MDK⁺ cancer-associated fibroblasts promote immunotherapy resistance through mitochondrial reprogramming in breast cancer.

Authors

Wei Deng, Yidan Fan, Hanqi Zhang, Song Wu, Kaiying Zhang, Yongzhou Luo, Wenwen Tian, Huajie Guan, Hailin Tang, Lewei Zhu, Zikun Ma, Rongfang He, Yutian Zou

Published in

Cancer letters. Pages 218884. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

Immunotherapy has improved outcomes for patients with breast cancer, yet therapeutic resistance remains a major clinical challenge. Therefore, we integrated single-cell and spatial transcriptomic data from breast cancer cohorts treated with immune checkpoint inhibitors to identify resistance-associated cellular populations and pathways, with validation across eight independent bulk RNA-seq immunotherapy cohorts. Cancer-associated fibroblasts (CAFs) were isolated from anti-PD-1-resistant breast tumors for functional studies, including in vitro co-culture and in vivo models. Mitochondrial function and metabolic alterations were assessed by flow cytometry, transmission electron microscopy, ATP and adenosine quantification, and JC-1 staining. Tumor mitochondrial metabolism was markedly upregulated in anti-PD-1 non-responders and consistently associated with poor therapeutic response across validation cohorts. MDK-expressing CAFs were enriched in resistant tumors, exhibited strong interactions with tumor cells, and were negatively associated with intratumoral CD8+ T cell infiltration. Single-cell source contribution and depletion analyses identified CAF-derived MDK as the major paracrine mediator linking stromal signaling to tumor metabolic adaptation and immune suppression. Mechanistically, MDK activated SDC1-dependent PI3K/AKT/mTOR signaling in cancer cells, promoting mitochondrial metabolic reprogramming, ATP production, and CD38/CD73-dependent extracellular adenosine accumulation, thereby suppressing CD8+ T cell cytotoxicity. Receptor-depletion experiments further identified SDC1 as the principal functional receptor mediating these effects. Importantly, CAF-specific MDK depletion or pharmacological MDK inhibition enhanced anti-PD-1 efficacy and restored CD8+ T cell effector activity in vivo. Collectively, MDK+ CAFs facilitate anti-PD-1 resistance via mitochondrial rewiring and adenosine-mediated immunosuppression, supporting the MDK-SDC1 axis as a potential therapeutic target for overcoming resistance and improving immunotherapy efficacy in breast cancer.

PMID:
42874987
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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