SPP1⁺ macrophage-derived WNT5A contributes to MMP11⁺ myCAF-mediated matrix remodeling and immunotherapy resistance in lung adenocarcinoma
- 1Zhejiang Cancer Hospital
- 2Zhejiang Chinese Medical University
- 3Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine
Abstract
Background Lung adenocarcinoma (LUAD) is the leading subtype of non-small cell lung cancer. However, the stromal-immune circuits that coordinate matrix remodeling and immunotherapy resistance in LUAD remain incompletely understood. This study aimed to characterize the stromal-immune interactions associated with LUAD progression and poor response to PD-1 blockade. Methods Bulk transcriptomic datasets, single-cell RNA sequencing, and spatial transcriptomic data were integrated with clinical immunotherapy cohorts. Weighted gene co‑expression network analysis, survival meta‑analysis, and tissue enrichment scoring identified high‑risk cell subpopulations. Cell‑cell communication, virtual gene knockout, and spatial deconvolution were used to predict ligand‑receptor interactions and colocalization. Multiplex immunohistochemistry of clinical specimens validated spatial relationships. In vitro, MMP11-overexpressing cancer-associated fibroblasts (CAFs) and SPP1-overexpressing macrophages (Macs) were generated, and a macrophage-CAF co‑culture system was constructed. Migration, contractility, extracellular matrix deposition, and YAP/INHBA pathway activation was measured. In vivo, a murine tumor model was established and evaluated using in vivo imaging, flow cytometry, atomic force microscopy assay, HE, masson staining, and multiplexed IHC staining. Results MMP11⁺ myofibroblastic CAF (MMP11⁺ myCAF) was identified as a high-risk CAF subset enriched in primary tumor and metastatic lesions, characterized by elevated expression of matrix-remodeling and contractile genes, including MMP11, ACTA2, and TAGLN. Increased abundance of MMP11⁺ myCAF was associated with advanced tumor stage, metastasis, poor overall survival, and reduced benefit from immune checkpoint blockade (ICB). Spatial transcriptomic deconvolution and multiplex immunohistochemistry revealed that MMP11⁺ myCAFs spatially co-localized with SPP1⁺ Mac, a pro-tumor myeloid population enriched in malignant and metastatic LUAD tissues. Ligand-receptor and downstream target analyses identified WNT5A as a key macrophage-derived mediator linking SPP1⁺ Mac to MMP11⁺ myCAF activation. Mechanistically, SPP1⁺ Mac exhibited activation of NFKB2/RELB-associated transcriptional programs, and SPP1 overexpression increased Nfkb2, Relb, and WNT5A protein levels in macrophages. WNT5A stimulation promoted YAP/INHBA-associated signaling in CAFs, enhancing CAF migration, contractility and extracellular matrix deposition. In animal models, activation of WNT5A signaling impaired the therapeutic efficacy of PD-1 blockade, reduced intratumoral CD8⁺ T-cell infiltration, and increased MMP11⁺ CAF-associated collagen deposition and tissue stiffness. Conclusions SPP1⁺ Mac-derived WNT5A may contribute to MMP11⁺ myCAF-mediated matrix remodeling and immunotherapy resistance in LUAD, highlighting a potential therapeutic strategy to overcome ICB resistance. Graphical Abstract
Related
- Metabolic signature of phosphoethanolamine and arginine pathways predicts prognosis and immunotherapy resistance in lung adenocarcinoma
- Epigenetic Silencing of ZNF471 Contributes to Osimertinib Resistance in Lung Adenocarcinoma: β-Hydroxybutyrate Associates with ZNF471 Re-Expression and Reduced Resistance-Associated Phenotypes
- ERK/GATAD2A/SAA1 axis drives osimertinib resistance via NF-κB and macrophage reprogramming in EGFR-mutated lung adenocarcinoma
- Intratumoral Klebsiella pneumoniae drives metabolic-immune remodeling and immunotherapy resistance in bladder cancer
- Impact of different TP53 mutation subtypes on response and outcome in advanced lung adenocarcinoma receiving first-line immunotherapy or chemo-immunotherapy
BibTeX
@article{wang2026spp1,
title = {{SPP1⁺ macrophage-derived WNT5A contributes to MMP11⁺ myCAF-mediated matrix remodeling and immunotherapy resistance in lung adenocarcinoma}},
author = {Menglei Wang and Pengcheng Zhang and Xuefeng Li and Lan Shao and Shijie Dai and Zhuo Chen},
journal = {Journal of Translational Medicine},
year = {2026},
month = oct,
doi = {10.1186/s12967-026-09069-y},
url = {https://doi.org/10.1186/s12967-026-09069-y},
note = {CC BY},
}
RIS
TY - JOUR
TI - SPP1⁺ macrophage-derived WNT5A contributes to MMP11⁺ myCAF-mediated matrix remodeling and immunotherapy resistance in lung adenocarcinoma
AU - Menglei Wang
AU - Pengcheng Zhang
AU - Xuefeng Li
AU - Lan Shao
AU - Shijie Dai
AU - Zhuo Chen
PY - 2026
DA - 2026/10/25
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-09069-y
UR - https://doi.org/10.1186/s12967-026-09069-y
AB - Background Lung adenocarcinoma (LUAD) is the leading subtype of non-small cell lung cancer. However, the stromal-immune circuits that coordinate matrix remodeling and immunotherapy resistance in LUAD remain incompletely understood. This study aimed to characterize the stromal-immune interactions associated with LUAD progression and poor response to PD-1 blockade. Methods Bulk transcriptomic datasets, single-cell RNA sequencing, and spatial transcriptomic data were integrated with clinical immunotherapy cohorts. Weighted gene co‑expression network analysis, survival meta‑analysis, and tissue enrichment scoring identified high‑risk cell subpopulations. Cell‑cell communication, virtual gene knockout, and spatial deconvolution were used to predict ligand‑receptor interactions and colocalization. Multiplex immunohistochemistry of clinical specimens validated spatial relationships. In vitro, MMP11-overexpressing cancer-associated fibroblasts (CAFs) and SPP1-overexpressing macrophages (Macs) were generated, and a macrophage-CAF co‑culture system was constructed. Migration, contractility, extracellular matrix deposition, and YAP/INHBA pathway activation was measured. In vivo, a murine tumor model was established and evaluated using in vivo imaging, flow cytometry, atomic force microscopy assay, HE, masson staining, and multiplexed IHC staining. Results MMP11⁺ myofibroblastic CAF (MMP11⁺ myCAF) was identified as a high-risk CAF subset enriched in primary tumor and metastatic lesions, characterized by elevated expression of matrix-remodeling and contractile genes, including MMP11, ACTA2, and TAGLN. Increased abundance of MMP11⁺ myCAF was associated with advanced tumor stage, metastasis, poor overall survival, and reduced benefit from immune checkpoint blockade (ICB). Spatial transcriptomic deconvolution and multiplex immunohistochemistry revealed that MMP11⁺ myCAFs spatially co-localized with SPP1⁺ Mac, a pro-tumor myeloid population enriched in malignant and metastatic LUAD tissues. Ligand-receptor and downstream target analyses identified WNT5A as a key macrophage-derived mediator linking SPP1⁺ Mac to MMP11⁺ myCAF activation. Mechanistically, SPP1⁺ Mac exhibited activation of NFKB2/RELB-associated transcriptional programs, and SPP1 overexpression increased Nfkb2, Relb, and WNT5A protein levels in macrophages. WNT5A stimulation promoted YAP/INHBA-associated signaling in CAFs, enhancing CAF migration, contractility and extracellular matrix deposition. In animal models, activation of WNT5A signaling impaired the therapeutic efficacy of PD-1 blockade, reduced intratumoral CD8⁺ T-cell infiltration, and increased MMP11⁺ CAF-associated collagen deposition and tissue stiffness. Conclusions SPP1⁺ Mac-derived WNT5A may contribute to MMP11⁺ myCAF-mediated matrix remodeling and immunotherapy resistance in LUAD, highlighting a potential therapeutic strategy to overcome ICB resistance. Graphical Abstract
SN - 1479-5876
ER -