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Results for “tumor-associated protein”

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PubMed2025

Abnormal levels of miRNA in pancreatic cancer are linked to tumor progression by regulating the translation of tumor-associated mRNA.

BACKGROUND: Pancreatic cancer remains one of the most malignant tumors, characterized by limited treatment efficacy. MAIN FINDINGS: microRNAs (miRNAs) play a crucial role in regulating the proliferation, invasion, migration, drug resistance, apoptosis, and cell cycle progression of pancreatic cancer cells by inhibiting tumor-associated proteins. Metscape analysis revealed that miRNA-targeted proteins associated with pancreatic cancer are enriched in processes such as cell proliferation, mitosis, and cell migration, and participate in multiple signaling pathways. These proteins primarily localize to classical pathways, including JAK/STAT, PI3K/AKT, and Wnt/β-catenin. Furthermore, gene mutations or abnormal alternative poly(A)denylation (APA) within miRNA-targeted regions can disrupt base pairing to the 3'-Untranslated Region (3'-UTR), thereby enhancing the translation of oncogenic mRNA translation. FUTURE DIRECTIONS: Collectively, these findings indicate that multiple miRNAs act cooperatively to influence pancreatic cancer progression. Consequently, therapeutic strategies aimed at restoring the balance of the miRNA system are essential to disrupt the 'mRNA-oncogene' vicious cycle.

Humans↗

PubMed2026

Translational Gap in Biomarker Discovery: Tumor Surface Markers Rarely Mirror Circulating Levels.

BACKGROUND: Tumor-associated cell surface proteins are frequently proposed as circulating biomarkers for colorectal cancer (CRC) based on their high tumor expression. However, many candidates identified through tissue-based analyses fail to translate into clinically useful biomarkers. We investigated the translational gap between tissue-level expression and circulating detectability in CRC, focusing on molecular subtypes defined by caudal-type homeobox 2 (CDX2) expression. METHODS: Transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to identify cell surface markers differentially expressed between CDX2-Low and CDX2-High CRCs. A clinical cohort of right-sided CRC patients was evaluated using paired tumor tissue and preoperative plasma samples. CDX2 expression was assessed by immunohistochemistry, and circulating concentrations of selected cell surface proteins were quantified using a multiplex ELISA platform. RESULTS: Several tumor-associated cell surface markers exhibited marked CDX2-dependent differences in tissue expression. However, for most markers, circulating plasma levels did not mirror tissue-level patterns. CEACAM1 was the sole marker demonstrating concordant CDX2-dependent differences in both tumor tissue and plasma, with significantly lower levels in CDX2-Low CRCs. In contrast, CEACAM5 showed a dissociation between tissue expression and circulating levels, despite analytical validation against serum carcinoembryonic antigen (CEA). CONCLUSIONS: Our findings demonstrate that tumor overexpression of cell surface markers does not necessarily translate into detectable circulating biomarkers. This translational disconnect underscores limitations of biomarker selection strategies based solely on tissue expression and highlights the importance of integrating systemic biology into biomarker development. While some tumor-associated proteins may lack utility as circulating biomarkers, they may still represent viable therapeutic targets in CRC.

CDX2↗

PubMed2026

Tumor-associated macrophages display differential protein cargo sorting in extracellular vesicles associated with poor survival in ovarian cancer.

Ovarian cancer (OC) progression and metastasis are promoted by ascites, which constitutes a central part of the tumor microenvironment (TME). In this fluid, tumor-associated macrophages (TAMs) represent a prominent immune cell type. In addition to tumor and other host cells such as TAMs, ascites is highly enriched in soluble factors as well as extracellular vesicles (EVs). How TAMs contribute to the EV compartment of the OC TME remains, however, underexplored. In this work peripheral blood monocytes from healthy donors were differentiated into monocyte-derived macrophages (MDMs) and polarized into classically activated (M1-like), alternatively activated (M2-like) and TAM-like (by ascites incubation). For all subtypes, serum-free conditioned medium was collected for 24 h and EVs were isolated and characterized by nano-flow cytometry (nFC), label-free mass spectrometry-based proteomics and electron microscopy, among others. Our results demonstrated distinct traits for EV release and cargo across the different macrophage subtypes. Specifically, TAM-like macrophages exhibited impaired release of small EVs and reduced frequency of tetraspanin-positive particles. These EV subpopulations displayed sizing profiles closer to M1-like than to M2-like samples. Also, the low EV release in TAM-like MDMs was accompanied by altered expression of biogenesis-related markers like flotillin-1 (FLOT1) and a decreased N-glycosylation of CD63 protein, which was validated in patient-derived samples. Remarkably, the EV-associated proteome of TAMs displayed significant enrichment in both pro- and anti-inflammatory molecules with clinical value. Markers significantly enriched in the ascites TAM-EV signature were mostly associated with poor prognosis, whereas M1-like EV-related markers (pro-inflammatory) were mostly associated with longer survival. Our results confirmed previous data for proteins like CD163 and MRC1 to be associated to TAM-EVs, while also describing novel candidates with diagnostic (i.e., COLEC12) and/or prognostic (i.e., MSR1) value in plasma. Taken together, our data support a unique secretory profile of TAMs in OC and provide new EV-associated biomarkers with translational impact. Our results pave the way for a better understanding of the mechanisms behind TAM-EV cargo loading and function, and how these cells participate in the TME landscape.

Humans↗

PubMed2026

Multi-omics Approaches to CCAAT/Enhancer-Binding Protein Beta in Oral Squamous Cell Carcinoma: Crosstalk Between Tumor Cells and Tumor-Associated Macrophages Driving Disease Progression.

BACKGROUND: CCAAT/Enhancer-Binding Protein Beta (CEBPB) is an important transcription factor that regulates tumor progression. However, the mechanism by which CEBPB regulates the progression of Oral Squamous Cell Carcinoma (OSCC) remains incompletely understood. Tumor progression depends on complex intercellular interactions within the tumor microenvironment. The purpose of this study was to investigate the role and epigenetic regulatory mechanisms of CEBPB in interactions between OSCC cells and tumor-infiltrating immune cells. METHODS: Bulk RNA-seq, ChIP-seq, and scRNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. The HOMER algorithm was employed to identify enhancers and predict the CEBPB-binding motif. Cell cluster analysis, functional enrichment, and intercellular interaction analysis were performed using the "Seurat" R package. H3K27ac enrichment at GAS6 enhancers was validated by ChIP-qPCR. Metastatic OSCC cells with CEBPB knockdown or GAS6 overexpression were established and co-cultured with THP-1 cells. IL-10 and IL-6 secretion from co-cultured THP-1 cells was detected via ELISA. Chemotaxis of OSCC cells toward THP-1 cells was assessed through a Transwell assay. RESULTS: CEBPB was upregulated in OSCC and correlated with poor prognosis. By integrating H3K27ac ChIP-seq and bulk RNA-seq data, 131 CEBPB-regulated enhancer-controlled genes were identified in lymph node metastatic OSCC cells. scRNA-seq analysis revealed eight major cell clusters in primary foci and lymph node metastases, including T/NK cells, malignant epithelial cells, B/plasma cells, macrophages, fibroblasts, dendritic cells, endothelial cells, and mast cells, with the malignant epithelial cells stratified into distinct sub-clusters. CEBPB expression was elevated in malignant epithelial cells of lymph node metastases compared to primary foci. Furthermore, 15 pairs of enhanced ligand-receptor interactions were identified in lymph node metastases relative to primary foci. GAS6 was a CEBPB-regulated enhancer-controlled gene, primarily mediating interactions between malignant cells and macrophages. CEBPB knockdown in metastatic OSCC cells significantly impaired their chemotaxis toward cocultured THP-1 cells, and downregulated IL-10/IL-6 secretion and CD206 expression in cocultured THP-1 cells. Conversely, GAS6 overexpression reversed these inhibitory effects. CONCLUSION: CEBPB activated GAS6 transcription in metastatic OSCC cells. The CEBPB/ GAS6 axis in metastatic OSCC cells enhanced their chemotaxis toward macrophages and promoted the M2 polarization of macrophages, thereby facilitating the establishment of an immunosuppressive microenvironment.

Humans↗

PubMed2026

Plasma Proteomic Profiling Identifies Candidate Biomarkers for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that is often diagnosed after curative treatment is no longer feasible. Existing biomarkers, particularly CA19-9, have limited sensitivity and specificity. Plasma proteins that capture tumor-associated biological alterations may therefore provide useful signals for earlier detection. METHODS: Plasma samples from 99 patients with PDAC and 30 healthy controls were analyzed using data-independent acquisition (DIA) proteomics. Differentially expressed proteins were identified using predefined statistical thresholds and further examined by functional enrichment analysis. Selected candidate biomarkers were validated by ELISA in an independent subset. RESULTS: Among 565 quantified plasma proteins, 52 were differentially expressed between PDAC and controls. These proteins were enriched in extracellular processes, cholesterol metabolism, complement and coagulation cascades, and pancreatic secretion pathways. ELISA validation confirmed higher plasma levels of Cathepsin S, CTRB2, MARCO, PIGR, PRDX6, REG1A, Trypsin-2, and PEP-FAP in patients with PDAC compared with healthy controls. ROC analyses showed moderate-to-good discriminatory performance for several candidates, and the MARCO + PEP-FAP model improved classification compared with either marker alone. CONCLUSION: These findings reveal circulating proteins linked to key PDAC-related biological processes and identify eight candidates for further evaluation in multi-protein diagnostic panels. Larger validation studies incorporating clinically relevant disease control groups are warranted to determine their diagnostic specificity and clinical utility.

Humans↗

PubMed2024

B4GALT1-dependent galectin-8 binding with TGF-β receptor suppresses colorectal cancer progression and metastasis.

Transforming growth factor (TGF)-β signaling is critical for epithelial-mesenchymal transition (EMT) and colorectal cancer (CRC) metastasis. Disruption of Smad-depednent TGF-β signaling has been shown in CRC cells. However, TGF-β receptor remains expressed on CRC cells. Here, we investigated whether the cooperation between tumor-associated N-glycosylation and a glycan-binding protein modulated the TGF-β-driven signaling and metastasis of CRC. We showed that galectin-8, a galactose-binding lectin, hampered TGF-β-induced EMT by interacting with the type II TGF-β receptor and competing with TGF-β binding. Depletion of galectin-8 promoted the migration of CRC cells by increasing TGF-β-receptor-mediated RAS and Src signaling, which was attenuated after recombinant galectin-8 treatment. Treatment with recombinant galectin-8 also induces JNK-dependent apoptosis in CRC cells. The anti-migratory effect of galectin-8 depended on β4-galactosyltransferase-I (B4GALT1), an enzyme involved in N-glycan synthesis. Increased B4GALT1 expression was observed in clinical CRC samples. Depletion of B4GALT1 reduced the metastatic potential of CRC cells. Furthermore, inducible expression of galectin-8 attenuated tumor development and metastasis of CRC cells in an intra-splenic injection model. Our results thus demonstrate that galectin-8 alters non-canonical TGF-β response in CRC cells and suppresses CRC progression.

Humans↗

PubMed2026

Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have shown remarkable efficacy in non-small cell lung cancer (NSCLC); however, many patients still develop resistance to immunotherapy. Although small cell lung cancer (SCLC) is also an important histological type of lung cancer, NSCLC accounts for the majority of lung cancer cases. Current research on ICI development, first-line treatment efficacy, and the mechanisms of lipid metabolism in tumor-associated macrophages (TAMs) is predominantly focused on NSCLC. In patients with advanced NSCLC, objective response rates (ORRs) with PD-1/PD-L1 inhibitor monotherapy remain limited. Only in patients with high PD-L1 expression [tumor proportion score (TPS) ≥50%] and without sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements does the ORR increase to approximately 40-45%. TAMs are a key component of the immunosuppressive tumor microenvironment (TME). Lipid metabolic reprogramming profoundly influences the functional and transcriptional features of TAMs. This review aims to integrate relevant evidence, elucidate how TAM lipid metabolism promotes immunosuppression and resistance to ICIs, and outline potential therapeutic strategies. METHODS: We searched PubMed/MEDLINE, Web of Science, and Scopus for publications up to June 2026 using terms combining lung cancer, TAMs, lipid metabolism, and immune checkpoint blockade/resistance. Mechanistic, translational, and clinically relevant studies were selected by author consensus. KEY CONTENT AND FINDINGS: Lipid uptake, de novo lipogenesis, fatty acid oxidation (FAO), cholesterol remodeling, and eicosanoid metabolism are not independent processes in TAMs. Lipid metabolic reprogramming in TAMs ultimately suppresses type I interferon (IFN-I) signaling, upregulates PD-L1 expression, and impairs the function of CD8+ T cells with stem-like features, thereby establishing an immunosuppressive TME and leading to resistance to ICIs. In lung cancer, hypoxia, high lactate levels, and tobacco exposure further shape the lipid phenotype of TAMs, such as lipid raft enrichment and lipid-laden macrophage subsets like SPP1+ macrophages. Different driver genomic backgrounds differentially impact tumor cell-intrinsic metabolism and the lipid metabolic programs of myeloid cells. In preclinical models, interventions targeting these metabolic axes, including TAM-directed delivery systems, have demonstrated potential therapeutic benefit when combined with anti-PD-1/PD-L1 therapy. CONCLUSIONS: Targeting TAM lipid metabolism to convert immunologically cold tumors into more inflamed, ICI-responsive tumors is a promising strategy to overcome resistance in NSCLC. Identification of predictive biomarkers of therapeutic response and development of cell-selective drug delivery systems come to be major challenges.

Non-small cell lung cancer (NSCLC)↗

PubMed2026

Profiling Dectin-2-Positive Tumor-Associated Macrophages Across Human Cancers by Immunohistochemistry.

PURPOSE: To characterize the prevalence and distribution of Dectin-2-positive macrophages across human tumors and develop a research immunohistochemistry (IHC) assay to assess Dectin-2 in cancer tissues. MATERIALS AND METHODS: C-type lectin domain family 6 member A (CLEC6A), the gene encoding Dectin-2, was evaluated across 38 tumor types using The Cancer Genome Atlas. A fit-for-purpose Dectin-2 IHC assay was developed using a monoclonal antibody selected from screening 11 anti-Dectin-2 antibodies. Assay performance was supported by Dectin-2-expressing and parental cell line controls, macrophage-associated staining patterns, and comparison with an orthogonal CLEC6A in situ hybridization method using RNAscope. Dectin-2 expression was assessed in tissue microarrays (n = 553 samples) across 6 cancer types and whole tissue sections (n = 137) across 7 cancer types. RESULTS: The Cancer Genome Atlas analysis identified enriched CLEC6A expression in several tumor types, including non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), and subsets of head and neck cancer (HNC) and colorectal cancer (CRC). By IHC, Dectin-2-positive macrophages were detected across tumor types, with notable heterogeneity within and across cancer types. In tissue microarrays, NSCLC showed the highest frequency of Dectin-2-positive macrophage infiltration, with 38% of cases with staining ≥1% of tumor area. Whole tissue section analysis confirmed and expanded these findings, with ≥50% of NSCLC, melanoma, HNC, TNBC, and CRC samples showing Dectin-2-positive macrophages in ≥1% tumor area. CONCLUSIONS: Dectin-2 expression was observed in subsets of tumor-associated macrophages across multiple human cancers, with relatively enriched expression in NSCLC, melanoma, HNC, TNBC, and CRC. To our knowledge, this study represents the first broad protein-level characterization of Dectin-2 across multiple human tumor types, identifies cancers with relatively enriched Dectin-2-positive macrophage infiltration, and provides a foundation for future translational studies of Dectin-2-targeted therapies.

Humans↗

PubMed2024

Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression.

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.

Decorin↗

PubMed2026

Context-dependent effects of MIR100HG on tumorigenic phenotypes and p38/MAPK-AKT signaling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide and is characterized by a hypoxic tumor microenvironment that promotes tumor progression, cellular adaptation, and therapeutic resistance. Increasing evidence indicates that long non-coding RNAs (lncRNAs) play critical roles in regulating tumor-associated signaling networks; however, the contribution of MIR100HG to hepatocellular carcinoma progression, particularly under hypoxic conditions, remains insufficiently understood. In this study, we investigated the expression pattern and functional significance of MIR100HG in hepatocellular carcinoma using epithelial-like Hep3B and mesenchymal-like SNU-398 cells, together with non-tumor hepatocytes (Clone-9). Gain- and loss-of-function approaches were employed to evaluate the impact of MIR100HG on tumor-associated cellular phenotypes under both normoxic and hypoxic conditions. Functional assays demonstrated that MIR100HG overexpression significantly enhanced cell proliferation, clonogenic potential, migration, and invasion, whereas MIR100HG silencing markedly suppressed these tumorigenic properties and increased apoptotic cell death. Mechanistic analyses revealed that MIR100HG promotes oncogenic signaling through the p38/MAPK and AKT pathways under normoxic conditions, whereas MIR100HG depletion reduced the phosphorylation of these key signaling proteins. Notably, additional pathway analyses under hypoxia-mimicking conditions revealed a distinct signaling response, in which the MIR100HG-associated activation of p38/MAPK and AKT observed under normoxia was not maintained. Moreover, the expression patterns of AKT-associated regulatory genes, including GAS6 and PTEN, were reversed under hypoxia-mimicking conditions. These findings suggest that the effects of MIR100HG on oncogenic signaling are highly dependent on the cellular oxygenation context and that hypoxia reshapes the downstream signaling consequences of MIR100HG expression in HCC cells. Collectively, our findings identify MIR100HG as a hypoxia-associated oncogenic regulator that enhances tumorigenic phenotypes and promotes survival signaling in hepatocellular carcinoma. These results highlight MIR100HG as a potential biomarker and therapeutic target in liver cancer and provide new insights into the molecular mechanisms underlying hypoxia-driven tumor progression.

Humans↗

PubMed2026

mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression.

Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.

Journal Article↗

PubMed2026

FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by profound immunosuppression that facilitates tumor progression and promotes therapeutic resistance. Fibroblast activation protein (FAP), a recognized theranostic target in multiple cancers, is upregulated in GBM and predominantly expressed by pericyte-like stromal cells. Here we identify a role for FAP⁺ pericyte-like cells in shaping the GBM immune microenvironment through monocyte recruitment and differentiation. Analysis of The Cancer Genome Atlas (TCGA) datasets, supported by reverse-transcription quantitative PCR and immunohistochemistry, revealed that elevated FAP expression-serving as a proxy for the abundance of FAP⁺ pericyte-like cells-is associated with an immune-enriched tumor microenvironment characterized by higher macrophage abundance and elevated expression of M2 polarization markers. Spatial analyses, including immunofluorescence and spatial transcriptomics, demonstrated that immunosuppressive macrophages preferentially localize in proximity to FAP⁺ pericytes. Single-cell RNA sequencing identified these FAP⁺ cells as a distinct perivascular stromal subset with a unique expression pattern of extracellular matrix components and cytokines, including CCL2 and CSF1, with corresponding receptors expressed on myeloid cells. Functional assays using patient-derived FAP⁺ pericyte-like cells confirmed their ability to attract monocytes via soluble mediators and to promote their differentiation and polarization into tumor-associated macrophages with immunoregulatory features, partly mediated by the CSF1-CSF1R axis. Orthotopic co-implantation experiments in mice further supported their capacity to enhance myeloid infiltration in vivo. Consistent with these biological effects, a transcriptional signature characteristic of FAP⁺ pericytes correlated with worse overall survival in patients with GBM. Together, these findings position FAP⁺ pericyte-like cells as modulators of the GBM immune landscape, fostering a tumor-permissive niche by promoting the differentiation of circulating monocytes into immunoregulatory macrophages. Targeting this stromal population may offer new therapeutic avenues to reprogram tumor-associated immune responses in GBM.

Journal Article↗

PubMed2026

MYBL2 promotes malignant phenotypes and M2-like macrophage polarization through CCL2 in non-small cell lung cancer.

Hub genes associated with non-small cell lung cancer (NSCLC) were identified through bioinformatics screening. In vitro experiments analyzed the potential mechanisms by which these genes regulate tumor malignant phenotypes and macrophage polarization. Differentially expressed genes were identified from The Cancer Genome Atlas (TCGA)-NSCLC and GSE32175 datasets, followed by protein-protein interaction (PPI) network analysis to screen hub genes. The effects of MYB Proto-Oncogene Like 2 (MYBL2) on NSCLC progression and macrophage polarization were evaluated using in vitro models. The regulatory relationship between MYBL2 and C-C motif chemokine ligand 2 (CCL2) was investigated by Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays, and rescue experiments were performed to validate the role of the MYBL2-CCL2 axis. Bioinformatics screening identified BUB1B, CDCA2 and MYBL2 as key hub genes with high expression in NSCLC, among which MYBL2 was significantly upregulated in NSCLC cells. Functional experiments confirmed that MYBL2 silencing markedly inhibited the malignant proliferation, migration and invasion of NSCLC cells. Tumor cell MYBL2 knockdown effectively reversed M2-like polarization and promoted M1-like polarization in the co-culture system. Mechanistically, MYBL2 directly bound to the CCL2 promoter region to enhance CCL2 transcriptional activity and upregulate CCL2 expression in NSCLC cells. Exogenous CCL2 supplementation significantly rescued the inhibitory effect of MYBL2 knockdown on macrophage M2-like polarization, verifying the mediating role of CCL2 in this regulatory axis. MYBL2 is strongly expressed in NSCLC cells and is associated with enhanced malignant phenotypes. It may affect macrophage M2-like polarization by upregulating CCL2, thus participating in NSCLC immune microenvironment remodeling.

CCL2↗

PubMed2025

Injury and inflammation promote cancer progression at the anorectal junction.

In anorectal cancer, epithelial tumors frequently develop in transition zones (TZs) between the anal and the rectal epithelia, a region subjected to inflammation and wounds. However, whether inflammation and wounds contribute to tumor development in the anorectal region remain totally unknown. Using mice with KRASG12D mutation selectively at the TZ cells, we found that recurrent wound and its associated sustained inflammation are essential to promote tumor development. We characterized at the single-cell level the malignant events that occurred at the TZ all along tumor development from early neoplastic, hyperplastic, to malignant transition. We showed that this tumoral development was under the influence of interleukin (IL)-17, a cytokine highly secreted by a γδ T lymphocyte subset, allowing the recruitment of neutrophils at the TZ, which was crucial for tumor progression. Hence, this study reveals the importance of wound and its associated IL-17/neutrophil inflammatory axis in cancer progression.

Animals↗

PubMed2026

Lactylome Reprogramming Mediates Therapeutic Response and Adaptation to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) exhibits high prevalence in China and poor prognosis despite neoadjuvant chemotherapy (NACT), with significant chemoresistance development. Tumor-associated metabolic reprogramming and NACT-induced cellular stress promote lactate accumulation, which serves as a precursor for lysine lactylation (Kla), a post-translational modification potentially regulating cancer progression. We hypothesized that systematic characterization of the lactylome in response to NACT could reveal critical molecular mechanisms underlying treatment and identify new therapeutic vulnerabilities in ESCC. Herein, through comprehensive proteomic and lactylome profiling of tumor and adjacent normal adjacent tissues from 31 ESCC patients (with or without NACT treatment), we identified 8281 proteins and 1836 Kla sites across 62 samples. NACT induced substantial lactylome alterations with 307 differentially expressed Kla sites predominantly in nonhistone proteins involved in DNA damage response and metabolic pathways. Our data revealed that while NACT-induced suppression of energy metabolism, coupled with upregulated 3-hydroxy-3-methylglutaryl reductase degradation 1 complex expression, may exert potential proapoptotic effects, the activation of ribosome biogenesis and increased nucleoprotein lactylation triggered tumor-protective mechanisms. Mechanistically, we demonstrated that DNA damage and elevated lactate levels induced poly(ADP-ribose) polymerase 1 K654 lactylation, enhancing its enzymatic activity and augmenting poly(ADP-ribosyl)ation of downstream targets, potentially playing a pivotal role in chemotherapy resistance-associated pathways. This comprehensive tissue-level landscape of Kla dynamics in ESCC response to chemotherapy establishes Kla as a critical regulatory mechanism in treatment response, potentially offering novel therapeutic targets and predictive biomarkers for personalized treatment strategies.

Humans↗

PubMed2026

Circulating tumor-associated autoantibody signatures for diagnosis and prognosis in small-cell lung cancer and lung adenocarcinoma.

BACKGROUND: Tumour-associated autoantibodies (TAAbs) are promising biomarkers for cancer detection, but their induction and clinical relevance in lung cancer remain unclear. METHODS: Serum samples from 695 individuals were analysed for TAAb profiling by protein-array screening and two-stage ELISA validation. Diagnostic models were constructed with identified TAAbs and compared with conventional tumour markers. Potential mechanisms, clinical and prognostic features of TAAb seropositivity were analysed and its presence in prediagnostic sera was evaluated to assess the potential for early detection. RESULTS: Six TAAbs for small cell lung cancer (SCLC) and four for lung adenocarcinoma (LUAD) were identified, demonstrating excellent diagnostic performance (AUC > 0.8) and outperforming ProGRP and CEA. TAAb induction correlated with antigen overexpression, somatic mutations and HLA class II amino acid polymorphisms. TAAb panel seropositivity was associated with older age and advanced stage in both subtypes, and predicted poor survival in SCLC but a favourable outcome in advanced LUAD. In prediagnostic sera, the TAAb concentration increased progressively, with detectability up to 2 years before clinical diagnosis. CONCLUSIONS: Distinct TAAb panels were identified for SCLC and LUAD, serving as accurate diagnostic markers that enable early detection and as indicators of prognosis in different clinical contexts.

Humans↗

PubMed2026

tRNA m1A modification orchestrates STING translation in macrophages to enhance antitumor immunity and CAR-macrophage immunotherapy.

Tumor-associated macrophages (TAMs) play crucial roles in tumor progression. However, the mechanisms underlying the posttranscriptional regulation of TAMs remain largely unknown. Here, we demonstrated that Trmt61a, the "writer" enzyme of tRNA N1-methyladenosine (m1A) modification, is highly expressed in proinflammatory macrophages in tumor microenvironment. We generated conditional knockout (KO) mice for Trmt61a and observed that Trmt61a deletion in macrophages significantly promoted tumor growth. Mechanistically, we identified that m1A maintains the translation of STING, enhances STING-TBK1-IFN-β signaling in macrophages and therefore suppresses tumor cell growth. We further generated TRMT61A-overexpressing human iPSC-derived CAR-macrophage and demonstrated that human TRMT61A effectively promoted antitumor CAR-macrophage therapy in vivo. Collectively, our findings reveal a novel regulatory mechanism of tRNA m1A modification in macrophages, highlighting the antitumor therapeutic potential of targeting tRNA m1A modification in macrophages.

Animals↗

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↗