bims-redobi Biomed News
on Redox Biology
Issue of 2024‒08‒04
two papers selected by
Vanesa Cepas López, Candiolo Cancer Institute



  1. Cancer Discov. 2024 Aug 02. 14(8): 1372-1374
      PARP inhibitors (PARPi) are used as a first-line treatment option for cancers with BRCA1/2 mutations, yet a significant number of patients show a limited response to these agents. In the present study, Lei and colleagues demonstrate that PARPi promote increased ferroptosis sensitivity and this can be exploited therapeutically to improve the response to PARPi, marking an important therapeutic concept to exploit ferroptosis-based strategies in clinical settings. See related article by Lei et al., p. 1476 (2).
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0775
  2. Immunity. 2024 Jul 25. pii: S1074-7613(24)00353-4. [Epub ahead of print]
      In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an "eat me" signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B's scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.
    Keywords:  ATG9b; FPR2; IL-33; annexin A1; cancer stem cell niche; cancer stem cells; large oncosomes; macrophages; squamous cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2024.07.004