Microenvironment-Dependent Role of PLOD3 in Glioblastoma: Associations with Matrix Remodeling and Myeloid Immune Remodeling
Wenwu Luo, Xiaodan Xu, Lv Zhou, Silei Gu, Wei Wang, Jinmei Fang, Xue Peng, Junjie He, Kai Huang, Dengqun Sun, Weiqiang Yu, Yu YinIntroduction/Objective:
Glioblastoma progression depends on reciprocal interactions between malignant cells, extracellular matrix remodeling, and myeloid immune suppression. However, whether PLOD3 drives glioblastoma through tumor cell-intrinsic or microenvironment- dependent mechanisms remains unclear.
Methods:
This retrospective multi-cohort observational study integrated transcriptomic datasets (GSE68848 and GSE16011), single-cell RNA sequencing reanalysis, immunohistochemistry of 70 glioma specimens, and functional validation in the GL261 murine model using in vitro assays and a subcutaneous syngeneic tumor model.
Results:
PLOD3 was significantly upregulated in glioblastoma and was associated with higher tumor grade, IDH1-wild-type status, and shorter overall survival. Higher PLOD3 expression was associated with increased macrophage infiltration, whereas computational immune-infiltration analyses indicated reduced CD8+ T-cell and natural killer (NK)-cell signatures. PLOD3 knockdown did not appreciably alter GL261 cell proliferation in vitro but significantly reduced subcutaneous tumor growth in immunocompetent mice, accompanied by decreased macrophage infiltration and collagen deposition.
Discussion:
These findings support a microenvironment-dependent role for PLOD3 in the GL261 model rather than a major cell-intrinsic effect on tumor-cell proliferation. Extracellular matrix (ECM) remodeling and cytokine-associated signaling identified by transcriptomic analysis represent candidate mechanisms that may contribute to macrophage-dominant microenvironmental remodeling, but these pathways were not directly validated.
Conclusion:
PLOD3 is upregulated in glioblastoma and is associated with poor prognosis and a macrophage-enriched tumor microenvironment. PLOD3 knockdown suppresses tumor growth in vivo and reduces macrophage infiltration and collagen deposition. These findings support a microenvironment-dependent role of PLOD3 in glioblastoma progression, while ECM remodeling and cytokine-associated signaling may contribute to this effect and require further mechanistic validation.