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

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.

Keywords: Cytosolic DNA accumulation; Mn(2+); Radiotherapy; cGAS-STING activation.