Pan-cancer characterization of m6A-mediated regulation of T cell exhaustion dynamics and clinical relevancies in human cancers
T cell exhaustion (TEX) is a major barrier to effective immunotherapy. The role of N6-methyladenosine (m6A) modification in regulating immune cell function has been recognized, but its impact on TEX dynamics across cancer types and clinical outcomes remains unclear. Here, we conducted a pan-cancer a...
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| Language: | English |
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000198 |
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| author | Weiping Ji Ye Fang Liwei Chen Yitong Zheng Yifei Pei Changqiu Mei Meng Zhou |
| author_facet | Weiping Ji Ye Fang Liwei Chen Yitong Zheng Yifei Pei Changqiu Mei Meng Zhou |
| author_sort | Weiping Ji |
| collection | DOAJ |
| description | T cell exhaustion (TEX) is a major barrier to effective immunotherapy. The role of N6-methyladenosine (m6A) modification in regulating immune cell function has been recognized, but its impact on TEX dynamics across cancer types and clinical outcomes remains unclear. Here, we conducted a pan-cancer analysis integrating multi-omics data from cell lines, single-cell RNA sequencing, and pan-cancer and immunotherapy datasets to explore the dynamic interplay between m6A modification and TEX. We found that m6A modification influences key TEX-associated genes at both the cellular and single-cell levels, with distinct expression patterns across the exhaustion spectrum. Based on m6A-TEX interactions, three pan-cancer subtypes were identified, each with unique molecular profiles, immune phenotypes, and survival outcomes. The TexLm6AL subtype, characterized by low m6A activity and low TEX, correlated with high immune infiltration, increased cytolytic activity, and favorable survival, whereas the TexLm6AH and TexHm6AH subtypes with higher m6A activity were associated with poorer survival. Multivariate analysis confirmed the prognostic value of this classification independent of traditional clinical factors. Moreover, m6A-TEX crosstalk influenced responses to immune checkpoint blockade therapies. Our findings provide novel insights into the role of m6A in TEX regulation and underscore the potential of m6A regulators as biomarkers and therapeutic targets for advancing cancer immunotherapy. |
| format | Article |
| id | doaj-art-2dfba7f7b35d425fabdd1bac9e1a958e |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-2dfba7f7b35d425fabdd1bac9e1a958e2025-02-07T04:47:27ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102465Pan-cancer characterization of m6A-mediated regulation of T cell exhaustion dynamics and clinical relevancies in human cancersWeiping Ji0Ye Fang1Liwei Chen2Yitong Zheng3Yifei Pei4Changqiu Mei5Meng Zhou6Department of Genaral Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Wenzhou Medical University, Zhejiang, P.R. ChinaDepartment of Genaral Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Wenzhou Medical University, Zhejiang, P.R. ChinaDepartment of Genaral Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Wenzhou Medical University, Zhejiang, P.R. ChinaDepartment of Genaral Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Wenzhou Medical University, Zhejiang, P.R. ChinaDepartment of Genaral Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Wenzhou Medical University, Zhejiang, P.R. ChinaDepartment of Genaral Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Wenzhou Medical University, Zhejiang, P.R. ChinaDepartment of Genaral Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Wenzhou Medical University, Zhejiang, P.R. China; Corresponding author: Meng Zhou, Department of Genaral Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Wenzhou Medical University, Zhejiang, P.R. China.T cell exhaustion (TEX) is a major barrier to effective immunotherapy. The role of N6-methyladenosine (m6A) modification in regulating immune cell function has been recognized, but its impact on TEX dynamics across cancer types and clinical outcomes remains unclear. Here, we conducted a pan-cancer analysis integrating multi-omics data from cell lines, single-cell RNA sequencing, and pan-cancer and immunotherapy datasets to explore the dynamic interplay between m6A modification and TEX. We found that m6A modification influences key TEX-associated genes at both the cellular and single-cell levels, with distinct expression patterns across the exhaustion spectrum. Based on m6A-TEX interactions, three pan-cancer subtypes were identified, each with unique molecular profiles, immune phenotypes, and survival outcomes. The TexLm6AL subtype, characterized by low m6A activity and low TEX, correlated with high immune infiltration, increased cytolytic activity, and favorable survival, whereas the TexLm6AH and TexHm6AH subtypes with higher m6A activity were associated with poorer survival. Multivariate analysis confirmed the prognostic value of this classification independent of traditional clinical factors. Moreover, m6A-TEX crosstalk influenced responses to immune checkpoint blockade therapies. Our findings provide novel insights into the role of m6A in TEX regulation and underscore the potential of m6A regulators as biomarkers and therapeutic targets for advancing cancer immunotherapy.http://www.sciencedirect.com/science/article/pii/S2162253125000198MT: BioinformaticsT cell exhaustionN6-methyladenosinepan-cancer |
| spellingShingle | Weiping Ji Ye Fang Liwei Chen Yitong Zheng Yifei Pei Changqiu Mei Meng Zhou Pan-cancer characterization of m6A-mediated regulation of T cell exhaustion dynamics and clinical relevancies in human cancers Molecular Therapy: Nucleic Acids MT: Bioinformatics T cell exhaustion N6-methyladenosine pan-cancer |
| title | Pan-cancer characterization of m6A-mediated regulation of T cell exhaustion dynamics and clinical relevancies in human cancers |
| title_full | Pan-cancer characterization of m6A-mediated regulation of T cell exhaustion dynamics and clinical relevancies in human cancers |
| title_fullStr | Pan-cancer characterization of m6A-mediated regulation of T cell exhaustion dynamics and clinical relevancies in human cancers |
| title_full_unstemmed | Pan-cancer characterization of m6A-mediated regulation of T cell exhaustion dynamics and clinical relevancies in human cancers |
| title_short | Pan-cancer characterization of m6A-mediated regulation of T cell exhaustion dynamics and clinical relevancies in human cancers |
| title_sort | pan cancer characterization of m6a mediated regulation of t cell exhaustion dynamics and clinical relevancies in human cancers |
| topic | MT: Bioinformatics T cell exhaustion N6-methyladenosine pan-cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125000198 |
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