通过将受体酪氨酸激酶分选到内溶酶体中，运输所需的内体分选复合物（ESCRT）被认为可以减弱肿瘤细胞中的致癌信号传导。矛盾的是，ESCRT 成员在肿瘤中表达上调。在这里，我们发现，在黑色素瘤和结肠癌小鼠模型中，肝细胞生长因子调节的酪氨酸激酶底物 (HRS)（一种关键的 ESCRT 成分）的破坏可通过促进 CD8 T 细胞浸润来抑制肿瘤生长。 HRS 消融导致错误折叠的蛋白质积累并引发内质网 (ER) 应激，导致 I 型干扰素通路以肌醇需求酶 1α (IRE1α)/X-box 结合蛋白 1 (XBP1) 依赖性方式激活。 HRS 在肿瘤突变负荷 (TMB) 高的肿瘤细胞中上调。 HRS 表达与高 TMB 肿瘤黑色素瘤患者对 PD-L1/PD-1 阻断治疗的反应相关。 HRS 消融使小鼠黑色素瘤模型中的抗 PD-1 治疗变得敏感。我们的研究揭示了高 TMB 肿瘤细胞逃避免疫监视的机制，并表明 HRS 是改善免疫治疗的一个有希望的靶标。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

By sorting receptor tyrosine kinases into endolysosomes, the endosomal sorting complexes required for transport (ESCRTs) are thought to attenuate oncogenic signaling in tumor cells. Paradoxically, ESCRT members are upregulated in tumors. Here, we show that disruption of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a pivotal ESCRT component, inhibited tumor growth by promoting CD8+ T cell infiltration in melanoma and colon cancer mouse models. HRS ablation led to misfolded protein accumulation and triggered endoplasmic reticulum (ER) stress, resulting in the activation of the type I interferon pathway in an inositol-requiring enzyme-1α (IRE1α)/X-box binding protein 1 (XBP1)-dependent manner. HRS was upregulated in tumor cells with high tumor mutational burden (TMB). HRS expression associates with the response to PD-L1/PD-1 blockade therapy in melanoma patients with high TMB tumors. HRS ablation sensitized anti-PD-1 treatment in mouse melanoma models. Our study shows a mechanism by which tumor cells with high TMB evade immune surveillance and suggests HRS as a promising target to improve immunotherapy.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.