As　a　stimulator　of　interferon　gene　(STING),　cyclic　dinucleotide　activates　a　broad　cellular　immune　response　for　anti-cancer　immunotherapy　(CIT).　However,　the　inherent　of　instability　of　2′　3′-cyclic-GMP-AMP　(cGAMP)　with　poor　cellular　targeting,　rapid　clearance,　and　inefficient　transport　to　the　cytoplasm　seriously　hinders　cGAMP　potency.　Here,　a　thiolated　and　Mn2+　coordinated　cyclic　dinucleotide　nanovaccine　(termed　as　Mn-cGAMP　NVs)　to　enable　direct　cytosolic　co-delivery　of　cGAMP　and　Mn2+　to　potentiate　the　antitumor　immune　response　is　presented.　In　the　NVs,　the　fixation　cGAMP　with　Mn2+　ions　not　only　improve　its　stability,　but　also　potentiate　the　activation　of　STING.　Meanwhile,　the　presence　of　polysulfides　on　the　NVs　surface　allowed　direct　cytosolic　delivery　while　avoiding　degradation.　In　this　way,　the　production　of　cytokines　for　activating　T　cells　immunity　is　greatly　elevated,　which　in　turn　suppressed　the　primary　and　distal　tumors　growth　through　long-term　immune　memory　and　led　to　long-term　survival　of　poorly　immunogenic　B16F10　melanoma　mice.　Moreover,　by　further　combining　with　anti-PD-L1　monoclonal　antibody,　synergistic　T　cells　antitumor　immune　response　is　elicited.　This　work　offers　a　promising　strategy　to　enhance　the　potency　of　cGAMP,　holding　a　considerable　potential　for　CIT　applications.　©　2021　Wiley-VCH　GmbH