A copper-based RNAi nanocomplex unleashes immunogenic ferroptosis by reversing metabolic adaptation and suppressing extracellular GPX4
- 1School of Pharmaceutical Sciences, Sun Yat-sen University, Shenzhen, 518107, China
- 2The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- 3School of Pharmaceutical Sciences, Sun Yat-sen University, Shenzhen, 518107, China; Corresponding author.
Abstract
Ferroptosis is an immunogenic form of regulated cell death with considerable potential for cancer immunotherapy, yet its efficacy is frequently limited by adaptive resistance mechanisms. Here, we uncover a previously unrecognized bidirectional role of copper-based ferroptosis inducers in breast cancer. On the one hand, copper suppresses the release of extracellular GPX4, an immunosuppressive damage-associated molecular pattern, preserving the immunostimulatory effects of ferroptotic cell death. On the other hand, copper-induced ferroptotic stress activates carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation, which limits polyunsaturated fatty acid (PUFA) availability and reduces ferroptosis susceptibility. To overcome this adaptive metabolic resistance, we developed siC@CuPP, a polyethylenimine-modified copper-doped polypyrrole nanocomplex that delivers Cpt1a siRNA while retaining the intrinsic ferroptosis-inducing activity of the CuPPy core. siC@CuPP efficiently silenced Cpt1a , inhibited fatty acid oxidation-driven PUFA consumption, promoted lipid remodeling, and impaired NADPH replenishment, thereby enhancing oxidative stress and ferroptosis sensitivity. Concurrently, copper-mediated suppression of extracellular GPX4 relieved ferroptosis-associated immunosuppression and facilitated dendritic cell activation. These coordinated effects established a positive feedback loop between immunogenic ferroptosis and antitumor immunity through interferon-γ–ACSL4 signaling. In an orthotopic 4T1 triple-negative breast cancer model, systemic administration of siC@CuPP elicited robust antitumor immune responses, significantly suppressing primary tumor growth and pulmonary metastasis. Collectively, this work identifies CPT1A-dependent metabolic adaptation and extracellular GPX4-mediated immunosuppression as two notable barriers to immunogenic ferroptosis and provides a coordinated strategy for overcoming both, thereby amplifying ferroptosis-driven cancer immunotherapy.
Related
- SGLT2 inhibitors attenuate diabetic kidney disease by suppressing YAP dependent ferroptosis
- CDCA5 promotes hepatocellular carcinoma progression by suppressing ferroptosis through PP2Ac/p53/STEAP3 signaling
- 4-Methoxydalbergione triggers ferroptosis in bladder cancer by suppressing the AKT/mTOR/GPX4 axis
- Double coordination-driven Fe-DOX synergy enhances ferroptosis and immunogenic cancer therapy.
- Early infiltration of ischemia-conditioned Tregs attenuates BBB damage via suppressing neutrophil extracellular traps in ischemic stroke
BibTeX
@article{yu2026copperbased,
title = {{A copper-based RNAi nanocomplex unleashes immunogenic ferroptosis by reversing metabolic adaptation and suppressing extracellular GPX4}},
author = {Mian Yu and Yuanqi Liu and Jiayin Yu and Shengjie Sun and Yanling Chen and Yixuan Fang and Yuk Chin Angel Chung and Xuande Zhu and Hui Cai and Meiying Wu},
journal = {Materials Today Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103775},
url = {https://doi.org/10.1016/j.mtbio.2026.103775},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - A copper-based RNAi nanocomplex unleashes immunogenic ferroptosis by reversing metabolic adaptation and suppressing extracellular GPX4
AU - Mian Yu
AU - Yuanqi Liu
AU - Jiayin Yu
AU - Shengjie Sun
AU - Yanling Chen
AU - Yixuan Fang
AU - Yuk Chin Angel Chung
AU - Xuande Zhu
AU - Hui Cai
AU - Meiying Wu
PY - 2026
DA - 2026/10/22
JO - Materials Today Bio
DO - 10.1016/j.mtbio.2026.103775
UR - https://doi.org/10.1016/j.mtbio.2026.103775
AB - Ferroptosis is an immunogenic form of regulated cell death with considerable potential for cancer immunotherapy, yet its efficacy is frequently limited by adaptive resistance mechanisms. Here, we uncover a previously unrecognized bidirectional role of copper-based ferroptosis inducers in breast cancer. On the one hand, copper suppresses the release of extracellular GPX4, an immunosuppressive damage-associated molecular pattern, preserving the immunostimulatory effects of ferroptotic cell death. On the other hand, copper-induced ferroptotic stress activates carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation, which limits polyunsaturated fatty acid (PUFA) availability and reduces ferroptosis susceptibility. To overcome this adaptive metabolic resistance, we developed siC@CuPP, a polyethylenimine-modified copper-doped polypyrrole nanocomplex that delivers Cpt1a siRNA while retaining the intrinsic ferroptosis-inducing activity of the CuPPy core. siC@CuPP efficiently silenced Cpt1a , inhibited fatty acid oxidation-driven PUFA consumption, promoted lipid remodeling, and impaired NADPH replenishment, thereby enhancing oxidative stress and ferroptosis sensitivity. Concurrently, copper-mediated suppression of extracellular GPX4 relieved ferroptosis-associated immunosuppression and facilitated dendritic cell activation. These coordinated effects established a positive feedback loop between immunogenic ferroptosis and antitumor immunity through interferon-γ–ACSL4 signaling. In an orthotopic 4T1 triple-negative breast cancer model, systemic administration of siC@CuPP elicited robust antitumor immune responses, significantly suppressing primary tumor growth and pulmonary metastasis. Collectively, this work identifies CPT1A-dependent metabolic adaptation and extracellular GPX4-mediated immunosuppression as two notable barriers to immunogenic ferroptosis and provides a coordinated strategy for overcoming both, thereby amplifying ferroptosis-driven cancer immunotherapy.
SN - 2590-0064
ER -