Table 7.

Impact of tumor microenvironment (TME) on ferroptosis in drug-resistant cancers.

TME Component	Mechanism of Action	Effect on Ferroptosis	Targetable Nodes
Hypoxic Microenvironment	HIF-1α → FASN/HILPDA upregulation → LD/PUFA-PL accumulation; HIF-2α → GPX4 downregulation	Promotes ferroptosis (↑substrates) + Resists ferroptosis (↑FSP1)	HIF-1α inhibitors (e.g., PX-478); HI LPDA siRNA (301, 302)
Cancer-Associated Fibroblasts (CAFs)	Secrete exosomal miR-423-5p → ABCB1 upregulation; IL-6 → STAT3 → SLC7A11 upregulation	Reduces ferroptosis (↑drug efflux + ↑antioxidant)	Exosome secretion inhibitors; IL-6/STAT3 blockers (303, 304)
Tumor-Associated Macrophages (TAMs)	M2 TAMs secrete IL-10 → GSTP1 upregulation; HO-1 → iron sequestration	Reduces ferroptosis (↑antioxidant + ↓LIP)	CD47 antibodies (deplete TAMs); HO-1 inhibitors (305, 306)
CD8+ T Cells	Secrete IFNγ → JAK/STAT → SLC7A11 downregulation; IFNγ → ACSL4 upregulation	Promotes ferroptosis (↓antioxidant + ↑substrates)	PD-1/PD-L1 inhibitors (enhance IFNγ secretion) (307, 308)