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

Abstract

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.

Abnormally Expressed Ferroptosis-Associated FANCD2 in Mediating the Temozolomide Resistance and Immune Response in Glioblastoma

“…Immunosuppressive microenvironment and programmed cell death participate in the immunotherapeutic resistance. Liu et al reported that ferroptosis inducer could combine with immune checkpoint blockade to generate a synergistic therapeutic outcome in GBM murine models ( Liu et al, 2022 ). In this study, we assessed the underlying roles of FANCD2 in the immune response of GBM patients and found that aberrant FANCD2 might regulate multiple immune-associated signatures in GBM pathogenesis, such as immune-stimulators, immune-inhibitors, chemokines, and their receptors.…”

“…In GBM, the inhibition of ferroptosis always contributes to the malignant characteristics and is closely related to poor prognosis. Activating ferroptosis can attenuate the immunosuppressive microenvironment and ameliorate the efficacy of immune checkpoint blockade ( Liu et al, 2022 ). However, the specific effects and potential mechanisms of ferroptosis in GBM pathogenesis and therapeutic response remain unclear.…”

Ferroptosis in Glioma Immune Microenvironment: Opportunity and Challenge

“…Ferroptosis shows a ‘double-edged sword’ role in diseases. It is easy to understand that ferroptosis plays different roles in different diseases such as the beneficial outcome of inducing ferroptosis in tumor cells is for disease ( 112 ), but inhibiting ferroptosis in stroke is beneficial to the prognosis ( 113 ). We hypothesize that ferroptosis may also play different roles in one disease, for example, and there may be tumor cells that choose to sacrifice themselves.…”

Mechanisms of long non-coding RNAs in biological phenotypes and ferroptosis of glioma

“…It is possible for others to develop some related and helpful therapy plans targeting lncRNAs involved in ferroptosis followed the same mind above accordingly. Several works have showed that the links between immune cells within TME and ferroptosis implicated that some immune therapy targeting ferroptosis might can be explored ( 86 , 87 ). More promisingly, it has been verified that CD4, CD8 and CD36 T cell within TME can induce the ferroptosis by accumulating the lipid ROS ( 88 ), which suggest we can mainly concentrate on some immune-related lncRNAs involved in the ferroptosis to scout the links and the potential therapy.…”