Targeting O-GlcNAcylation in tumor-associated macrophages: from metabolic reprogramming to osteolytic niche formation in bone-invasive solid tumors
7 affiliations
- 1Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University
- 2School of Stomatology of Qingdao University
- 3Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology
- 4Key Laboratory of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University
- 5Department of Stomatology, Shaanxi Provincial People’s Hospital
- 6Department of Endodontics, The Affiliated Hospital of Qingdao University
- 7Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China
Abstract
Bone-invasive solid tumors (BISTs) represent a clinically devastating and therapeutically challenging group of malignancies characterized by aggressive bone destruction, high morbidity, and poor prognosis due to limited effective treatments. Although bone invasion frequently occurs in advanced oral, breast, and prostate cancers, its underlying molecular mechanisms remain poorly understood, impeding the development of targeted therapies. Tumor-associated macrophages (TAMs), as the predominant immune cells within the tumor microenvironment, play central roles in promoting tumor progression, immune suppression, and pathological bone remodeling. Growing evidence identifies O-GlcNAcylation, a nutrient-sensitive post-translational modification, as a critical regulator of TAM polarization, metabolic reprogramming, and functional interactions with bone cells such as osteoclasts, osteoblasts, and mesenchymal stem cells. Emerging evidence suggests that dysregulated O-GlcNAcylation in TAMs is closely associated with an osteoclastogenic microenvironment, potentially facilitating bone invasion across various solid tumors. To address the broad knowledge gap regarding the molecular drivers of macrophage plasticity, this review systematically summarize currently identified O-GlcNAcylated protein substrates within TAMs. We highlight how these specific substrates remodel cellular energy cascades to induce a phenotypic transition in TAMs, thereby modulating the secretion of bone-resorbing cytokines and antitumor immune responses. We also explore emerging therapeutic strategies, including O-GlcNAcylation, macrophage repolarization, and advanced nanomedicine-based delivery systems designed for spatially and cell-type-specific targeting within the bone tumor microenvironment. Elucidating O-GlcNAc-mediated metabolic control of TAMs offers transformative insights and paves the way for novel combinatorial therapies aimed at suppressing bone invasion and improving outcomes in patients with advanced BISTs.
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BibTeX
@article{li2026targeting,
title = {{Targeting O-GlcNAcylation in tumor-associated macrophages: from metabolic reprogramming to osteolytic niche formation in bone-invasive solid tumors}},
author = {Shengqian Li and Yuan Zhi and Shaoming Li and Wenhao Ren and Zhipeng Xu and Jingjing Zheng and Changlun Shao and Ling Gao and Keqian Zhi},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.2002254},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.2002254/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting O-GlcNAcylation in tumor-associated macrophages: from metabolic reprogramming to osteolytic niche formation in bone-invasive solid tumors
AU - Shengqian Li
AU - Yuan Zhi
AU - Shaoming Li
AU - Wenhao Ren
AU - Zhipeng Xu
AU - Jingjing Zheng
AU - Changlun Shao
AU - Ling Gao
AU - Keqian Zhi
PY - 2026
DA - 2026/11/04
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.2002254
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.2002254/full
AB - Bone-invasive solid tumors (BISTs) represent a clinically devastating and therapeutically challenging group of malignancies characterized by aggressive bone destruction, high morbidity, and poor prognosis due to limited effective treatments. Although bone invasion frequently occurs in advanced oral, breast, and prostate cancers, its underlying molecular mechanisms remain poorly understood, impeding the development of targeted therapies. Tumor-associated macrophages (TAMs), as the predominant immune cells within the tumor microenvironment, play central roles in promoting tumor progression, immune suppression, and pathological bone remodeling. Growing evidence identifies O-GlcNAcylation, a nutrient-sensitive post-translational modification, as a critical regulator of TAM polarization, metabolic reprogramming, and functional interactions with bone cells such as osteoclasts, osteoblasts, and mesenchymal stem cells. Emerging evidence suggests that dysregulated O-GlcNAcylation in TAMs is closely associated with an osteoclastogenic microenvironment, potentially facilitating bone invasion across various solid tumors. To address the broad knowledge gap regarding the molecular drivers of macrophage plasticity, this review systematically summarize currently identified O-GlcNAcylated protein substrates within TAMs. We highlight how these specific substrates remodel cellular energy cascades to induce a phenotypic transition in TAMs, thereby modulating the secretion of bone-resorbing cytokines and antitumor immune responses. We also explore emerging therapeutic strategies, including O-GlcNAcylation, macrophage repolarization, and advanced nanomedicine-based delivery systems designed for spatially and cell-type-specific targeting within the bone tumor microenvironment. Elucidating O-GlcNAc-mediated metabolic control of TAMs offers transformative insights and paves the way for novel combinatorial therapies aimed at suppressing bone invasion and improving outcomes in patients with advanced BISTs.
SN - 1664-3224
ER -