Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux issus de patients atteints d'un cancer du poumon à petites cellules, cette étude met en évidence un mécanisme par lequel l'activation de la voie de signalisation de STING au niveau vasculaire favorise l'infiltration intratumorale et l'activité antitumorale des cellules NK
Small cell lung cancer (SCLC) typically displays a “cold” tumor microenvironment with a paucity of immune infiltrate. Neuroendocrine SCLC cells also profoundly repress MHC-I expression, rendering them vulnerable to NK cell-mediated cytotoxicity. Here, we confirm that neuroendocrine SCLC cells are sensitive to NK cell-mediated attack, yet the quantitative spatial profiling of the SCLC immune microenvironment in patient samples reveals that effector immune cells, including NK cells, are excluded from MHC-Ilow/neg SCLC regions. To study this biology, we develop dynamic single-cell RNA sequencing of microphysiological immune tumor environments (DynaMITE-seq) and integrate findings with spatial transcriptomics in patient tissue, unveiling the microvasculature as a major checkpoint restricting NK cell extravasation/recruitment. We demonstrate that the activation of vascular Stimulator of Interferon Genes (STING) signaling restores NK cell infiltration and killing of neuroendocrine SCLC, suggesting a strategy to overcome this key SCLC immunologic barrier and prime therapeutic response to DLL3-targeted CAR-NK cell therapy.
Cancer Cell , article en libre accès, 2026