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 (Fe3O4 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 Fe3O4-containing nanoformulation (GBP@Fe3O4). 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 Fe3O4in 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.