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.