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Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.

Cancer cell 2026 Vol.44(4) p. 858-878.e16

Campisi M, Osaki T, Dryg I, Stornante C, Wolff J, Weirather J, Weaver N, Tarannum M, Gillanders I, Bers A, Bobilev E, Lineberry MS, Schol P, Chen M, Ota K, Park SR, Fahey CG, Thai TC, Li Y, Li Z, Li ZH, Shelton S, Hirose S, Padrick C, Ivanova E, Ha M, Yang S, Olszewski H, Kivlehan S, Lizotte P, Hagen K, Gjeci I, Haller W, Zasadil LM, El Zarif T, Berchuck JE, Knelson EH, Brea EJ, Odintsov I, Liu T, Chiono V, Tuladhar B, Ngo K, Rosentrater E, Raizer J, Lineberry N, Sur M, Pfaff K, Freedman M, Hodi FS, Tolstorukov MY, Oser MG, Sheffer M, Mitsiades CS, Barnes MJ, Appleman VA, Gokhale PC, Kamm RD, Paweletz CP, Romee R, Rodig S, Barbie DA, Mahadevan NR

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Small cell lung cancer (SCLC) typically displays a "cold" tumor microenvironment with a paucity of immune infiltrate.

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APA Campisi M, Osaki T, et al. (2026). Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.. Cancer cell, 44(4), 858-878.e16. https://doi.org/10.1016/j.ccell.2026.02.008
MLA Campisi M, et al.. "Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.." Cancer cell, vol. 44, no. 4, 2026, pp. 858-878.e16.
PMID 41791380

Abstract

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-I 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.

MeSH Terms

Humans; Killer Cells, Natural; Small Cell Lung Carcinoma; Lung Neoplasms; Membrane Proteins; Tumor Microenvironment; Animals; Mice; Cell Line, Tumor; Signal Transduction; STING Protein