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

Small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, is among the most immune-desert tumor types and exhibits poor response to immunotherapy. However, the mechanisms underlying this immune resistance remain unclear. Here, we identify a unique immune-excluding vascular (IEV) barrier in SCLC, distinct from non-small cell lung cancer (NSCLC) and other cancers, composed of tightly connected endothelial cells, a thickened basement membrane, and dense pericyte coverage. Functionally, this barrier restricts immune cell infiltration, contributing to SCLC’s immunotherapy resistance. Mechanistically, we show that ASCL1, the master transcription factor of SCLC, is essential for IEV barrier formation. ASCL1 drives expression of insulin-like growth factor-binding protein 5 (IGFBP5), and depletion of IGFBP5 in tumor cells reduces IGF1 signaling in endothelial cells. Endothelial-specific disruption of IGF1R impairs barrier integrity. Importantly, targeting this axis either through IGFBP5 knockout or treatment with the IGF1R inhibitor OSI-906 enhances CD8+ T cell infiltration and synergizes with anti-PD1 therapy in SCLC. Furthermore, we demonstrate that this ASCL1-IGFBP5-IGF1R axis and the IEV barrier are conserved across multiple neuroendocrine cancers (NECs). Our findings reveal a previously unrecognized vascular barrier in NECs and propose novel therapeutic strategies to overcome immune exclusion and enhance immunotherapy efficacy in these recalcitrant cancers.