Immunotherapy　has　become　a　primary　and　secondary　treatment　for　gastric　cancer　(GC)　patients　with　mismatch　repair　deficiency　(dMMR),　and　is　used　in　both　perioperative　and　advanced　stages.　The　tumor　immune　microenvironment　(TiME)　is　crucial　for　immunotherapy　efficacy,　yet　the　impact　of　MMR　status　on　TiME　remains　understudied.　We　employed　single-cell　RNA　sequencing　(scRNA-seq)　to　analyze　33　fresh　tissue　samples　from　25　patients,　which　included　10　normal　tissues,　6　dMMR　tumor　tissues,　and　17　pMMR　tumor　tissues,　aiming　to　characterize　the　cellular　and　molecular　components　of　the　TiME.　The　proficient　mismatch　repair　(pMMR)　group　displayed　a　significantly　higher　prevalence　of　a　specific　GC　cell　type,　termed　GC2,　characterized　by　increased　hypoxia,　epithelial-mesenchymal　transition　(EMT),　and　angiogenic　activities　compared　to　the　dMMR　group.　GC2　cells　overexpressed　BEX3　and　GPC3,　and　they　significantly　correlated　with　poorer　survival.　The　pMMR　group　also　showed　increased　infiltration　of　SPP1　+　macrophages　and　FAP　+　fibroblasts,　exhibiting　strong　hypoxic　and　pro-angiogenic　features.　Furthermore,　a　higher　proportion　of　E2　endothelial　cells,　involved　in　extracellular　matrix　(ECM)　remodeling　and　showing　heightened　VEGF　pathway,　HIF　pathway,　and　angiogenesis　activity,　were　identified　in　pMMR　patients.　Intercellular　communication　analyses　revealed　that　GC2　cells,　SPP1　+　macrophages,　FAP　+　fibroblasts,　and　E2　endothelial　cells　interact　through　VEGF,　SPP1,　and　MIF　signals,　forming　a　TiME　characterized　by　hypoxia,　pro-angiogenesis,　and　ECM　remodeling.　This　study　uncovered　TiME　heterogeneity　among　GC　patients　with　different　MMR　states,　highlighting　that　the　pMMR　TiME　is　distinguished　by　hypoxia,　pro-angiogenesis,　and　ECM　remodeling,　driven　by　the　presence　of　GC2　cells,　SPP1　+　macrophages,　FAP　+　fibroblasts,　and　E2　endothelial　cells.　These　findings　are　pivotal　for　developing　targeted　immunotherapies　for　GC　patients　with　pMMR.　©　The　Author(s)　2024.