周边神经胶质细胞，特别是雪旺氏细胞（SCs），已被认为在肿瘤微环境（TME）的形成和癌症进展中起作用。然而，在肿瘤带瘤小鼠的不同器官里，关于癌症如何重新编程SC功能的体内和体外分析是缺乏的。我们生成了Plp1-CreERT/tdTomato小鼠，这些小鼠具有荧光标记的髓鞘和非髓鞘形成SCs。我们展示了这个模型使得我们可以从皮肤和多个其他器官中高纯度分离SCs。我们使用这个模型研究了肿瘤毗邻的皮肤中SC的表型和功能重编程。与无肿瘤小鼠的皮肤SCs相比，周围肿瘤的皮肤SCs的转录组分析表明，前者存在于通常在神经和组织损伤时激活的修复样状态中。毗邻肿瘤的皮肤SCs也下调了与保护性抗肿瘤反应相关的炎性基因和通路。体内和体外的功能测定确认了毗邻肿瘤的皮肤SCs的免疫抑制活性。特别地，黑色素瘤重编程的SCs上调了12/15-脂氧合酶（12/15-LOX）和环氧合酶（COX）-2，并增加了抗炎多不饱和脂肪酸（PUFA）代谢物前列腺素E2（PGE2）和脂氧素A4/B4的产生。抑制SCs中12/15-LOX或COX2，或是淋巴细胞上的EP4受体，可以逆转SC依赖性的抗肿瘤T细胞激活抑制。因此，在黑色素瘤肿瘤附近的皮肤中的SCs展示了功能转换为修复样免疫抑制细胞，伴随着失调的脂质氧化。我们的研究提示了黑色素瘤相关修复性毗邻肿瘤的SCs在局部和系统性抗肿瘤免疫反应调节中的作用。 ©2023作者。许可证由Taylor＆Francis Group，LLC发布。

Peripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, in vivo and ex vivo analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs. We show that this model enables the isolation of the SCs with high purity from the skin and multiple other organs. We used this model to study phenotypic and functional reprogramming of the SCs in the skin adjacent to melanoma tumors. Transcriptomic analyses of the peritumoral skin SCs versus skin SCs from tumor-free mice revealed that the former existed in a repair-like state typically activated during nerve and tissue injury. Peritumoral skin SCs also downregulated pro-inflammatory genes and pathways related to protective anti-tumor responses. In vivo and ex vivo functional assays confirmed immunosuppressive activities of the peritumoral skin SCs. Specifically, melanoma-reprogrammed SCs upregulated 12/15-lipoxygenase (12/15-LOX) and cyclooxygenase (COX)-2, and increased production of anti-inflammatory polyunsaturated fatty acid (PUFA) metabolites prostaglandin E2 (PGE2) and lipoxins A4/B4. Inhibition of 12/15-LOX or COX2 in SCs, or EP4 receptor on lymphocytes reversed SC-dependent suppression of anti-tumor T-cell activation. Therefore, SCs within the skin adjacent to melanoma tumors demonstrate functional switching to repair-like immunosuppressive cells with dysregulated lipid oxidation. Our study suggests the involvement of the melanoma-associated repair-like peritumoral SCs in the modulation of locoregional and systemic anti-tumor immune responses.© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.