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

Marco Campisi1, Tatsuya Osaki2, Ian Dryg3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Cancer Cell
|March 6, 2026
PubMed

Insights

Small cell lung cancer (SCLC) has a cold tumor microenvironment. Activating STING signaling can restore NK cell infiltration and killing, improving responses to CAR-NK cell therapy for SCLC.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Biology

Background:

  • Small cell lung cancer (SCLC) exhibits a "cold" tumor microenvironment with limited immune cell infiltration.
  • Neuroendocrine SCLC cells suppress MHC-I expression, making them susceptible to Natural Killer (NK) cell cytotoxicity.
  • Despite susceptibility, effector immune cells, including NK cells, are spatially excluded from MHC-I low/negative SCLC regions in patient samples.

Purpose of the Study:

  • To investigate the spatial immune landscape of SCLC and identify barriers to NK cell infiltration.
  • To develop novel methods for studying the tumor immune microenvironment in SCLC.
  • To explore strategies for enhancing NK cell activity against SCLC.

Main Methods:

  • Dynamic single-cell RNA sequencing of microphysiological immune tumor environments (DynaMITE-seq).
  • Integration of DynaMITE-seq findings with spatial transcriptomics in patient tissues.
  • Quantitative spatial profiling of the SCLC immune microenvironment.

Main Results:

  • The tumor microvasculature acts as a significant checkpoint, restricting NK cell extravasation and recruitment into SCLC tumors.
  • Activation of vascular Stimulator of Interferon Genes (STING) signaling was shown to restore NK cell infiltration.
  • Restored NK cell infiltration led to enhanced killing of neuroendocrine SCLC cells.

Conclusions:

  • The tumor microvasculature is a critical barrier to NK cell-mediated immunity in SCLC.
  • STING pathway activation represents a viable strategy to overcome SCLC's immunologic barriers.
  • Enhancing NK cell infiltration via STING activation may prime SCLC for DLL3-targeted CAR-NK cell therapy.
Keywords:
3D microphysiological systemsSTING agonismnatural killer cellssmall cell lung cancerspatial transcriptomics and proteomicstumor-immune microenvironment

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