Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and immunotherapy resistance.

BACKGROUND Immunosuppressive microenvironment is a major cause of immunotherapeutic resistance in glioma. In addition to secreting compounds, tumor cells under programmed cell death (PCD) processes release abundant mediators to modify the neighboring microenvironment. However, the complex relationship among PCD status, immunosuppressive microenvironment and immunotherapy is still poorly understood. METHODS Four independent glioma cohorts comprising 1,750 patients were enrolled for analysis. The relationships among PCD status, microenvironment cellular components and biological phenotypes were fully explored. Tissues from our hospital and experiments in vitro and in vivo were used to confirm the role of ferroptosis in glioma. RESULTS Analyses to determine enriched PCD processes showed that ferroptosis was the main type of PCD in glioma. Enriched ferroptosis correlated with progressive malignancy, poor outcomes and aggravated immunosuppression in glioblastoma (GBM) patients. Enhanced ferroptosis was shown to induce activation and infiltration of immune cells but attenuated antitumor cytotoxic killing. Tumor-associated macrophages (TAMs) were found to participate in ferroptosis-mediated immunosuppression. Preclinically, ferroptosis inhibition combined with PD-1/L1 blockade generated a synergistic therapeutic outcome in GBM murine models. CONCLUSIONS This work provides a molecular, clinical and biological landscape of ferroptosis, suggesting a role of ferroptosis in glioma malignancy and a novel synergic immunotherapeutic strategy that combines immune checkpoint blockade (ICB) treatment with ferroptosis inhibition.

• Publication year

  2022

• Venue

  Neuro-Oncology

• Publication date

  2022-02-11

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1093/neuonc/noac033PMID 35148413PMCID PMC9248406
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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