肿瘤抑制细胞竞争（TSCC）是一种保守的监视机制，其中邻近细胞主动消除致癌细胞。尽管大量研究表明未折叠蛋白反应（UPR）在各种肿瘤中失调，但 UPR 是否抑制或促进肿瘤发生仍然存在争议。在这里，我们以果蝇眼上皮为模型，发现了 UPR 的 Ire1 分支在调节细胞极性基因 scribble (scrib) 丢失诱导的 TSCC 中具有令人惊讶的决定性作用。 Ire1 的突变和过度激活分别通过诱导细胞凋亡和自噬加速 scrib 克隆的消除。出乎意料的是，相对 Ire1 活性对于决定失败者细胞的命运也至关重要，因为周围健康细胞中 Ire1 信号传导失调通过减少细胞凋亡来逆转 Scrib 克隆的“失败者”状态。此外，我们发现 Ire1 是哺乳动物细胞中细胞竞争所必需的。总之，这些发现提供了对 scrib 介导的 TSCC 的分子见解，并强调 Ire1 作为失败者细胞命运的关键决定因素。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Tumor-suppressive cell competition (TSCC) is a conserved surveillance mechanism in which neighboring cells actively eliminate oncogenic cells. Despite overwhelming studies showing that the unfolded protein response (UPR) is dysregulated in various tumors, it remains debatable whether the UPR restrains or promotes tumorigenesis. Here, using Drosophila eye epithelium as a model, we uncover a surprising decisive role of the Ire1 branch of the UPR in regulating cell polarity gene scribble (scrib) loss-induced TSCC. Both mutation and hyperactivation of Ire1 accelerate elimination of scrib clones via inducing apoptosis and autophagy, respectively. Unexpectedly, relative Ire1 activity is also crucial for determining loser cell fate, as dysregulating Ire1 signaling in the surrounding healthy cells reversed the "loser" status of scrib clones by decreasing their apoptosis. Furthermore, we show that Ire1 is required for cell competition in mammalian cells. Together, these findings provide molecular insights into scrib-mediated TSCC and highlight Ire1 as a key determinant of loser cell fate.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.