Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer
Abstract Loss or downregulation of major histocompatibility complex (MHC) molecules represents a key mechanism by which tumours escape immune recognition and acquire resistance to immunotherapeutic interventions. This review focuses on the central regulatory pathways. These includes transcriptional...
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| Format: | Article |
| Language: | English |
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Wiley
2025-07-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70403 |
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| author | Pei Lin Yunfan Lin Xu Chen Xinyuan Zhao Li Cui |
| author_facet | Pei Lin Yunfan Lin Xu Chen Xinyuan Zhao Li Cui |
| author_sort | Pei Lin |
| collection | DOAJ |
| description | Abstract Loss or downregulation of major histocompatibility complex (MHC) molecules represents a key mechanism by which tumours escape immune recognition and acquire resistance to immunotherapeutic interventions. This review focuses on the central regulatory pathways. These includes transcriptional repression, lysosomal degradation, and post‐translational modifications that disrupt MHC stability, trafficking, and surface expression. We highlight how these mechanisms impair antigen presentation and contribute to tumour immune evasion. In addition, we explore emerging therapeutic strategies focused on reactivating MHC expression to enhance tumour immunogenicity and improve the efficacy of immunotherapy. Finally, we discuss the translational potential of these approaches and the remaining challenges, including tumour heterogeneity, immunotoxicity and dynamic regulation within the tumour microenvironment, that must be addressed to optimize MHC‐targeted interventions in cancer immunotherapy. Highlights Tumour cells evade immune surveillance by downregulating MHC expression through transcriptional repression, lysosomal degradation and post‐translational modifications. Pharmacological agents interventing epigenetic and metabolic can upregulate MHC expression and improve T cell activation. Combination strategies potentiate immunotherapy efficacy by reinvigorating tumour immunogenicity. |
| format | Article |
| id | doaj-art-ef7dc4bc170d4e0fbe055d56994bccf4 |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-ef7dc4bc170d4e0fbe055d56994bccf42025-08-22T06:42:10ZengWileyClinical and Translational Medicine2001-13262025-07-01157n/an/a10.1002/ctm2.70403Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancerPei Lin0Yunfan Lin1Xu Chen2Xinyuan Zhao3Li Cui4School of Stomatology Stomatological Hospital Southern Medical University Guangzhou Guangdong ChinaSchool of Stomatology Stomatological Hospital Southern Medical University Guangzhou Guangdong ChinaSchool of Stomatology Stomatological Hospital Southern Medical University Guangzhou Guangdong ChinaSchool of Stomatology Stomatological Hospital Southern Medical University Guangzhou Guangdong ChinaSchool of Stomatology Stomatological Hospital Southern Medical University Guangzhou Guangdong ChinaAbstract Loss or downregulation of major histocompatibility complex (MHC) molecules represents a key mechanism by which tumours escape immune recognition and acquire resistance to immunotherapeutic interventions. This review focuses on the central regulatory pathways. These includes transcriptional repression, lysosomal degradation, and post‐translational modifications that disrupt MHC stability, trafficking, and surface expression. We highlight how these mechanisms impair antigen presentation and contribute to tumour immune evasion. In addition, we explore emerging therapeutic strategies focused on reactivating MHC expression to enhance tumour immunogenicity and improve the efficacy of immunotherapy. Finally, we discuss the translational potential of these approaches and the remaining challenges, including tumour heterogeneity, immunotoxicity and dynamic regulation within the tumour microenvironment, that must be addressed to optimize MHC‐targeted interventions in cancer immunotherapy. Highlights Tumour cells evade immune surveillance by downregulating MHC expression through transcriptional repression, lysosomal degradation and post‐translational modifications. Pharmacological agents interventing epigenetic and metabolic can upregulate MHC expression and improve T cell activation. Combination strategies potentiate immunotherapy efficacy by reinvigorating tumour immunogenicity.https://doi.org/10.1002/ctm2.70403cancer immunotherapyimmune responsesMHC losstumour microenvironment |
| spellingShingle | Pei Lin Yunfan Lin Xu Chen Xinyuan Zhao Li Cui Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer Clinical and Translational Medicine cancer immunotherapy immune responses MHC loss tumour microenvironment |
| title | Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer |
| title_full | Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer |
| title_fullStr | Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer |
| title_full_unstemmed | Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer |
| title_short | Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer |
| title_sort | decoding mhc loss molecular mechanisms and implications for immune resistance in cancer |
| topic | cancer immunotherapy immune responses MHC loss tumour microenvironment |
| url | https://doi.org/10.1002/ctm2.70403 |
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