Research on the interactive mechanisms between mitochondrial variations and immune responses in gliomas based on...

Gliomas, as the most invasive primary malignant tumors of the central nervous system, exhibit a significant correlation between their pathological features and clinical prognosis. Among them, glioblastoma multiforme (GBM) is classified as a Grade Ⅳ tumor by the World Health Organization (WHO), with a 5-year survival rate of less than 5% (WHO statistics), and its prognostic indicators are significantly lower than those of other nervous system tumors. Existing studies have demonstrated that mitochondrial dysfunction and tumor immune escape mechanisms play critical regulatory roles in the malignant progression of gliomas. This review systematically integrates existing research on the molecular interaction networks between mitochondrial variations and immunological effects in gliomas, and provides an integrated visual elaboration of the regulatory mechanisms of their signaling pathways based on existing studies. In terms of metabolic reprogramming, the research confirmed that lactic acid metabolites can significantly inhibit the cytotoxic functions of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, while promoting the polarization of tumor-associated macrophages (TAMs) toward the M2-type immunosuppressive phenotype. The citrate metabolic pathway establishes an effective immune escape mechanism through dual regulation of CD47 molecule expression and the ubiquitination-degradation process of major histocompatibility complex class Ⅰ (MHC-Ⅰ) molecules. Additionally, α-ketoglutarate-dependent epigenetic modifications and nutrient competition in the tumor microenvironment exert significant regulatory effects on the functional status of immune cells. At the molecular mechanism level, the study revealed that mitochondrial DNA (mtDNA) mutations lead to downregulated expression of MHC-Ⅰ molecules, significantly reducing the immunogenicity of tumor cells. However, the immune responses induced by mutation-associated neoantigens are antagonized by immunosuppressive factors such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). mtDNA release activates innate immune responses through the Toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathways, but is accompanied by upregulated expression of programmed death-ligand 1 (PD-L1), thereby forming an immune escape phenotype. Mitochondrial fragmentation caused by abnormal mitochondrial dynamics significantly inhibits the function of the MHC-Ⅰ antigen-presenting system via reactive oxygen species (ROS) and interferes with the effector functions of immune cells. Impaired mitophagy results in the accumulation of damaged mitochondria, which promotes the secretion of immunosuppressive factors through the ROS-NF-κB signaling axis. Meanwhile, mtDNA release exacerbates local inflammatory responses, significantly affecting antigen-presenting efficiency and macrophage polarization status. This study systematically elucidates the molecular mechanisms by which mitochondrial variations regulate the tumor immune microenvironment through multiple pathways, including metabolic reprogramming, signal transduction, and antigen presentation. It provides a new theoretical framework for in-depth understanding of tumor-immune interactions and holds important translational medical value for the development of targeted therapeutic strategies and improvement of patient prognosis.