MAP3K8 is a serine/threonine kinase that is widely expressed in immune cells, non-immune cells, and many tumor types. The expression, clinical significance, biological role, and the underlying molecular mechanisms of MAP3K8 in glioma have not been investigated yet. Here, we discovered that MAP3K8 was aberrantly overexpressed in glioma and correlated with poor clinicopathological features of glioma by analysis on different datasets and immunohistochemistry staining. MAP3K8 is an independent prognostic indicator and significantly correlates with the progression of glioma. We also performed the function and pathway enrichment analysis of MAP3K8 in glioma to explore its biological functions and underlying molecular mechanisms in glioma. MAP3K8 co-expressed genes were mainly enriched in immune-related biological processes such as neutrophil activation, leukocyte migration, neutrophil-mediated immunity, lymphocyte-mediated immunity, T-cell activation, leukocyte cell–cell adhesion, regulation of leukocyte cell–cell adhesion, B-cell-mediated immunity, myeloid cell differentiation, and regulation of cell–cell adhesion. Single-cell RNA sequencing data and immunohistochemistry analysis demonstrated that MAP3K8 is expressed in malignant and immune cells and mainly enriched in the microglia/macrophage cells of glioma. The expression of MAP3K8 was positively correlated with immune infiltration, including effector memory CD4⁺ T cells, plasmacytoid dendritic cells, neutrophils, myeloid dendritic cells, mast cells, and macrophage in glioma. Further correlation analysis demonstrated that a series of inhibitory immune checkpoint molecules, chemokines, and chemokine receptors was positively correlated with the expression of MAP3K8. MAP3K8 might play an essential role in tumor immunity, and inhibition of MPA3K8 is a plausible strategy for glioma immunotherapy.

Background: Mitogen‐activated protein kinase 4 (MAPK4) is an atypical member of the mitogen‐activated protein kinase (MAPK) family. We report here that MAPK4 is overexpressed in glioma. The clinical significance, biological roles and underlying molecular mechanisms through which MAPK4 acts in glioma remain unclear.Methods: Analysis of MAPK4 expression and associated survival in glioma patients was performed based on data obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases and confirmed in human glioma tissue by immunohistochemistry. MAPK4 function and pathway enrichment were analyzed through Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO). The viability and migration ability of MAPK4‐silenced glioblastoma multiforme (GBM) cells were evaluated using CCK8 and transwell assays, respectively, and cell cycle and apoptosis analyses were performed using flow cytometry. Immunoblotting was used to analyze the protein level in MAPK4 knockdown glioma cells. We also analyzed the correlation of MAPK4 expression with immune infiltration and immune checkpoints in glioma.Results: MAPK4 was overexpressed in IDH wild‐type (wt) and 1p/19q non‐codeletion gliomas. MAPK4 expression predicted poor prognosis of glioma patients. MAPK4 was significantly related to functional states, including stemness, metastasis, cell cycle, differentiation and proliferation, in glioma at single‐cell resolution. MAPK4 silencing inhibited proliferation and migration and induced G1 cell cycle arrest in glioma cells via the AKT/mTOR pathway. In vivo, MAPK4 knockdown markedly suppressed the growth of primary glioma. In addition, MAPK4 expression correlated negatively with the infiltration of plasmacytoid DC cells, CD8⁺ T cells and T helper cells. Moreover, MAPK4 expression correlated positively with expression of the main immunoinhibitor checkpoint molecules and some chemokines in glioma.Conclusion: MAPK4 functions as a prognostic indicator in glioma and promotes the proliferation and migration of GBM cells through the AKT/mTOR pathway. MAPK4 may participate in immune infiltration and the expression of immune checkpoints in the glioma microenvironment.

Mitogen‐Activated Protein Kinase Kinase Kinase 1 (MAP3K1) is overexpressed in gliomas; however, its clinical significance, biological functions, and underlying molecular mechanisms remain unclear. Abnormal overexpression of MAP3K1 in glioma is strongly associated with unfavourable clinicopathological characteristics and disease progression. MAP3K1 could potentially serve as a reliable diagnostic and prognostic biomarker for glioma. MAP3K1 silencing suppressed the migration but had no effect on the proliferation and cell death of Glioblastoma Multiforme (GBM) cells. MAP3K1 knockdown exacerbated the temozolomide (TMZ) induced inhibition of glioma cell proliferation and death of GBM cells. In addition, MAP3K1 knockdown combined with TMZ treatment significantly inhibited the growth and increased cell death in organoids derived from GBM patients. MAP3K1 knockdown reversed TMZ resistance of GBM in intracranial glioma model. In terms of molecular mechanisms, the phosphorylation level of ERK was significantly decreased by MAP3K1 silencing. No significant change in the JNK pathway was found in MAP3K1‐silenced GBM cells. Inhibition of ERK phosphorylation suppressed the migration and enhanced the TMZ sensibility of GBM cells. MAP3K1 was correlated with the immune infiltration in glioma. MAP3K1 could facilitate the migration and TMZ resistance of GBM cells through MEK/ERK signalling.

Background: Cancer-associated fibroblasts (CAFs) promote colorectal cancer (CRC) progression through immunosuppression, but their functional heterogeneity and specific mechanisms in recruiting myeloid cells remain poorly defined. Methods: Using functional screening, transcriptomics, and bioinformatics analyses, we identified functionally enriched CAF subsets with differing monocyte-recruiting capacities in CRC. Surface markers were validated via immunofluorescence, immunohistochemistry, and flow cytometry. The role of the identified CAF subset was examined using in vitro co-culture and in vivo tumor models. Animal models were utilized to study the impact of ICAM-1 ⁺ CD51 ⁺ CAFs on CRC tumor growth and immune cell infiltration. Cytokine array profiling, western blotting, and bioinformatics analyses were employed to explore the underlying signaling pathways. Results: We identified a functionally enriched CAF subset defined by co-expression of ICAM-1 and CD51 (ICAM-1⁺CD51⁺ CAFs), which exhibits potent monocyte-recruiting capacity and drives monocytes to acquire M2-like tumor-associated macrophages (TAMs) and monocytic myeloid-derived suppressor cells (M-MDSCs) associated phenotype and suppressive feature. In clinical CRC samples, the abundance of ICAM-1⁺CD51⁺ CAFs correlated positively with intratumoral TAM infiltration. In vivo validation confirmed that ICAM-1⁺CD51⁺ CAFs promote intratumoral accumulation of both TAMs and MDSCs, thereby accelerating tumor progression. Mechanistically, osteopontin (OPN) engagement of CD51 integrin activated the FAK/p38 MAPK pathway within CAFs, enhancing secretion of key cytokines MCP-3, CXCL5, and IL-6, which orchestrate myeloid cell recruitment and differentiation. Conclusion: Our study demonstrates that ICAM-1⁺CD51⁺ CAFs regulate cytokine secretion and contribute to myeloid cell recruitment and differentiation in CRC through the OPN/CD51-FAK/p38 MAPK axis. Targeting this CAF subset may represent a promising therapeutic strategy for CRC, which warrants further investigation.