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Maintaining manganese in tumor to activate cGAS-STING pathway evokes a robust abscopal anti-tumor effect

Chao Wang1, Zhaoyi Sun1, Chenxuan Zhao1

  • 1State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|February 5, 2021
PubMed

Insights

Synchronizing manganese (Mn2+) delivery with radiotherapy-induced DNA damage enhances the cyclic GMP-AMP synthase (cGAS)-STING pathway, boosting antitumor immunity and significantly improving survival rates.

Area of Science:

  • Immunology
  • Oncology
  • Biochemistry

Background:

  • Radiotherapy (RT) can trigger antitumor immune responses by releasing DNA into the cytosol.
  • However, the effectiveness of this response is limited by insufficient cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA and its degradation by host DNases.

Purpose of the Study:

  • To investigate if synchronizing manganese (Mn2+) delivery with RT-induced cytosolic DNA accumulation can enhance the cGAS-STING pathway and improve antitumor immunity.

Main Methods:

  • Intratumoral Mn2+ injections were administered at different time points post-RT.
  • Alginate was used to control the release profile of Mn2+ within tumors.
  • The study evaluated tumor inhibition rates and survival times.

Main Results:

  • Intratumoral Mn2+ injection 24 hours after RT, but not immediately after, enhanced the immune response.
  • Alginate-controlled Mn2+ release, synchronized with DNA accumulation, led to over 90% tumor inhibition.
  • This strategy significantly extended survival times, even in unirradiated tumors.

Conclusions:

  • Synchronizing Mn2+ delivery with RT-induced DNA accumulation effectively activates the cGAS-STING pathway.
  • This approach represents a novel strategy to potentiate RT-induced antitumor immunity and improve therapeutic outcomes.
Keywords:
Cytosolic DNA accumulationMn(2+)RadiotherapycGAS-STING activation

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