2. Academic Validation
  3. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma

STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma

  • Nature. 2023 Mar 29. doi: 10.1038/s41586-023-05880-5.
Jing Hu 1,  Francisco J Sánchez-Rivera 1 2 3,  Zhenghan Wang 1,  Gabriela N Johnson 1,  Yu-Jui Ho 1,  Karuna Ganesh 4 5,  Shigeaki Umeda 6,  Siting Gan 1,  Adriana M Mujal 7,  Rebecca B Delconte 7,  Jessica P Hampton 1,  Huiyong Zhao 8,  Sanjay Kottapalli 9,  Elisa de Stanchina 8,  Christine A Iacobuzio-Donahue 6 10,  Dana Pe'er 9 11 12,  Scott W Lowe 1 12,  Joseph C Sun 7,  Joan Massagué 13 14
Affiliations

Affiliations

  • 1 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 3 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 4 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 9 Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 11 The Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 12 Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 13 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • 14 The Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
PMID: 36991128 DOI: 10.1038/s41586-023-05880-5
Abstract

Metastasis frequently develops from disseminated Cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1-6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify Cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFβ. STING expression in Cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require Cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.

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