State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
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.
J Control Release. 2021 Mar 10;331:480-490. doi: 10.1016/j.jconrel.2021.01.036. Epub 2021 Feb 3.
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 Mn delivery with accumulated cytosolic DNA after RT can promote the activation of cGAS-STING pathway, thereby enhancing RT-induced antitumor immunity. Intratumoral Mn injection immediately after RT cannot enhance RT, while intratumoral Mn injection 24 h after RT can. Direct-injected Mn 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 Mn in tumor for up to 24 h due to it can chelate divalent cations. When the release profile of Mn 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.
放射治疗（RT）引起的 DNA 损伤漏入细胞质可引发宿主抗肿瘤免疫反应。然而，由于细胞质 DNA 被宿主核酸酶固有地消化，环状鸟苷酸-腺苷酸合酶（cGAS）对其的识别有限，因此这种反应率并不理想。在这里，我们表明，在 RT 后同步 Mn 递送到积累的细胞质 DNA 可以促进 cGAS-STING 途径的激活，从而增强 RT 诱导的抗肿瘤免疫。RT 后立即进行瘤内 Mn 注射不能增强 RT，而 RT 后 24 小时进行瘤内 Mn 注射可以增强 RT。直接注射的 Mn 可以在数分钟内从肿瘤中代谢出来，而 RT 诱导的 DNA 损伤需要细胞有丝分裂进展长达 24 小时才能积累到细胞质中。由于藻酸盐可以螯合二价阳离子，因此它可以将 Mn 维持在肿瘤中长达 24 小时。当 Mn 的释放曲线通过藻酸盐（Alg）控制并与 RT 诱导的 DNA 损伤的积累同步时，即使在未辐照的肿瘤中也可以获得超过 90%的抑制率，并且生存时间显著延长。这种同步策略为有效激活肿瘤中的 cGAS-STING 途径并促进 RT 诱导的免疫提供了一种简单而新颖的方法。
