Metabolic Control by Heat Stress Determining Cell Fate to Ferroptosis for Effective Cancer Therapy

Abstract

Flexible manipulation of the fate of cancer cells through exogenous stimulation-induced metabolic reprogramming could handle the cellular plasticity-derived therapies resistance, which provides an effective paradigm for the treatment of refractory and relapsing tumors in clinical settings. Herein, we demonstrated that moderate heat (45 °C) could significantly regress the expression of antioxidants and trigger specific lipid metabolic reprogramming in cancer cells synergized with iron oxide nanoparticles (Fe 3 O 4 NPs). This metabolic control behavior destroyed the tumor redox homeostasis and produced overwhelming lipid peroxides, consequently sensitizing the tumor to ferroptosis. Based on these findings, a heat-triggered tumor-specific ferroptosis strategy was proposed by the rational design of a polypeptide-modified and 1H-perfluoropentane (1H-PFP)-encapsulated Fe 3 O 4 -containing nanoformulation (GBP@Fe 3 O 4 ). When irradiated by an 808 nm laser, the phase transition of 1H-PFP was triggered by localized moderate heat (45 °C), leading to burst release of Fe 3 O 4 in situ to produce potent reactive oxygen species through the Fenton reaction in the tumor microenvironment. Together with the antioxidant inhibition response and distinctive lipid metabolic reprogramming by heat stress, this oxidative damage was amplified to induce tumor ferroptosis and achieve sufficient antitumor effects. Importantly, we confirmed that ACSBG1, an acyl-CoA synthetase, was the key pro-ferroptotic factor in this heat-induced ferroptosis process. Moreover, knockout of this gene could realize cancer cell death fate conversion from ferroptosis to non-ferroptotic death. This work provides mechanistic insights and practical strategies for heat-triggered ferroptosis in situ to reduce the potential side effects of direct ferroptosis inducers and highlights the key factor in regulating cell fate under heat stress.

Targeting iron metabolism in cancer therapy

“…A recent study showed that cisplatin loaded iron oxide nanoparticles can induce ferroptosis via accelerated Fenton reaction to inhibit orthotopic brain tumor growth 167 . Iron oxide nanoparticles can also synergize with heat stress to produce overwhelming levels of lipid peroxides, and consequently sensitize the tumor to ferroptosis 168 .…”

Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy

“…tPF@PCM mainly accumulated in the liver and spleen, which is in line with other reports of nano-formulations. 45 , 46 Furthermore, there was a moderate aggregation of tPF@PCM at the tumor site, with the highest level observed at 24 h post-injection ( Figure S11 ), which reveals the ideal timing for the initiation of reliable tumor-targeting photothermal therapy.…”

Multifunctional Nanomaterials for Ferroptotic Cancer Therapy

“…The heat generated by the MPDA NPs upon NIR laser irradiation boosted the effect of ferroptosis. Furthermore, the application of moderate heat (45°C) in the presence of the IONPs could significantly suppress the expression of the antioxidative proteins and cause tumor cells to undergo specific lipid metabolism ( Xie et al, 2021 ). By virtue of the IONPs and 1H-perfluoropentane (1H-PFP), a heat-responsive ferroptosis strategy was rationally designed by utilizing a polypeptide-modified, IO-containing nanomaterial that loaded 1H-PFP.…”