A blood-brain barrier-like vascular gate limits immunotherapy efficacy in neuroendocrine cancers
Summary
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, co
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# A blood-brain barrier-like vascular gate limits immunotherapy efficacy in neuroendocrine cancers
*Published: 2026 May 7*
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