Rationale:　Immuno-virotherapy　has　emerged　as　a　promising　approach　for　cancer　treatment,　as　it　directly　and　cytotoxically　eliminates　tumors　with　systemic　immune　stimulation.　However,　the　clinical　efficacy　of　this　approach　remains　limited　by　inappropriate　delivery　routes,　robust　antiviral　responses,　and　the　tumor　immunosuppressive　microenvironment.　Methods:　To　address　these　challenges,　we　propose　a　surface　engineering　strategy　that　masks　oncolytic　herpes　simplex　virus　(oHSV)　with　a　galactose-polyethylene-glycol　(PEG)　polymer　chain　to　minimize　host　antiviral　responses　and　selectively　targets　tumors　by　limiting　exposure　to　circulation　upon　systemic　administration.　We　evaluated　the　antitumor　efficacy　of　glycosylated-PEG-oHSV　by　examining　tumor　growth　in　animal　models　and　analyzing　tumor-infiltrating　CD8+T　cells　and　NK　cells　in　the　tumor　microenvironment　(TME).　To　assess　the　neutralizing　antibody　levels　after　systemic　administration　of　glycosylated-PEG-oHSV,　we　utilized　a　mouse　model　and　measured　oHSV-specific　IgG.　Results:　We　demonstrate　that　the　glycosylated-PEG　modified　oHSV　does　not　affect　the　replication　of　oHSV　yet　exhibits　high　specificity　to　the　asialoglycoprotein　receptor　(ASGPR)　overexpressed　in　hepatocellular　carcinoma　cells.　This　results　in　selectively　targeting　cancer　cells　and　deep　penetration　into　tumors　while　avoiding　spreading　into　the　brain.　Our　approach　also　effectively　reduces　oHSV-specific　neutralizing　antibody　levels　to　mitigate　host　antiviral　immune　response.　Notably,　our　glycosylated-PEG-oHSV　alleviates　the　immunosuppressive　microenvironment　within　tumors　by　reducing　regulatory　T　cells,　augmenting　the　infiltration　of　activated　CD8+T　cells　and　NK　cells　with　increasing　release　of　anti-tumor　cytokines,　to　impede　tumor　progression.　Conclusion:　Our　findings　offer　a　widely　applicable　and　universal　strategy　to　enhance　cancer　immuno-virotherapy　through　systemic　administration　of　non-genetically　engineered　oncolytic　viruses.　This　approach　has　the　potential　to　overcome　the　limitations　of　current　immune-virotherapy　strategies　and　may　improve　clinical　outcomes　for　cancer　patients.　©　The　author(s).