Ferritin internalized into
tumor cells is degraded and releases
iron ions via ferritinophagy.
Iron ions participate in Fenton reaction to produce
reactive oxygen species for lipid peroxidation and ferroptosis. Inhibition of indoleamine-2,3-dioxygenase (IDO) decreases
tryptophan elimination to induce T cells activation for
tumor immunosuppression relief. The active
tumor targeting nanoparticles containing
ferritin and a pH-sensitive molecular-switch (FPBC@SN) are developed to utilize ferritinophagy-cascade ferroptosis and
tumor immunity activation for
cancer therapy. FPBC@SN disintegrates in acidic cytoplasm and releases
sorafenib (SRF) and IDO inhibitor (
NLG919). SRF upregulates
nuclear receptor coactivator 4 (NCOA4) to induce
ferritin and endogenous
iron pool degradation by ferritinophagy, then obtained
iron ions participate in the Fenton reaction to produce
lipid peroxide (LPO). Meanwhile, SRF blocks
glutathione synthesis to downregulate
glutathione peroxidase 4 (GPX4) which can scavenge LPO as a different pathway from ferritinophagy to promote ferroptosis in
tumor cells.
NLG919 inhibits IDO to reduce
tryptophan metabolism, so immunity in
tumors is aroused to anti-
tumor. In vitro and in vivo experiments prove FPBC@SN inhibits
tumor cell growth and
metastasis, indicating the potential of FPBC@SN for
breast cancer therapy based on the combination of ferritinophagy-cascade ferroptosis and
tumor immunity activation.