-type tumors, substantial heterogeneity was observed among EGFR subtypes. Specifically, L858R and rare-variant subtypes exhibited higher tumor mutational burden, greater CD8 + T-cell density, and enrichment of T-cell-dominant cellular neighborhoods relative to 19del subtype, consistent with a comparatively immune-infiltrated phenotype. In contrast, 19del tumors showed lower T-cell infiltration. TP53 co-mutation was also associated with enhanced CD8 + T-cell infiltration. These cross-sectional findings identify hypothesis-generating spatial immune phenotypes across EGFR-mutant LUAD subtypes; their potential relevance to perioperative treatment selection requires prospective validation in outcome-annotated treatment cohorts.

Humans↗

PubMed2026

Metabolism pathway-based subtyping in pancreatic adenocarcinoma: an integrated study by bulk RNA-sequence and machine learning algorithms.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is highly aggressive, and its tumor microenvironment has significant metabolic and immune microenvironment complexity and genomic instability. In this study, by integrating the metabolic pathway activity score and clinical data, we constructed a novel risk assessment model to reveal the unique biological behavior and clinical significance behind different PAAD subtypes. METHODS: In this study, the transcriptome and clinical data of TCGA and GSE57495 databases were integrated to explore the interaction between metabolic pathways. Based on unsupervised clustering analysis of pathway activity and survival prognosis, patients with PAAD were classified into metabolic subtypes with significant prognostic differences. Subsequently, we assessed the heterogeneity of these subtypes in terms of clinical outcomes, genomic characteristics, and immune microenvironment composition. Based on the differentially expressed genes (DEGs) among metabolic subtypes, a clinical prognostic risk model and nomogram were constructed, which were double-validated by GSE57495-independent cohort and GSE57495 + TCGA-PAAD combined cohort. Finally, the correlations between risk scores (RSs) and signaling pathway activity and tumor immune microenvironment characteristics were evaluated. RESULTS: Based on metabolic pathway correlation and prognostic information, 240 patients in the TCGA-PAAD and GSE57495 datasets were divided into three subgroups. There were significant differences between subgroups in gene expression, pathway activity, clinical prognosis, and immune infiltration characteristics among the subtypes. Using machine learning algorithms, an RS model was constructed from DEGs among the subgroups, with the random forest method showing the best performance. A nomogram integrating the RS and clinical indicators demonstrated excellent predictive accuracy for 1-, 3-, and 5-year survival rates, confirming the RS as an independent prognostic factor. High- and low-risk groups exhibited significant differences in immune infiltration, pathway activity, and gene mutations. Drug sensitivity analysis showed that the high-risk group was more sensitive to AZD6244, ABT737, and other drugs. CONCLUSION: This study stratified patients with PAAD into three subgroups based on metabolic pathways and prognostic information, revealing significant differences in clinical outcomes, immune characteristics, and genetic mutations. The robust RS model developed from these findings demonstrated strong predictive power for patient survival and identified promising therapeutic strategies, providing valuable insights for advancing precision medicine in PAAD.

immune microenvironment↗

PubMed2024

Construction and Analysis of a Mitochondrial Metabolism-Related Prognostic Model for Breast Cancer to Evaluate Survival and Immunotherapy.

As one of the most prevalent malignancies among women, breast cancer (BC) is tightly linked to metabolic dysfunction. However, the correlation between mitochondrial metabolism-related genes (MMRGs) and BC remains unclear. The training and validation datasets for BC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases, respectively. MMRG-related data were obtained from the Molecular Signatures Database. A risk score prognostic model incorporating MMRGs was established based on univariate, LASSO, and multivariate Cox regression analyses. Independent factors affecting BC prognosis were identified through regression analysis and presented in a nomogram. Single-sample gene set enrichment analysis was employed to assess the immune levels of high-risk (HR) and low-risk (LR) groups. The sensitivity of BC patients in the two groups to common anti-tumor drugs was evaluated by utilizing the Genomics of Drug Sensitivity in Cancer database. 12 MMRGs significantly associated with survival were selected from 1234 MMRGs. A 12-gene risk score prognostic model was built. In the multivariate regression analysis incorporating classical clinical factors, the MMRG-related risk score remained an independent prognostic factor. As revealed by tumor immune microenvironment analysis, the LR group with higher survival rates had elevated immune levels. The drug sensitivity results unmasked that the LR group demonstrated higher sensitivity to Irinotecan, Nilotinib, and Oxaliplatin, while the HR group demonstrated higher sensitivity to Lapatinib. The development of MMRG characteristics provides a comprehensive understanding of mitochondrial metabolism in BC, aiding in the prediction of prognosis and tumor microenvironment, and offering promising therapeutic choices for BC patients with different MMRG risk scores.

Humans↗

PubMed2025

Immune landscape and novel therapeutic targets of epidermal growth factor receptor and anaplastic lymphoma kinase wild type never-smoker lung adenocarcinoma.

BACKGROUND: Never-smoker lung adenocarcinoma (NSLA) exhibits distinct immunosuppressive profiles and a lower tumor mutation burden compared with lung adenocarcinoma in smokers. These correlate with poor responses to immune checkpoint inhibitors. In this study, we aimed to elucidate the tumor-immune microenvironment of NSLA without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations and identify novel therapeutic targets. METHODS: We analyzed genome, transcriptome, and proteomic data from 102 NSLA tumor samples and 16 normal adjacent tissues. We classified tumors into distinct immune clusters (IC) based on gene signatures by profiling the tumor-infiltrating immune cells. RESULTS: The tumors were stratified into three ICs: hot, intermediate, and cold. Notably, only 21 (20.6%) patients exhibited hot IC enriched in cytotoxic T cells, natural killer cells, and B-cell signatures, which correlated with improved recurrence-free survival. Cold ICs (37.3%) exhibited higher myeloid-derived suppressor cell (MDSC) levels and M2 macrophage signatures, with poor immune cell infiltration and relatively low stimulatory cytokines and chemokines expression. CEACAM1, and NECTIN2 were upregulated in intermediate and cold ICs and correlated with MDSC and M2 macrophage infiltration. High expression of these genes was associated with poor survival outcomes. Protein-protein network analysis of 20 upregulated molecules associated with cancer- and driver-related proteins in cold IC identified XPO 1 as a key component. CONCLUSION: Our proteogenomic analysis highlighted the immunosuppressive properties of NSLA without EGFR and ALK alterations and identified novel therapeutic targets. These findings may provide novel treatment strategies that could improve the clinical outcomes of patients with NSLA.

Humans↗

PubMed2025

Spatially organized lymphocytic microenvironments in high grade primary prostate tumors.

The spatial organization and composition of the tumor-immune microenvironment (TME) play a critical role in shaping the progression of many solid cancers, but the organization of the TME in primary prostate cancer (PCa) remains poorly characterized. We therefore profiled the abundance and spatial distributions of major cell types involved in adaptive immunity in 29 radical prostatectomy specimens stratified into high (HGG; n=14) and low Gleason-grade (LGG; n=15). Compared to LGG, HGG PCa exhibited significantly greater B and T cell infiltration with many immune cells organized into clusters, some of which resembled tertiary lymphoid structures (TLSs). In HGG tumors, these clusters were dense, symmetric, rich in PD-1+ T cells, and frequently proximate to the tumor compartment. LGG clusters were less well organized, and T cell depleted. Thus, a subset of high-grade PCa harbor organized immune clusters that may play a role in tumor control and contain therapeutically targetable T and B cells.

Prostate cancer↗

PubMed2026

An oxidative stress - and immunotherapy-related six-gene signature defines immune subtypes and predicts prognosis and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Oxidative stress and the tumor immune microenvironment jointly shape hepatocellular carcinoma (HCC) progression and response to immunotherapy, yet integrated biomarkers linking these processes are lacking. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify oxidative stress- and immunotherapyrelated differentially expressed genes (OSIRDEGs). Functional enrichment, weighted gene co-expression network analysis (WGCNA) and LASSO-Cox regression were used to construct a prognostic signature. Consensus clustering, TIDE, CIBERSORT and ssGSEA characterized immune phenotypes. Somatic mutation, copy-number and drug-response data were integrated to assess genomic alterations and drug sensitivity. Expression of model genes was validated by qRT-PCR and western blotting in HCC cell lines. RESULTS: We identified 24 OSIRDEGs enriched in cell-cycle and mitotic pathways. WGCNA intersection yielded 18 module genes, from which a six-gene signature (BUB1B, CDKN2A, CENPE, HMMR, PTTG1, SPP1) was derived. The signature robustly stratified patients into high- and low-risk groups with significantly different progression-free and disease-free survival in both TCGA-LIHC and GSE14520. Based on signature expression, two molecular subtypes were defined, exhibiting distinct survival, immune landscapes and predicted immunotherapy responsiveness. Model genes harbored recurrent alterations and showed significant correlations with anticancer agents. All six genes were upregulated at mRNA and protein levels in metastatic HCC cell lines versus normal hepatocytes. CONCLUSIONS: We systematically explored the landscape of OSIRDEGs in HCC, and proposed a validated six-gene signature that refines prognostic stratification, delineates immunerelevant HCC subtypes and highlights candidate biomarkers for therapeutic selection and mechanistic investigation.

Humans↗

PubMed2026

Integrative subtyping by bile acid metabolism identifies CLCA1/UGT2A3/ZG16 as markers of immune dysfunction and poor prognosis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the primary driver of cancer-related death and illness across the world. Despite the full-scale shift of the treatment approach for some colorectal cancer patients due to the use of immune checkpoint inhibitors (ICIs), primary resistance still poses a huge challenge to clinicians. Bile acid metabolism is involved in the pathogenesis of CRC. However, its particular function in shaping the tumor immune microenvironment (TIME) and its effect on prognosis and immune treatment response remain unclear. METHODS: Based on the transcriptome and clinical data from The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) cohort, we performed unsupervised consensus clustering and classified patients into different molecular subtypes according to bile acid metabolism. We subsequently compared overall survival (OS), immune cell infiltration levels, and differentially expressed genes among the subtypes. In addition, protein-protein interaction (PPI) network and Cox proportional hazards regression were used to identify key hub genes. Finally, the expression of these crucial hub genes was validated in the Gene Expression Omnibus (GEO) cohort and independent clinical patients. RESULTS: The bile-low group showed a significant reduction in OS time (p = 0.0049). The infiltration levels of CD8+ T cells (p < 0.05) and M1 macrophages (p < 0.01) were significantly higher in the bile-low group than in the bile-high group. We identified three key genes-CLCA1, UGT2A3, and ZG16-and found that they all were downregulated in tumor tissues across the TCGA-COAD and GEO datasets, as well as in independent clinical samples. Survival analysis showed that high CLCA1 expression was significantly associated with favorable overall survival (p < 0.001), whereas UGT2A3 (p = 0.23) and ZG16 (p = 0.17) did not reach statistical significance. The three hub genes were negatively correlated with the (TIDE) score (CLCA1: R = - 0.24, p < 0.001; UGT2A3: R = - 0.15, p = 0.0022; ZG16: R = - 0.14, p = 0.0039). CONCLUSION: Our findings suggest that bile acid metabolism could shape the TIME via key genes CLCA1, UGT2A3, and ZG16, and subsequently modify CRC prognosis and immunotherapy responses. These genes may serve as potential prognostic indicators and mechanistic mediators linking bile acid metabolism to T-cell dysfunction, offering insights for future combination strategies targeting the metabolism-barrier-immunity axis.

CLCA1↗

PubMed2026

The fall of the genome protectors triad: PBRM1, SETD2, and BAP1's impact on metabolism and immunity in clear cell renal cell carcinoma.

The loss of chromosome 3p and the inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) were identified in clear cell renal cell carcinomas (ccRCC) over three decades ago. Since then, mutations in genes for the three chromatin modulators, polybromo 1 (PBRM1), SET domain-containing 2 (SETD2), and BRCA1-associated protein-1 (BAP1), have been recognized as common in ccRCC. Although these genomic alterations are central to understanding ccRCC's development, other deregulated cellular processes are also prominent in these tumors. Metabolic reprogramming is a key hallmark of this disease, characterized by various changes linked to the stabilization of hypoxia-inducible factors (HIF), including increased aerobic glycolysis, elevated lipid levels, and glutamine dependence for cell survival. Additionally, HIF-α stabilization plays a crucial role in regulating the immune system, thereby enhancing CD8+ T lymphocyte cytotoxicity. Immune checkpoint inhibitors (ICI) are now used as first-line treatments to target the often highly infiltrated tumor microenvironment of ccRCC. However, the effectiveness of ICI varies and is difficult to predict. Although emerging studies are beginning to provide insight, evidence suggests roles for PBRM1, SETD2, and BAP1 in metabolic regulation and in shaping the tumor immune microenvironment in ccRCC. Here, we review recent advances in this field and examine their impact on the management of ccRCC.

BAP1↗

PubMed2025

T cell subsets of urine-derived lymphocytes (UDLs) serve as an indicator of TILs and reflect immunological sex differences in bladder cancer.

BACKGROUND: Bladder cancer is unique among visceral malignancies in that urine, which can be easily obtained, has prolonged contact with bladder tumors. Urinary biomarkers offer the potential to provide insight into the host and tumor immune microenvironment to guide therapeutic strategies. We evaluated the immune cellular composition of urine (urine-derived lymphocytes (UDLs)) versus tumor (tumor-infiltrating lymphocytes (TILs)). METHODS: We employed high-dimensional flow cytometry analyses on immune cells from tumors (TILs), urine (UDLs), and peripheral blood (peripheral blood mononuclear cells) among patients with bladder cancer. We performed multiplexed immunofluorescence (mIF) of matched tumors to provide spatial context to our findings, comparing deep/invasive and superficial/urine-facing regions of matched tumors. RESULTS: Our findings suggest that the CD4+ and CD8+ T cell subsets of UDLs characterized by flow cytometry had similar phenotypic profiles to those found in TILs (cell clusters quantified by multidimensional scaling and differentiation states). Results of mIF imaging with a panel of phenotypic and functional T cell markers suggested that UDLs reflected TILs in both superficial and deep tumor sections. We also found sex-dependent patterns in TILs and UDLs, indicating the male bladder cancer tumor microenvironment is enriched in exhausted CD4+ and CD8+ T cells, while the female bladder cancer microenvironment is enriched for activated T cells. CONCLUSIONS: Assessment of UDLs opens avenues of non-invasive biomarker development in clinical settings where bladder cancer TILs are hypothesized to predict clinical response. UDLs may also reflect sex-based differences in antitumor immunity.

Humans↗

PubMed2025

Prognostic and immunological implications of sialylation-associated gene signatures in hepatocellular carcinoma.

OBJECTIVE: The absence of effective biomarkers continues to limit early diagnostic accuracy and prognostic evaluation in patients with hepatocellular carcinoma (HCC). Aberrant sialylation (SI) has been demonstrated to contribute to therapeutic resistance and tumor progression. The aim of this investigation was to identify a sialylation-related gene (SRG) signature, evaluate its prognostic significance, and investigate associated immunological characteristics in HCC. METHODS: Transcriptomic profiles and corresponding clinical data for patients with HCC were obtained from UCSC Xena, the International Cancer Genome Consortium (ICGC), and the Molecular Signatures Database (MsigDB). Differential expression analysis, Cox regression analysis modeling, and least absolute shrinkage and selection operator (LASSO) regression analysis were applied to identify independent prognostic markers and develop predictive models. The tumor immune microenvironment and its relationship with the identified SRGs were assessed by evaluating immune infiltration patterns. A gene co-expression network for the prognostic SRGs was constructed using GeneMANIA to identify potentially targetable signaling pathways. RESULTS: Four SRGs (ST6GALNAC4, B4GALT5, B4GALNT1, and NEU1) were significantly associated with the prognosis of patients with HCC. Prognostic models constructed using these genes demonstrated strong predictive performance. Notable differences were observed in immune cell populations and immune checkpoint expression between the high-risk and low-risk groups. Additionally, the half-maximal inhibitory concentration values for 101 therapeutic compounds varied between these groups. Lipopolysaccharide and sphingolipid metabolism were identified as key biological processes linked to tumor progression and modulation of the immune microenvironment. CONCLUSION: The four identified SRGs were significantly associated with clinical outcomes and immunological features in HCC. These findings provide a foundation for advancing early diagnostic strategies, refining prognostic assessments, and guiding personalized therapeutic approaches for patients with HCC.

Humans↗

PubMed2026

Integrated pan-cancer profiling highlights OSR2 as a prognostic indicator and immune-associated biomarker.

BACKGROUND: Odd-skipped-related 2 (OSR2), encoded by the OSR2 gene, has been reported to function as a checkpoint associated with CD8⁺ T-cell exhaustion in the tumor microenvironment of solid malignancies, suggesting its potential as a therapeutic target to improve immunotherapeutic responses. Nevertheless, the molecular and clinical significance of OSR2 across diverse cancer types has not yet been systematically investigated, and its pan-cancer expression profile, prognostic implications, and associations with tumor immunity remain to be fully elucidated. METHODS: In this study, we integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) portal, and the Human Protein Atlas to construct a systematic pan-cancer profile of OSR2. The prognostic value of OSR2 was comprehensively assessed using univariate Cox regression, survival analysis, and receiver operating characteristic (ROC) curve analysis. In addition, we performed an in-depth analysis of the relationships between OSR2 and multiple molecular and immunological features, including copy number variation (CNV), DNA methylation, tumor mutational burden (TMB), microsatellite instability (MSI), immune-related gene expression, immune cell infiltration, and drug sensitivity, with the aim of exploring its potential immunological associations with the tumor microenvironment. RESULTS: OSR2 expression was significantly upregulated or downregulated in the majority of tumor tissues relative to normal counterparts and exhibited distinct cancer-type-specific patterns across clinical stages. CNV alterations and aberrant DNA methylation were closely associated with abnormal OSR2 mRNA expression in multiple cancers. Prognostic analyses indicated that OSR2 expression was significantly associated with overall survival, disease-specific survival, disease-free interval, and progression-free interval across multiple cancer types, showing either risk-associated or protective associations in a tumor-context-dependent manner. Furthermore, OSR2 expression showed strong associations with immune cell infiltration, particularly T-cell subsets, and was significantly correlated with the expression of multiple immune checkpoint-related genes across diverse malignancies. OSR2 expression was also closely associated with TMB, MSI, and sensitivity to multiple anticancer agents. CONCLUSION: Taken together, these findings suggest that OSR2 is associated with prognosis and immune-related features across multiple cancer types. OSR2 may be linked to features of the tumor immune microenvironment through its relationships with immune cell infiltration, immune checkpoint gene expression, and genomic instability, and thus may serve as a candidate biomarker for further investigation in cancer immunotherapy.

CD8⁺ T-cell↗

PubMed2026

Mature Tertiary Lymphoid Structures in Breast Cancers Are Associated With Antitumor Immunity and Better Prognosis.

Tertiary lymphoid structures (TLSs) are immune cells accumulated in nonlymphoid tissues, with an inner core of B cells encompassed by T cells. The aim of this study was to evaluate the clinical importance of mature TLSs in breast cancer, including their association with immunotherapy response and their role in modulating the tumor immune microenvironment. We analyzed histopathological data of 726 consecutive primary breast cancers and transcriptomic data of 824 breast cancer samples from the publicly available The Cancer Genome Atlas database to estimate the clinical and immunological values of mature TLSs in breast cancer. Additionally, we utilized pretreatment transcriptomic data of 69 patients with breast cancer from the publicly available I-SPY2 clinical trial to investigate the relation between TLS-related gene signatures and patient responses to immune checkpoint inhibitors. The existence of mature TLSs was identified in ⁓5.6% (41/726) of all patients with breast cancer (hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+HER2-): 0.92%; triple-negative breast cancer (TNBC): 14.96%; and human epidermal growth factor receptor-2 positive (HER2+): 10.98%) and was independently associated with improved recurrence-free survival after adjusting for subtypes, tumor-infiltrating lymphocyte levels, and tumor stage after the multivariable Cox regression analysis in our patient cohort. Notably, the presence of mature TLSs was related to immune cell infiltration in our breast cancer patient cohort. In line with these findings, TLS-related gene signatures analyzed through transcriptomic data reliably reflected the existence of mature TLSs and were related to better clinical responses to immune checkpoint inhibitors in patients with breast cancer. In conclusion, our findings show that mature TLS formation is linked with immune cell infiltration, contributes to a favorable prognosis, and may function as a potential complementary biomarker for immunotherapy response in breast cancer.

Humans↗

PubMed2026

Analysis and validation of abnormal signaling pathways and immune cell infiltration characteristics in digestive system cancers based on peroxisome-related genes.

BACKGROUND: Although emerging evidence suggests a role for peroxisomes in tumorigenesis, their functions in digestive cancers remain unclear. This study aims to investigate the association between peroxisomes and digestive tract tumors. METHODS: To systematically investigate peroxisomal functions in digestive cancers, we first constructed and validated tumor-specific prognostic signatures based on peroxisome-related genes (PRGs) through univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses. We then characterized the tumor immune microenvironment (TIME) with CIBERSORT, X-CELL, and EPIC algorithms, and identified tumor-specific and common signalings via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Focusing on hepatocellular carcinoma (HCC), we experimentally validated peroxisome-related therapeutic responses by profiling signature genes in radioresistant cells and an orthotopic transarterial chemoembolization (TACE) rat model. PEX13 knockdown further assessed peroxisomal role in radiosensitivity and targeted therapy response. Clinical relevance of PEX13 was evaluated in HCC cohort. Single-cell RNA sequencing dataset and lipidomics further revealed peroxisomal mechanisms in HCC progression. Finally, peroxisomal function in colorectal cancer (CRC) was validated in vitro. RESULTS: Novel peroxisome-related prognostic signatures demonstrated strong predictive power in HCC, colon adenocarcinoma, rectal adenocarcinoma, pancreatic adenocarcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, and cholangiocarcinoma. High-risk patients displayed an immunosuppressive microenvironment, characterized by increased infiltration of regulatory T cells, M2 macrophages, Th2 cells, or cancer-associated fibroblasts, or Th1 cells' reduction. Peroxisomes engaged in several distinct yet convergent pathways, most notably "positive regulation of response to stimuli". HCC prognostic genes were dynamically regulated in response to therapeutic stimuli, including radiotherapy, targeted therapy, and TACE. Clinically, the expression of PEX13 was markedly upregulated in tumor tissues from therapy-resistant HCC patients. Mechanistically, peroxisomal dysfunction induced by silencing PEX13 in HCC or UBE2D2 in CRC may overcome therapeutic resistance (radiotherapy/ lenvatinib resistance in HCC, radioresistance in CRC) through reprogramming lipid metabolism. CONCLUSIONS: Peroxisomes act as pivotal regulators of digestive cancer progression by modulating signaling pathways, the TIME, therapeutic resistance, and lipid metabolism. Targeting peroxisomal function, particularly in high-risk subgroups of HCC and CRC, warrants further exploration as a promising therapeutic strategy.

Peroxisomes↗

PubMed2026

Monocarboxylate Transporter 2 (MCT2) Reduction Is Associated with Increased Lung Tumor Growth and Alterations in the Immune Microenvironment in a Subcutaneous Tumor Model.

Monocarboxylate transporter 2 (MCT2; SLC16A7) is a high-affinity pyruvate transporter implicated in cancer metabolism. However, its role in lung cancer progression and the tumor microenvironment remains unclear. This study examined the effects of MCT2 reduction on tumor growth and cell-type-specific transcriptional changes within the tumor microenvironment. MCT2 loxP/loxP mice were crossed with mCre-Tg mice, and MCT2 deletion was induced by tamoxifen. Control (CO) mice received vehicle treatment. TC1 cells (100,000 cells/mouse) were injected subcutaneously, and tumors were harvested after 24 days. Single-nucleus RNA sequencing (snRNA-seq) was performed on isolated tumor nuclei (4000 nuclei/sample; n = 3 per group) using the 10x Genomics Chromium platform. Data were processed with Cell Ranger v3.0.2 and Seurat v5.2.1, followed by differential expression and pathway enrichment analyses integrated with macrophage bulk RNA-seq data. Tumors in mice with systemic MCT2 reduction grew significantly faster than those in control mice, demonstrating an association between host MCT2 reduction and increased tumor growth. Transcriptomic analysis generated high-quality profiles from 6864 CO and 10,055 KO nuclei. Clustering identified 12 cellular populations and cell types. MCT2 reduction altered pathways involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid metabolism across multiple populations. Macrophages showed prominent transcriptional changes, including enrichment of MAPK, PI3K-Akt, IgSF-CAM, ECM, and cytokine-cytokine signaling pathways. These findings were supported by macrophage bulk RNA-seq data. Systemic MCT2 reduction was associated with increased tumor growth and broad transcriptional alterations within the tumor micro-environment. Differences in metabolic and immune-related transcriptional programs, particularly in macrophages, identify potential mechanisms associated with tumor progression that warrant further functional investigation.

Animals↗

PubMed2025

Progressive T cell exhaustion and predominance of aging tissue associated macrophages with advancing disease stage in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited understanding of the tumor immune microenvironment (TIME). The interplay between PSCC and the immune system across disease progression and HPV infection status remains poorly characterized. This study aims to assess the TIME changes from localized to advanced disease and between HPV-positive versus negative tumors to identify potential immune evasion mechanisms in advanced PSCC. scRNA-seq was performed on ten PSCC tissue samples from penile, lymph node and distant metastatic sites with four matched penile and lymph node samples to understand the cellular heterogeneity within PSCC tumors. Analysis of immune cell populations and transcriptional hallmarks were performed stratified by localized (pT1-3, N0) versus advanced (N1-3, M0 or any N, M1) disease states and HPV infection status. We observed significant differences in immune cell infiltration between localized and advanced PSCC disease states and by HPV status. Advanced disease states demonstrated an exhausted immune phenotype, characterized by terminally exhausted CD8+ T cells, M2-like macrophages and hypoxic signature, while localized disease states demonstrated an active innate immune system characterized by increased DCs. HPV-negative tumors displayed low immune cell infiltration while HPV-positive tumors demonstrated an immune exhausted phenotype. These findings offer valuable insights into the evolving PSCC immune landscape, paving the way for the development of potential therapeutic approaches for advanced PSCC.

Humans↗

PubMed2026

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

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

Arachidonic acid metabolism↗