{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "School of Pharmaceutical Sciences, Sun Yat-sen University, Shenzhen, 518107, China",
    "The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China",
    "School of Pharmaceutical Sciences, Sun Yat-sen University, Shenzhen, 518107, China; Corresponding author."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Mian Yu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuanqi Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Jiayin Yu"
    },
    {
      "affs": [
        0
      ],
      "name": "Shengjie Sun"
    },
    {
      "affs": [
        0
      ],
      "name": "Yanling Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Yixuan Fang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuk Chin Angel Chung"
    },
    {
      "affs": [
        1
      ],
      "name": "Xuande Zhu"
    },
    {
      "affs": [
        0
      ],
      "name": "Hui Cai"
    },
    {
      "affs": [
        2
      ],
      "name": "Meiying Wu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2w5kt4w77c3sp.bib",
  "cited_by": 0,
  "doi": "10.1016/j.mtbio.2026.103775",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S2590006426010203",
  "id": "2w5kt4w77c3sp",
  "issns": [
    "2590-0064"
  ],
  "landing_url": "https://doi.org/10.1016/j.mtbio.2026.103775",
  "language": "en",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Full Length Article"
    ],
    [
      "lcc",
      "QH301-705.5"
    ],
    [
      "lcc",
      "R5-920"
    ],
    [
      "openalex",
      "2740|Ferroptosis and cancer prognosis"
    ]
  ],
  "openalex": "W7223203143",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13721940/pdf/?tool=EBI",
  "pmcid": "PMC13721940",
  "pmid": "42965146",
  "published": "2026-10-22",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/2w5kt4w77c3sp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:47:23Z",
      "native_id": "a9579edd3ea34f53aa523509c6e5212c",
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      "url": "https://doi.org/10.1016/j.mtbio.2026.103775"
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    {
      "first_seen": "2026-10-31T12:21:37Z",
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      "url": "https://europepmc.org/article/PMC/PMC13721940"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Ferroptosis and cancer prognosis",
      "subfield": "general"
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  ],
  "title": "A copper-based RNAi nanocomplex unleashes immunogenic ferroptosis by reversing metabolic adaptation and suppressing extracellular GPX4",
  "title_text": "A copper-based RNAi nanocomplex unleashes immunogenic ferroptosis by reversing metabolic adaptation and suppressing extracellular GPX4",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:22:32Z",
  "url": "https://research.draconitic.com/paper/2w5kt4w77c3sp",
  "venue": "Materials Today Bio",
  "versions": []
}