A blood-brain barrier-like vascular gate limits immunotherapy efficacy in neuroendocrine cancers PMID: 42102817

ADC Targets in Oncology

2026-04-10

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

Cell. 2026 Jun 25;189(13):3922-3939.e20. doi: 10.1016/j.cell.2026.04.017.

Yiyun Wang ¹ , Ailing Zhong ¹ , Bo Wang ² , Xiaoqian Zhai ³ , Chang Lei ¹ , Zuoyu Liang ⁴ , Xintong Deng ¹ , Jian Zhong ⁵ , Chaoxin Xiao ¹ , Jianan Zheng ¹ , Baohong Wu ¹ , Lanxin Zhang ¹ , Yuying Wang ¹ , Xiangmeng Luo ¹ , Jian Wang ¹ , Mengsha Zhang ¹ , Hongyu Liu ¹ , Xudong Wan ¹ , Siqi Dai ¹ , Yucen Yang ¹ , Shiyu Zhang ⁶ , Weiya Wang ⁴ , Shengyong Yang ⁷ , Jianxin Xue ¹ , Chengjian Zhao ⁷ , Tuomas Tammela ⁸ , Zhiming Li ⁹ , Yan Zhang ¹⁰ , Feifei Na ¹¹ , Manli Wang ¹² , Yu Liu ¹³ , Chong Chen ¹⁴

Affiliations

1. Department of Thoracic Oncology, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
2. Department of Thoracic Oncology, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, China.
3. Department of Medical Oncology, Cancer Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Lung Cancer Center, Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
4. Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
5. Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, Sichuan 610041, China.
6. Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
7. Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
8. Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9. West China School of Public Health, West China Fourth Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
10. Lung Cancer Center, Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: [email protected].
11. Department of Thoracic Oncology, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: [email protected].
12. TCM Prevention and Treatment of Metabolic and Chronic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, China. Electronic address: [email protected].
13. Department of Hematology, Institute of Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China. Electronic address: [email protected].
14. Department of Thoracic Oncology, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China. Electronic address: [email protected].

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.

Keywords

ASCL1-IGFBP5-IGF1R axis; OSI-906; SCLC; T cell infiltration; blood-brain barrier-like vascular gate; immunotherapy; neuroendocrine cancers.