血脑屏障样血管门限制免疫治疗在神经内分泌癌中的疗效

血脑屏障样血管门限制免疫治疗在神经内分泌癌中的疗效

作者： 小柯机器人 发布时间：2026/5/9 13:54:14

本期文章：《细胞》：Online/在线发表

四川大学陈崇小组取得一项新突破。他们开发出血脑屏障样血管门限制了免疫治疗在神经内分泌癌中的疗效。2026年5月7日，国际知名学术期刊《细胞》发表了这一成果。

小组在SCLC中发现了一个血脑屏障样血管门（BVG），不同于非SCLC （NSCLC）和其他癌症，它由紧密连接的内皮细胞、增厚的基底膜和致密的周细胞覆盖组成。在功能上，这种血脑屏障样血管门限制了免疫细胞的浸润，有助于SCLC的免疫治疗抵抗。机制上，SCLC的主转录因子achaette - sche家族基本螺旋环螺旋 （bHLH）转录因子1 （ASCL1）通过调节胰岛素样生长因子结合蛋白5 (IGFBP5)，激活内皮细胞中IGF1信号，对BVG的形成至关重要。IGFBP5敲除或IGF1R抑制剂osii -906治疗可增强CD8 + T细胞浸润并与抗PD1治疗协同作用。

此外，ASCL1-IGFBP5-IGF1R轴和BVG在多种神经内分泌癌（NECs）中是保守的。他们的发现揭示了NECs中以前未被识别的血管门，并提出了新的治疗策略来提高这些顽固性癌症的免疫治疗效果。

研究人员表示，小细胞肺癌（SCLC）是一种高度侵袭性的神经内分泌恶性肿瘤，对免疫治疗反应较差，其潜在机制尚不清楚。

附：英文原文

Title: A blood-brain barrier-like vascular gate limits immunotherapy efficacy in neuroendocrine cancers

Author: Yiyun Wang, Ailing Zhong, Bo Wang, Xiaoqian Zhai, Chang Lei, Zuoyu Liang, Xintong Deng, Jian Zhong, Chaoxin Xiao, Jianan Zheng, Baohong Wu, Lanxin Zhang, Yuying Wang, Xiangmeng Luo, Jian Wang, Mengsha Zhang, Hongyu Liu, Xudong Wan, Siqi Dai, Yucen Yang, Shiyu Zhang, Weiya Wang, Shengyong Yang, Jianxin Xue, Chengjian Zhao, Tuomas Tammela, Zhiming Li, Yan Zhang, Feifei Na, Manli Wang, Yu Liu, Chong Chen

Issue&Volume: 2026-05-07

Abstract: Small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, exhibits poor response to immunotherapy, and the underlying mechanisms remain unclear. Here, we identify a blood-brain barrier-like vascular gate (BVG) in SCLC, distinct from non-SCLC (NSCLC) and other cancers, composed of tightly connected endothelial cells, a thickened basement membrane, and dense pericyte coverage. Functionally, this blood-brain barrier-like vascular gate restricts immune cell infiltration, contributing to SCLC’s immunotherapy resistance. Mechanistically, achaete-scute family basic-helix-loop-helix (bHLH) transcription factor 1 (ASCL1), the master transcription factor of SCLC, is essential for BVG formation by regulating insulin-like growth factor-binding protein 5 (IGFBP5), which activates the IGF1 signaling in endothelial cells. IGFBP5 knockout or treatment with the IGF1R inhibitor OSI-906 enhances CD8+ T cell infiltration and synergizes with anti-PD1 therapy. Furthermore, this ASCL1-IGFBP5-IGF1R axis and the BVG are conserved across multiple neuroendocrine cancers (NECs). Our findings reveal a previously unrecognized vascular gate in NECs and propose novel therapeutic strategies to enhance immunotherapy efficacy in these recalcitrant cancers.

DOI: 10.1016/j.cell.2026.04.017

Source: https://www.cell.com/cell/abstract/S0092-8674(26)00452-6

主题：免疫治疗