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

Affiliation

Wang C(1), Sun Z(1), Zhao C(1), Zhang Z(1), Wang H(1), Liu Y(1), Guo Y(1), Zhang B(1), Gu L(2), Yu Y(2), Hu Y(3), Wu J(4).
Author information:

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

(2)State Key Laboratory of Pharmaceutical Biotechnology, Medical School of
Nanjing University, School of Life Sciences, Nanjing University, Nanjing 210093,
PR China; Affiliated Drum Tower Hospital, Medical School of Nanjing University,
Nanjing University, Nanjing 210008, PR China.

(3)State Key Laboratory of Pharmaceutical Biotechnology, Medical School of
Nanjing University, School of Life Sciences, Nanjing University, Nanjing 210093,
PR China; Jiangsu Key Laboratory for Nano Technology, Nanjing University,
Nanjing 210093, PR China.

(4)State Key Laboratory of Pharmaceutical Biotechnology, Medical School of
Nanjing University, School of Life Sciences, Nanjing University, Nanjing 210093,
PR China; Chemistry and Biomedicine Innovation Center, Nanjing University,
Nanjing 210023, PR China; Jiangsu Key Laboratory for Nano Technology, Nanjing
University, Nanjing 210093, PR China. Electronic address: [Email]

Abstract

Radiotherapy (RT)-induced DNA damage leaked into cytosol can elicit host antitumor immune response. However, such response rate is unpromising due to limited cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA, which could be digested inherently by host DNases. Here we show that synchronizing Mn2+ delivery with accumulated cytosolic DNA after RT can promote the activation of cGAS-STING pathway, thereby enhancing RT-induced antitumor immunity. Intratumoral Mn2+ injection immediately after RT cannot enhance RT, while intratumoral Mn2+ injection 24 h after RT can. Direct-injected Mn2+ can be metabolized out from tumor in minutes while RT-induced DNA damage need cells mitotic progression for up to 24 h to accumulate into cytosol. Alginate can maintain Mn2+ in tumor for up to 24 h due to it can chelate divalent cations. When the release profile of Mn2+ is controlled by alginate (Alg) and synchronized with the accumulation of RT-induced DNA damage, over 90% inhibition rate can be obtained even in the unirradiated tumor, and survival time is significantly extended. This synchronizing strategy provides a simple and novel approach to effectively activate cGAS-STING pathway in tumor and promote RT-induced immunity.

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