Table 2.

The functions and mechanisms of various ferroptotic cells in the TIME

Cell Types	Targets	Ferroptotic consequences	Mechanisms	Tumor types	References
Pancreatic tumor cells	GPX4	Infiltration and activation of M2 macrophages to promote pancreatic tumorigenesis	Ferroptotic pancreatic cells result in the release of 8-OHG, a component of damage-associated molecular pattern (DAMP), which promotes the infiltration and M2 polarization of macrophages via the STING pathway	Pancreatic tumor	[98, 99]
Bladder cancer cells	GPX4	Promotion of the proliferation, migration, and invasion of tumor cells via Prostaglandin E2 (PGE2) released by ferroptotic cancer cells	Following chemotherapy, tumor cells express lower levels of GPX4. This reduction in GPX4 expression is accompanied by the release of PGE2, a prostaglandin that stimulates the proliferation of cancer stem cells (CSCs), allowing them to repopulate the tumor during the period between chemotherapy cycles	Bladder cancer	[103]
Natural killer cells (NK cells)	GPX4	Decreased capability of natural killer (NK) cells to eliminate tumor cells	L-Cysteine (L-KYN) has been demonstrated to impair natural killer (NK) cell survival in the tumor microenvironment (TME) by inducing cellular ferroptosis in an aromatic hydrocarbon receptor (AHR)-independent manner	Gastric cancer	[106]
Dendritic cells (DCs)	GPX4	Reduced cytokine production capacity, impaired promotion of MCH I expression, and impaired T-cell activation	The RSL3-GPX4-induced ferroptosis observed in DC cells is manifested by lipid peroxidation, the production of oxidized polyunsaturated fatty acids, and the release of HMGB1. Ferroptotic DCs are unable to secrete pro-inflammatory cytokines or express MHC I molecules in response to lipopolysaccharide maturation signals. They are unable to induce CD8 + T cells to produce IFNγ	Pancreatic ductal adenocarcinoma	[108]
CD8+ T cells	CD36	Decreased production of cytotoxic cytokines and anti-tumor capacity	CD36 expression is upregulated in tumor-infiltrating CD8+ T cells, which is accompanied by an increase in cholesterol in the TME and induces CD8+ T cells to undergo ferroptosis. This process results in a reduction in the production of cytotoxic cytokines as well as the anti-tumor capacity of CD8+ T cells	Melanoma	[87, 110]
Tc9 cells	STAT3	Inhibition of the specific killing function	The activation of STAT3 by IL-9 derived from Tc9 cells resulted in the upregulation of fatty acid oxidation and mitochondrial activity, as well as the reduction of lipid peroxidation and resistance to tumor- or ROS-induced ferroptosis. Deficiency in IL-9/STAT3 signaling ultimately leads to impaired longevity and antitumor ability of Tc9 cells	Melanoma	[110, 111]
Treg cells	GPX4	Inhibition of tumor growth and enhances anti-tumor immunity	Gpx4-deficient Treg cells undergo aberrant accumulation of lipid peroxides and ferroptosis in response to T cell receptor (TCR) and co-stimulatory signaling	Colorectal cancer, Melanoma	[86]
TAMs	APOC1	Improvement of the efficacy of anti-PD1 immunotherapy	Inhibition of APOC1 promotes the conversion of M2 macrophages to M1 macrophages via the ferroptosis pathway, thereby altering the tumor immune microenvironment	Hepatocellular carcinoma (HCC)	[114]
TAMs	SLC7A11	Improvement of the anti-tumor effect of anti-PD-L1 therapy	Downregulating SLC7A11 regulates macrophage phenotypes by inducing ferroptosis, which in turn activates the SOCS3-STAT6-PPARγ signaling pathway, consequently affecting tumor progression and metastasis	Hepatocellular carcinoma (HCC)	[115]