Unlocking therapeutic synergy: IDH inhibitors and immunotherapy combination in preclinical and clinical IDH mutant glioma models − A systematic review

(1) Background: Over 80 % of low-grade gliomas have IDH mutations, leading to 2-hydroxyglutarate accumulation, an oncometabolite that promotes gliomagenesis by altering metabolism and impairing anti-tumour immunity. Previously, treatment options included surgical resection (debulking) with or without chemo/radiotherapy based on tumour risk. Vorasidenib, an IDH inhibitor (IDHi), demonstrates promising activity in IDH-mutant low-grade gliomas. While immunotherapy has succeeded in other solid tumours, its efficacy as a single agent in gliomas remains limited. This review explores potential synergies between IDHi and immunotherapy in IDH-mutant glioma across preclinical and clinical studies; (2) Methods: A systematic review (Prospero: CRD42024523861) was performed using Medline, Cochrane, EMBASE and ClinicalTrials.Gov. Findings were summarised using descriptive analysis without meta-analysis; (3) Results: This review included four preclinical murine and two clinical studies. Preclinical findings suggest that combining IDHi with immunotherapy enhances anti-tumour immunity and survival. Clinical trials are underway, but limitations include small sample sizes and treatment heterogeneity; (4) Conclusions: The high certainty of evidence and satisfactory risk of bias provide further rationale for future research investigating this combination, including larger randomised, blinded studies with standardised treatment regimens to validate preclinical findings and enhance translational relevance. Moreover, future preclinical studies should integrate multiple cell-line models, including patient-derived models.