MAGEA4, a member of the Melanoma-Associated Antigen (MAGE) family, is a cancer-testis antigen mainly expressed in testes, but aberrantly overexpressed in multiple cancers [2,3]. It plays crucial roles in several biological processes related to tumorigenesis. MAGEA4 interacts with the RING ubiquitin ligase RAD18, activating trans-lesion DNA synthesis (TLS) which may promote tumor evolution [2]. It also participates in multiple pathways such as ubiquitination and degradation of tumor suppressor P53, regulation of cell cycle and apoptosis, modulation of DNA damage repair, and enhancement of cancer cell survival, thus promoting tumor initiation and progression [3].

Studies have shown that factors like TWIST1 can upregulate MAGEA4 expression. TWIST1, a bHLH transcription factor, indirectly binds to the E-boxes of MAGEA4 promoter sequence and upregulates its expression, which may be related to tumor cell invasiveness and aggressiveness [4]. In addition, MAGEA4-coated extracellular vesicles (EVs) are stable under common storage conditions and can be assembled in vitro, holding potential for EV-based anti-cancer applications [1]. Also, MAGEA4-based TCR-T cell therapy and cancer vaccines show clinical potential for treating solid tumors [3].

In conclusion, MAGEA4 is significant in tumor-related biological processes. Its overexpression in various cancers and its role in promoting tumor development make it a potential target for cancer immunotherapy. The stability of MAGEA4-EVs and the promising results of MAGEA4-based immunotherapies further emphasize its importance in cancer research and treatment.

References:

1. Reinsalu, Olavi, Samel, Anneli, Niemeister, Elen, Kurg, Reet. 2021. MAGEA4 Coated Extracellular Vesicles Are Stable and Can Be Assembled In Vitro. In International journal of molecular sciences, 22, . doi:10.3390/ijms22105208. https://pubmed.ncbi.nlm.nih.gov/34069064/

2. Griffith-Jones, Simonne, Álvarez, Lucía, Mukhopadhyay, Urbi, Hennig, Janosch, Bhogaraju, Sagar. 2024. Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins. In The EMBO journal, 43, 1273-1300. doi:10.1038/s44318-024-00058-9. https://pubmed.ncbi.nlm.nih.gov/38448672/

3. Zhu, Weijian, Yi, Qiang, Chen, Zheng, Zhong, Jianing, Zhong, Jinghua. 2025. Exploring the role and mechanisms of MAGEA4 in tumorigenesis, regulation, and immunotherapy. In Molecular medicine (Cambridge, Mass.), 31, 43. doi:10.1186/s10020-025-01079-8. https://pubmed.ncbi.nlm.nih.gov/39905312/

4. Forghanifard, Mohammad Mahdi, Rad, Abolfazl, Farshchian, Moein, Moghbeli, Meysam, Abbaszadegan, Mohammad Reza. 2016. TWIST1 upregulates the MAGEA4 oncogene. In Molecular carcinogenesis, 56, 877-885. doi:10.1002/mc.22541. https://pubmed.ncbi.nlm.nih.gov/27533647/