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The aim of the present study was to elucidate the cellular and molecular mechanisms underlying refractory recurrent in-stent restenosis (RISR), thereby facilitating the identification of potential therapeutic targets. Coronary blood samples were obtained from culprit lesions of patients with RISR and non-ISR controls and subjected to single-cell RNA sequencing to comprehensively characterize immune cell heterogeneity and identify pathogenic signaling pathways. Key molecular mechanisms were validated in independent clinical samples using flow cytometry, monocyte-vascular smooth muscle cell (VSMC) coculture systems, and in vitro functional assays. Causality was further assessed using a monocyte-specific Fos knockdown mouse model of carotid wire injury to evaluate its role in vascular remodeling. Results revealed a pronounced inflammatory immune signature in RISR, with marked upregulation of activator protein-1 (AP-1) gene expression and transcriptional activity in monocytes as a central feature. Upstream mechanistic analyses identified the CCL5-CCR1/p38 MAPK axis as a key driver of AP-1 activation, promoting proinflammatory cytokine release and inducing a proliferative phenotypic switch in VSMCs. In vivo, monocyte-specific Fos knockdown significantly attenuated neointimal hyperplasia and luminal stenosis following vascular injury. Targeting monocyte AP-1 signaling may represent a novel therapeutic strategy for refractory restenosis driven by localized coronary inflammation.