小柯机器人

中国科学院生物物理研究所Likun Wang团队近期取得重要工作进展，他们研究发现癌细胞固有的XBP1通过促进胆固醇生成驱动瘤内髓样细胞的免疫抑制重编程。相关论文2022年11月8日在线发表于《细胞—代谢》杂志上。

研究人员发现，在癌细胞中，UPR组分X-box结合蛋白1（XBP1）有利于胆固醇的合成和分泌，从而激活骨髓源性抑制细胞（MDSC）并引起免疫抑制。胆固醇以小细胞外囊泡的形式递送，并通过大胞饮作用被MDSC内化。XBP1的遗传或药理学耗竭或降低肿瘤胆固醇含量会显著下调MDSC的丰度并引发强烈的抗肿瘤反应。这些数据揭示了XBP1/胆固醇信号在肿瘤生长调节中的细胞非自主作用，抑制该信号可以作为提高癌症免疫治疗效果的有效策略。

据介绍，肿瘤组织中的不良微环境会破坏内质网稳态并诱导未折叠蛋白反应（UPR）。癌细胞和肿瘤浸润白细胞中的慢性UPR可能有助于逃避免疫监测。然而，癌细胞中的UPR如何削弱抗肿瘤免疫反应尚不清楚。

附：英文原文

Title: Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production

Author: Zaili Yang, Yazhen Huo, Shixin Zhou, Jingya Guo, Xiaotu Ma, Tao Li, Congli Fan, Likun Wang

Issue&Volume: 2022-11-08

Abstract: A hostile microenvironment in tumor tissues disrupts endoplasmic reticulum homeostasisand induces the unfolded protein response (UPR). A chronic UPR in both cancer cellsand tumor-infiltrating leukocytes could facilitate the evasion of immune surveillance.However, how the UPR in cancer cells cripples the anti-tumor immune response is unclear.Here, we demonstrate that, in cancer cells, the UPR component X-box binding protein1 (XBP1) favors the synthesis and secretion of cholesterol, which activates myeloid-derivedsuppressor cells (MDSCs) and causes immunosuppression. Cholesterol is delivered inthe form of small extracellular vesicles and internalized by MDSCs through macropinocytosis.Genetic or pharmacological depletion of XBP1 or reducing the tumor cholesterol contentremarkably decreases MDSC abundance and triggers robust anti-tumor responses. Thus,our data unravel the cell-non-autonomous role of XBP1/cholesterol signaling in theregulation of tumor growth and suggest its inhibition as a useful strategy for improvingthe efficacy of cancer immunotherapy.

DOI: 10.1016/j.cmet.2022.10.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00461-2

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