BGN/MDK Axis in the Melanoma Tumor Microenvironment Strengthens Tumor Malignancy by Modulating Cancer Cells and Cancer‐Associated Fibroblasts Crosstalk

ABSTRACT While the function of biglycan (BGN) is recognized in various cancers, its precise role and the mechanisms underlying cancer‐associated fibroblasts (CAFs) formation within the melanoma tumor microenvironment (TME) remain poorly understood. Utilizing spatial transcriptomics, single‐cell RNA sequencing (scRNA‐seq), vitro/vivo assays, function analysis and molecular assays, this study comprehensively investigated the BGN regulatory network. We discovered that N6‐methyladenosine (m6A) modulators—specifically YTHDF3, YTHDC1, and METTL14—cooperatively upregulate BGN expression in a parallel, non‐hierarchical manner converging on functional m6A sites within melanoma cells. Consequently, BGN significantly promoted melanoma proliferation and metastasis. Within the TME, spatial transcriptomics and scRNA‐seq revealed that CAFs, rather than tumor cells, exhibited the highest BGN expression. Cell trajectory analysis indicated that myCAFs ^BGN‐high may originate from iCAFs ^BGN‐low to interact with melanoma cells. Furthermore, midkine (MDK) signaling pathways was identified by cell chat analysis. Transcriptomic and spatial analysis revealed that BGN could regulate its expression at RNA and protein levels in CAFs through the regulator AE binding protein 1 (AEBP1). And the tumor promotion effect of CAFs may be executed by BGN/MDK axis, which also reduced CD8⁺ T cell infiltration in TME. Pharmacological inhibition of MDK also suppressed tumor growth with increased CD8⁺ T cell infiltration. Finally, this BGN/MDK axis could also drive the activation of normal fibroblasts into a CAF‐like phenotype verified by vitro assays. In conclusion, the interplay between cancer cells and CAFs mediated by the BGN/MDK axis is a critical driver of malignancy in melanoma, highlighting it as a promising therapeutic target for intervention.