Despite　significant　advancements　in　identifying　novel　therapeutic　targets　and　compounds,　cancer　stem　cells　(CSCs)　remain　pivotal　in　driving　therapeutic　resistance　and　tumor　progression　in　gastric　cancer　(GC).　High-resolution　knowledge　of　the　transcriptional　programs　underlying　the　role　of　CSC　niche　in　driving　tumor　stemness　and　progression　is　still　lacking.　Herein,　spatial　and　single-cell　RNA　sequencing　of　32　human　gastric　mucosa　tissues　at　various　stages　of　malignancy,　illuminating　the　phenotypic　plasticity　of　tumor　epithelium　and　transcriptional　trajectory　from　mature　gastric　chief　cells　to　the　CSC　state,　which　is　associated　with　activation　of　EGFR　and　WNT　signaling　pathways,　is　conducted.　Moreover,　the　CSCs　interact　with　not　only　the　immunosuppressive　CXCL13+　T　cells　and　CCL18+　M2　macrophages　to　evade　immune　surveillance,　but　also　the　inflammatory　cancer-associated　fibroblasts　(iCAFs)　to　promote　tumorigenesis　and　maintain　stemness,　which　construct　the　CSC　niche　leading　to　inferior　prognosis.　Notably,　it　is　uncovered　that　amphiregulin　(AREG)　derived　from　iCAFs　promotes　tumor　stemness　by　upregulating　the　expression　of　SOX9　in　tumor　cells,　and　contributes　to　drug　resistance　via　the　AREG-ERBB2　axis.　This　study　provides　valuable　insight　into　the　characteristics　of　CSC　niche　in　driving　tumor　stemness　and　progression,　offering　novel　perspective　for　designing　effective　strategies　to　overcome　GC　therapy　resistance.