ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1595907
This article is part of the Research TopicCommunity Series in Novel Biomarkers for Predicting Response to Cancer Immunotherapy: Volume IIIView all 19 articles
TGM2 Regulated by Transcription Factor NR3C1 Drives p38 MAPK-Mediated Tumor Progression and Immune Evasion in Lung Squamous Cell Carcinoma
Provisionally accepted
Chunlong Lin1,2,3Shangfu Li1,2,3Liang Yi1,2Huiling Zhou1,2,3Zhiyi Xiao1,2,3Zhuo Yang1,2,3Qingping Chen1,2,3Xiangyang Peng1,2,3Kanao Li1,2,3Qing Wang1,2,3Wei Liu4
Ni Li4Lun Li1Duanglin Du1Qi Xu1,2,3*
Lingge Yang1,2,3*- 1Department of Respiratory and Critical Care Medicine, Yueyang People's Hospital of Hunan Normal University, Yueyang, China
- 2Department of Oncology, Yueyang People's Hospital of Hunan Normal University, Yueyang, China
- 3Yueyang Municipal Key Laboratory of Molecular Biology for Respiratory Oncology, Yueyang, China
- 4Department of Pathology, Yueyang People's Hospital of Hunan Normal University, Yueyang, China
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Background: 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. Methods: The prognostic value of TGM2 was analyzed using the TCGA LUSC cohort. Key genes were screened via 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. Results: 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). Conclusion: TGM2 drives LUSC progression via 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.
Keywords: Lung squamous cell carcinoma, TGM2, p38 MAPK signaling, Immune Evasion, Tumor Microenvironment, NR3C1
Received: 18 Mar 2025; Accepted: 01 Sep 2025.
Copyright: © 2025 Lin, Li, Yi, Zhou, Xiao, Yang, Chen, Peng, Li, Wang, Liu, Li, Li, Du, Xu and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qi Xu, Department of Respiratory and Critical Care Medicine, Yueyang People's Hospital of Hunan Normal University, Yueyang, China
Lingge Yang, Department of Respiratory and Critical Care Medicine, Yueyang People's Hospital of Hunan Normal University, Yueyang, China
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