Work

MGP hi cancer-associated fibroblasts orchestrate MDSC-mediated immunosuppression in melanoma through TNF signaling

Year: 2026

Type: article

Abstract: Background Melanoma is an aggressive skin cancer with a highly immunosuppressive tumor microenvironment. This study investigated the role of matrix Gla protein (MGP)-high cancer-associated fibroblasts (MGP hi CAFs) in melanoma progression and their potential relevance to immunotherapy.Methods Single-cell RNA sequencing and tissue validation were used to characterize MGP expression, and its association with prognosis was analyzed. In vitro assays and mouse melanoma models were used to investigate the effects of MGP hi CAFs on tumor progression, myeloid-derived suppressor cell (MDSC) recruitment and apoptosis. The role of MDSCs was further examined by adoptive transfer. The antitumor effects of vitamin K2, anti-programmed cell death protein 1 (PD-1) and their combination were evaluated in vivo. Normality was assessed using the Shapiro-Wilk test. Group differences were analyzed using two-tailed paired or unpaired Student’s t-tests or one-way or two-way analysis of variance followed by Tukey’s multiple comparisons test. Survival curves were compared using the log-rank test.Results MGP expression was reduced in melanoma tissues, and low MGP expression was associated with poor prognosis. MGP hi CAFs inhibited melanoma cell proliferation and migration and suppressed tumor growth. Mechanistically, MGPhi CAFs reduced C-X-C motif chemokine ligand 2/C-X-C motif chemokine receptor 2-mediated MDSC recruitment and promoted MDSC apoptosis by inhibiting tumor necrosis factor receptor 2-cellular FLICE-like inhibitory protein signaling and activating caspase-8. Adoptive transfer of MDSCs reversed the antitumor effects of MGPhi CAFs. Vitamin K2 increased MGP protein levels in CAFs isolated from tumors. Combined vitamin K2 and anti-PD-1 treatment produced greater antitumor activity than either monotherapy.Conclusions MGP hi CAFs suppress melanoma progression by reducing MDSC recruitment and survival. These findings identify an MGPhi CAF-MDSC regulatory axis and support further evaluation of vitamin K2 combined with anti-PD-1 therapy in melanoma.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-016095