AHR, a novel inhibitory immune checkpoint receptor, is a potential therapeutic target for chemoresistant glioblastoma.

PURPOSE: This study aims to elucidate the mechanism underlying temozolomide resistance in patients with MGMT promoter hypomethylated glioblastoma, which is correlated with poor prognosis. The objective is to identify therapeutic targets and drugs suitable for temozolomide-resistant glioblastoma patients using big data analysis. METHODS: In this retrospective study, transcriptome sequencing data from 457 glioblastoma patients, multi-omics data, and single-cell sequencing data were employed to assess the expression pattern, prognostic value, and biological functions of AHR in glioblastoma. The HERB database was utilized to screen for AHR-targeted drugs for glioblastoma treatment. Validation of our findings was conducted using multiplex immunofluorescence staining of clinical samples and T cells and tumor cells co-culture models. RESULTS: Our findings demonstrated that patients with MGMT promoter unmethylation did not benefit from postoperative temozolomide chemotherapy due to resistance arising from DNA repair function and tumor immune response. AHR was found to be expressed in immune cells and exhibited an immunomodulatory role in glioblastoma with MGMT promoter unmethylation. AHR was identified as a potential novel inhibitory immune checkpoint receptor, serving as a therapeutic target for temozolomide-resistant glioblastoma. Furthermore, targeting AHR with Semen aesculi markedly enhanced the cytotoxic effect of T cells on glioma cells. CONCLUSIONS: In addition to DNA repair function, the tumor immune response plays a pivotal role in temozolomide resistance of glioblastoma. Herbal compounds targeting AHR may offer an effective treatment for temozolomide-resistant glioblastoma.