Fig. 2: Ferroptosis-driven immunomodulation in glioblastoma.
From: Harnessing ferroptosis to transform glioblastoma therapy and surmount treatment resistance
This illustration depicts how ferroptosis influences the immune landscape within the glioblastoma microenvironment. On the left, ferroptotic glioblastoma cells release damage-associated molecular patterns (DAMPs), including 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and HMGB1, which modulate tumor-associated macrophages (TAMs). Lipid peroxidation (LP) products and iron (Fe²⁺) promote TAM reprogramming, converting perivascular and stromal TAMs into pro-inflammatory M1-like macrophages that secrete TNF-α and IL-1β, while suppressing immunosuppressive M2-like phenotypes. On the right, ferroptotic glioblastoma cells also enhance dendritic cell (DC) activation and cross-priming of CD8⁺ T-cells by releasing tumor neoantigens and lipid peroxidation (LP) byproducts. These signals promote T-cell recruitment (via CXCL9/10), activation, and cytotoxic responses, including engagement of cytotoxic T lymphocytes (CTLs) and antigen-presenting cells (APCs). However, persistent antigen exposure and extracellular matrix (ECM) remodeling can also lead to T-cell exhaustion and rescue by IL-12, TNF-α and IL-1β. Together, the figure highlights the dual role of ferroptosis in modulating innate and adaptive immunity in glioblastoma. The figure was created with BioRender.com.
