Work

A copper-based RNAi nanocomplex unleashes immunogenic ferroptosis by reversing metabolic adaptation and suppressing extracellular GPX4

Year: 2026

Type: article

Abstract: 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.

Source: Materials Today Bio

DOI: 10.1016/j.mtbio.2026.103775