Ferroptosis in immunostimulation and immunosuppression

Abstract

SummaryFerroptosis is a form of iron‐dependent regulated cell death characterized by the accumulation of toxic lipid peroxides, particularly in the plasma membrane, leading to lytic cell death. While it plays a crucial role in maintaining the overall health and proper functioning of multicellular organisms, it can also contribute to tissue damage and pathological conditions. Although ferroptotic damage is generally recognized as an immunostimulatory process associated with the release of damage‐associated molecular patterns (DAMPs), the occurrence of ferroptosis in immune cells or the release of immunosuppressive molecules can result in immune tolerance. Consequently, there is ongoing exploration of targeting the upstream signals or the machinery of ferroptosis to therapeutically enhance or inhibit the immune response. In addition to introducing the core molecular mechanisms of ferroptosis, we will focus on the immune characteristics of ferroptosis in pathological conditions, particularly in the context of infection, sterile inflammation, and tumor immunity.

Targeting ferroptosis in gastric cancer: Strategies and opportunities

“…Recent studies have indicated that ferroptosis‐related genes influence cancer development by affecting immunosuppression and infiltration of immune cells such as macrophages, CD4 + T cells, and CD8 + T cells 136,137 . Ferroptosis is known to induce and enhance immune responses by releasing intracellular contents, such as damage‐associated molecular patterns (DAMPs) 138–140 . Additionally, ferroptosis contributes positively to antitumor immunity.…”

Cuproptosis: unveiling a new frontier in cancer biology and therapeutics

“…The formal adoption of the term "Ferroptosis" in 2012 helped categorize this iron-dependent, non-apoptotic death pathway [ 131 ]. Notable morphological changes during ferroptosis include alterations in mitochondria, such as decreased cristae, denser membranes, and rupture, alongside lipid peroxidation, increased ROS, and the modulation of ferroptosis-specific genes [ 132 – 134 ].…”

Targeting the MCP‐GPX4/HMGB1 Axis for Effectively Triggering Immunogenic Ferroptosis in Pancreatic Ductal Adenocarcinoma

“…[ 6 , 7 , 8 ] However, some in vivo studies have reported that stimulation of ferroptosis can promote certain types of cancers. [ 9 , 10 , 11 ] The variable characteristics of the tumor immune microenvironment stimulated by ferroptotic cancer cells may account for the inconsistent outcomes when using ferroptosis as a target for cancer therapy. [9] For example, when GPX4 is suppressed in liver cancer, ferroptotic cancer cells activate the myeloid‐derived suppressor cells to boost tumor growth, [10] and induction of ferroptosis by H 2 O 2 in pancreatic cancer cells facilitates the polarization of tumor‐promoting pro‐resolution M2‐like macrophages.…”

“…[ 9 , 10 , 11 ] The variable characteristics of the tumor immune microenvironment stimulated by ferroptotic cancer cells may account for the inconsistent outcomes when using ferroptosis as a target for cancer therapy. [9] For example, when GPX4 is suppressed in liver cancer, ferroptotic cancer cells activate the myeloid‐derived suppressor cells to boost tumor growth, [10] and induction of ferroptosis by H 2 O 2 in pancreatic cancer cells facilitates the polarization of tumor‐promoting pro‐resolution M2‐like macrophages. [12] In contrast, ferroptosis enhances the antitumor immune reaction due to inhibition of GPX4 in triple‐negative breast cancer, [13] and cancer cells undergoing ferroptosis lead to efficient antitumor immunity when vaccinated into tumor‐bearing mice.…”