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Objectives: To identify aberrantly expressed immune molecules in keloids and to explore their possible biologic significance., Methods: Immune molecules with abnormal expression were identified based on immune gene sequencing of keloids, microarray datasets and high-throughput sequencing datasets and methylation microarray datasets from the Gene Expression Omnibus (GEO) database, and real-time quantitative PCR analysis., Results: Upregulation of tumor necrosis factor superfamily member 4 (TNFSF4) in keloids was identified. Enrichment analysis found that high TNFSF4 expression was associated with immune processes, such as regulation of neutrophil chemotaxis, dendritic cell chemotaxis, and antigen processing and presentation. Single-cell RNA sequencing (scRNA) results suggested that TNFSF4 was upregulated in mesenchymal fibroblasts, which are the critical cells in skin fibrosis. This high expression of TNFSF4 enhanced cell-to-cell interactions in fibrosis-related pathways, including the fibronectin 1 (FN1) and collagen pathways. Mesenchymal fibroblasts expressing TNFSF4 significantly upregulated gene expression in extracellular matrix organization and wound healing processes., Conclusions: Our study revealed upregulation of the immune molecule TNFSF4 in keloids at the multi-omics level and its effects on intercellular crosstalk and transcriptional profiles of mesenchymal fibroblasts. Investigation of TNFSF4 as an immune checkpoint molecule may represent a new direction for keloid treatment research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (AJTR Copyright © 2023.)