在鳞状细胞癌 (SCC) 中，巨噬细胞对白细胞介素 (IL)-33 作出反应，形成富含 TGF-β 的基质微环境，维持癌症干细胞 (CSC)，部分通过激活 NRF2 抗氧化程序来逃避化疗诱导的细胞凋亡。在这里，我们研究了源自 CSC 的 IL-33 如何促进免疫抑制微环境的发展。具有高 NRF2 活性的 CSC 将核 IL-33 重新分配到细胞质，并作为大肿瘤体 (LO) 的货物释放 IL-33。从机制上讲，NRF2 增加了脂质扰乱酶 ATG9B 的表达，从而在 LO 表面暴露出“吃我”信号，导致膜联蛋白 A1 (ANXA1) 加载。这些 LO 促进 AXNA1 受体骨髓前体分化为免疫抑制性巨噬细胞。阻断 ATG9B 的扰乱酶活性或消耗 ANXA1 可减少巨噬细胞的数量并阻碍肿瘤进展。因此，IL-33 通过 LO 从活 CSC 中释放，以促进替代激活的巨噬细胞的分化，与炎症和组织修复的其他情况具有潜在相关性。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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.Copyright © 2024 Elsevier Inc. All rights reserved.