MGPhi cancer-associated fibroblasts orchestrate MDSC-mediated immunosuppression in melanoma through TNF signaling
- 1Department of Plastic and Cosmetic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- 2Department of Burn and Plastic Surgery, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China
- 3The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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 (MGPhi 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 MGPhi 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. MGPhi 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: MGPhi 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.
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BibTeX
@article{tu2026mgphi,
title = {{MGPhi cancer-associated fibroblasts orchestrate MDSC-mediated immunosuppression in melanoma through TNF signaling}},
author = {Liying Tu and Min Yi and Zengyang Feng and Yingying Wang and Tianyi Ni and Lifan Zhou and Binlin Luo and Youzhi Tang and Shujie Ruan and Wei Yan and Weicheng Gao},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-016095},
url = {https://doi.org/10.1136/jitc-2026-016095},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - MGPhi cancer-associated fibroblasts orchestrate MDSC-mediated immunosuppression in melanoma through TNF signaling
AU - Liying Tu
AU - Min Yi
AU - Zengyang Feng
AU - Yingying Wang
AU - Tianyi Ni
AU - Lifan Zhou
AU - Binlin Luo
AU - Youzhi Tang
AU - Shujie Ruan
AU - Wei Yan
AU - Weicheng Gao
PY - 2026
DA - 2026/10/26
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-016095
UR - https://doi.org/10.1136/jitc-2026-016095
AB - 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 (MGPhi 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 MGPhi 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. MGPhi 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: MGPhi 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.
SN - 2051-1426
ER -