Oncolytic　virotherapy　can　lead　to　tumor　lysis　and　systemic　anti-tumor　immunity,　but　the　therapeutic　potential　in　humans　is　limited　due　to　the　impaired　virus　replication　and　the　insufficient　ability　to　overcome　the　immunosuppressive　tumor　microenvironment　(TME).　To　solve　the　above　problems,　we　identified　that　Indoleamine　2,　3-dioxygenase　1　(IDO1)　inhibitor　Navoximod　promoted　herpes　simplex　virus　type　1　(HSV-1)　replication　and　HSV-1-mediated　oncolysis　in　tumor　cells,　making　it　a　promising　combination　modality　with　HSV-1-based　virotherapy.　Thus,　we　loaded　HSV-1　and　Navoximod　together　in　an　injectable　and　biocompatible　hydrogel　(V-Navo@gel)　for　hepatocellular　carcinoma　(HCC)　virotherapy.　The　hydrogel　formed　a　local　delivery　reservoir　to　maximize　the　viral　replication　and　distribution　at　the　tumor　site　with　a　single-dose　injection.　Notably,　V-Navo@gel　improved　the　disease-free　survival　time　of　HCC-　bearing　mice　and　protects　the　mice　against　tumor　recurrence.　What＇s　more,　V-Navo@gel　also　showed　an　effective　therapeutic　efficacy　in　the　rabbit　orthotopic　liver　cancer　model.　Mechanistically,　we　further　discovered　that　our　combination　strategy　entirely　reprogramed　the　TME　through　single-cell　RNA　sequencing.　All　these　results　collectively　indicated　that　the　combination　of　Navoximod　with　HSV-1　could　boost　the　viral　replication　and　reshape　TME　for　tumor　eradication　through　the　hydrogel　reservoir.　An　injectable　and　biocompatible　hydrogel　loaded　with　both　Indoleamine　2,　3-dioxygenase　1　(IDO1)　inhibitor　and　herpes　simplex　virus　type　1　(HSV-1)　displays　synergistic　anti-cancer　effects　in　vivo　by　remodeling　the　tumor　microenvironment　and　generating　immune　memory　effects.