Purpose: mRNA vaccines represent a promising and innovative strategy within the realm of cancer immunotherapy. However, their efficacy in treating lower-grade glioma (LGG) requires evaluation. Ferroptosis exhibits close associations with the initiation, evolution, and suppression of cancer. In this study, we explored the landscape of the ferroptosis-associated tumor microenvironment to facilitate the development of mRNA vaccines for LGG patients.
Patients and Methods: Genomic and clinical data of the LGG patients was obtained from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Ferroptosis-related tumor antigens were identified based on differential expression, mutation status, correlation with antigen-presenting cells, and prognosis, relevance to immunogenic cell death (ICD). Antigen expression levels in LGG specimens and cell lines were validated using real time-polymerase chain reaction (RT-PCR). Consensus clustering was employed for patient classification. The immune landscapes of ferroptosis subtypes were further characterized, including immune responses, prognostic ability, tumor microenvironment, and tumor-related signatures.
Results: Five tumor antigens, namely, HOTAIR, IDO1, KIF20A, NR5A2, and RRM2 were identified in LGG. RT-PCR demonstrated higher expression of these genes in LGG compared to the control. Twelve gene modules and four ferroptosis subtypes (FS1-FS4) of LGG were defined. FS2 and FS4, characterized as “cold” tumors due to their decreased tumor mutation burden (TMB) and immune checkpoint proteins (ICPs), were deemed appropriate candidates for the mRNA vaccine.
Conclusion: HOTAIR, IDO1, KIF20A, NR5A2, and RRM2 were identified as promising candidate antigens for the development of an LGG mRNA vaccine, particularly offering potential benefits to FS2 and FS4 patients.

Keywords: ferroptosis, lower grade glioma, mRNA vaccine, immunotherapy