Although　tumor-specific　neoantigen-based　cancer　vaccines　hold　tremendous　potential,　it　still　faces　low　cross-presentation　associated　with　severe　degradation　via　endocytosis　pathway.　Herein,　a　thiolated　nano-vaccine　allowing　direct　cytosolic　delivery　of　neoantigen　and　Toll　like　receptor　9　agonist　CpG-ODN　is　developed.　This　approach　is　capable　of　bypassing　the　endo-/lysosome　degradation,　increasing　uptake　and　local　concentration　of　neoantigen　and　CpG-ODN　to　activate　antigen-presenting　cells,　significantly　strengthening　the　anti-cancer　T-cell　immunity.　In　vivo　immunization　with　thiolated　nano-vaccine　enhanced　the　lymph　organ　homing　and　promoted　the　antigen　presentation　on　dendritic　cells,　effectively　inhibited　tumor　growth,　and　significantly　prolonged　the　survival　of　H22-bearing　mice.　Strikingly,　further　combination　of　the　thiolated　nano-vaccine　with　anti-programmed　cell　death　protein-1　antibody　(alpha　PD-1)　could　efficiently　reverse　immunosuppression　and　enhance　response　rate　of　tumors,　which　led　to　enhanced　tumor　elimination,　complete　prevention　of　tumor　re-challenge,　and　long-term　survival　above　150　d.　Collectively,　a　versatile　methodology　to　design　cancer　vaccines　for　strengthening　anti-cancer　T-cell　immunity　in　solid　tumors　is　presented,　which　could　be　further　remarkably　enhanced　by　combining　with　immune　checkpoint　inhibitors.