{"doi":"10.3389/fimmu.2025.1595907","title":"TGM2 regulated by transcription factor NR3C1 drives p38 MAPK-mediated tumor progression and immune evasion in lung squamous cell carcinoma","abstract":"<h4>Background</h4>Lung squamous cell carcinoma (LUSC) is highly malignant with limited therapeutic targets. Prior studies indicate transglutaminase 2 (TGM2) regulates the tumor microenvironment, but its mechanisms in driving LUSC progression and immune evasion remain unclear.<h4>Methods</h4>The prognostic value of TGM2 was analyzed using the TCGA LUSC cohort. Key genes were screened <i>via</i> random forest algorithm. Functional validation was performed in NCI-H520 and SK-MES-1 cell lines. Proteomics, GSEA, and TIMER2.0 assessed downstream pathways and immune infiltration. Transcriptional regulatory databases predicted the upstream transcription factors of TGM2, which was then validated by chromatin immunoprecipitation (ChIP)-qPCR.<h4>Results</h4>TGM2 was an independent prognostic factor for LUSC. High TGM2 expression correlated with reduced overall survival (OS, P = 0.00018) and disease-free survival (DFS, P = 0.00019). TGM2 promoted proliferation, migration, invasion, clonogenicity, and suppressed apoptosis in LUSC cells by activating p38 MAPK signaling. Elevated TGM2 levels were associated with an immunosuppressive microenvironment: decreased Th1 (R = -0.186, P < 0.0001) and NK cell infiltration (R = -0.116, P = 0.0092), and increased M2 macrophage (R = 0.164-0.528, P < 0.0001) and cancer-associated fibroblast infiltration (R = 0.469, P < 0.0001). NR3C1 was identified as a key transcription factor regulating TGM2. ChIP-qPCR analysis confirmed that NR3C1 binds to a specific site (921-935) within the TGM2 promoter, and their expression showed a strong positive correlation (R = 0.53, P < 0.0001).<h4>Conclusion</h4>TGM2 drives LUSC progression <i>via</i> p38 MAPK activation and shapes an immunosuppressive microenvironment, which is transcriptionally regulated by NR3C1. This study supports TGM2 as a prognostic biomarker and suggests its potential as a therapeutic target, which may inform future combination immunotherapy strategies.","journal":"Frontiers in Immunology","year":2025,"id":7823,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0426,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-09-18","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":70798,"name":"Shangfu Li","orcid":null,"position":1,"is_corresponding":false},{"id":70799,"name":"Liang Yi","orcid":null,"position":2,"is_corresponding":false},{"id":70800,"name":"Huiling Zhou","orcid":"0000-0001-6409-6329","position":3,"is_corresponding":false},{"id":70801,"name":"Zhiyi Xiao","orcid":null,"position":4,"is_corresponding":false},{"id":63992,"name":"Zhuo Yang","orcid":"0000-0002-5296-8596","position":5,"is_corresponding":false},{"id":70802,"name":"Qingping Chen","orcid":null,"position":6,"is_corresponding":false},{"id":70803,"name":"Xiangyang Peng","orcid":null,"position":7,"is_corresponding":false},{"id":70804,"name":"Kanao Li","orcid":null,"position":8,"is_corresponding":false},{"id":70805,"name":"Qing Wang","orcid":"0009-0003-7328-8762","position":9,"is_corresponding":false},{"id":52948,"name":"Wei Liu","orcid":"0000-0002-1737-8013","position":10,"is_corresponding":false},{"id":61641,"name":"Ni Li","orcid":"0000-0001-5530-7745","position":11,"is_corresponding":false},{"id":70806,"name":"Lun Li","orcid":"0000-0003-3242-031X","position":12,"is_corresponding":false},{"id":70807,"name":"Duanlin Du","orcid":null,"position":13,"is_corresponding":false},{"id":70808,"name":"Qi Xu","orcid":"0000-0002-4646-6936","position":14,"is_corresponding":false},{"id":70809,"name":"Lingge Yang","orcid":"0000-0003-0853-3963","position":15,"is_corresponding":false},{"id":22190,"name":"Yi Liang","orcid":"0000-0002-4814-0761","position":16,"is_corresponding":false},{"id":4389,"name":"Peng Xu","orcid":"0000-0001-8007-9879","position":17,"is_corresponding":false},{"id":70810,"name":"Kathy Pei Li","orcid":null,"position":18,"is_corresponding":false},{"id":70797,"name":"Chunlong Lin","orcid":"0000-0002-1861-1278","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}