Transcriptional Patterns of Lower-Grade Glioma Patients with Distinct Ferroptosis Levels, Immunotherapy Response, and Temozolomide Sensitivity

Background: Many studies have defined a critical role for Ferroptosis in Cancer progression and therapy, but it is unclear how Ferroptosis regulates tumor immunity or tumor microenvironment (TME).

Methods: In this study, 24 ferroptosis-regulators were assessed by nonnegative matrix factorization (NMF) consensus clustering to identify Ferroptosis patterns in lower-grade gliomas (LGGs). Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) method and single sample gene set enrichment analysis (ssGSEA) were used to quantify immune cell infiltrations. The PCA algorithm was used to develop the ferroptosis-related score (FRscore) to measure Ferroptosis levels.

Results: Two LGG subgroups named ferroptosis-related clusters 1 (FRC1) and 2 (FRC2), with distinct Ferroptosis levels, immune infiltrations, and clinical outcomes were determined in 1,407 LGG samples. A well-designed scoring system was developed to evaluate the Ferroptosis levels in LGG patients based on the FRSig gene profile and divided patients into low- and high-FRscore subgroups. Patients with low FRscores had lower Ferroptosis levels and prolonged survival time and were expected to benefit from immune checkpoint blockade (ICB) therapy and showed higher sensitivity to TMZ chemotherapy. Findings also showed that the PI3K-AKT-mTOR pathway is activated by Ferroptosis induction in SW1088 cells.

Conclusions: This study highlights the critical role of Ferroptosis in TME formation and shaping, and quantitatively assessing Ferroptosis levels in individual tumors can help to define the intratumor microenvironment and formulate precise treatment strategies for LGG patients.