Tumor Microenvironment Suppresses Ferroptosis via Iron and Lipid Control [Apr. 21, 2026]

1. Peritumoural adipose tissue promotes ferroptosis resistance by 3-hydroxykynurenine-mediated suppression of ferritinophagy (Nature Cell Biology, 2026)
Summary: Cancer cells take up kynurenine released by peritumoural adipose tissue (PAT) and convert it intracellularly into 3-HK, which directly binds NCOA4 and blocks ferritinophagy, the NCOA4-mediated degradation of ferritin, thereby retaining iron within ferritin and depleting the free iron pool required for ferroptosis. Inhibiting kynurenine biosynthesis restored ferroptosis sensitivity and improved the efficacy of immune checkpoint blockade, identifying PAT–tumour metabolic crosstalk as a potential therapeutic target.

Highlighted technique: To test whether PAT and kynurenine-pathway metabolites alter ferroptosis-related oxidative damage and iron availability, the authors quantified lipid peroxidation in treated cancer cells using C11-BODIPY staining followed by flow cytometry. They also assessed intracellular ferrous iron using an iron assay kit, as well as FerroOrange-based detection by imaging or flow cytometry.

2. Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis(Nature Cell Biology, 2026)
Summary: In this study, the authors showed that in the acidic microenvironment of aggressive tumors, cancer cells remodel the glycocalyx, a sugar-rich layer covering the cell surface, to form a chondroitin sulfate (CS)-rich surface structure that limits the uptake of extracellular lipid particles. This CS-rich surface barrier works together with lipid droplets that increase under acidic stress to protect tumor cells from lipid overload and ferroptosis, and the finding that simultaneous inhibition of CS-glycocalyx formation and lipid droplet formation triggers lipid peroxidation and ferroptotic cell death suggests a new therapeutic vulnerability in acidic tumors.

Highlighted technique: To examine lipid accumulation in acidic tumors, the authors visualized lipid droplets in patient tumor sections, patient-derived cells, and 3D spheroids using fluorescent probe–based imaging. They then fluorescently labeled extracellular vesicles, LDL, and HDL, and measured their binding to or uptake by cells with confocal microscopy and flow cytometry to assess extracellular lipid particle uptake.