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SPP1+ Macrophage/FAP+ Fibroblast Crosstalk Predicts Disease Progression and Immunosuppressive Niche in Prostate Cancer

M. Zheng^1,2, T. Xie³, G. Xu³, Y. Li², Y. Wei^2,4, H. Guo¹, J. Zhuang^1,3

¹Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Department of Urology, Nanjing, China
²Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Department of Urology, Nanjing, China
³Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Department of Urology, Nanjing, China
⁴Traditional Chinese Medicine Hospital of Ili Kazak Autonomous Prefecture, Department of Urology, Ili, China

Introduction:

The immunosuppressive tumor microenvironment (TME) is a key driver of prostate cancer (PCa) progression, yet the dynamic interplay between stromal and immune cells remains poorly characterized. Through integrative analysis of single-cell transcriptomes and clinical cohorts, we identified a coordinated stromal-immune axis involving tumor-associated macrophages(TAM) and cancer-associated fibroblasts (CAFs) that orchestrates TME remodeling.

Material and methods:

Single-cell RNA sequencing (scRNA-seq) was performed on 48 PCa and 25 adjacent normal tissues. Clinical correlations were validated in the TCGA cohort and two independent PCa cohorts. Intercellular communication (CellChat) and spatial co-localization (multiplex immunofluorescence, mIF) were employed to decode intercellular communication. A machine learning-based composite risk score integrating SPP1+ macrophage and FAP+ fibroblast features was developed to predict progression-free survival (PFS). Xenograft model was utilized to assess the therapeutic efficacy of dual-targeting strategy.

Results:

scRNA-seq identified SPP1+ macrophages as a predominant M2-polarized subset enriched in tumors versus normal tissues. Their abundance positively correlated with FAP+ fibroblast (r=0.62, p<0.001) and inversely with cytotoxic T lymphocytes (CTLs, r=-0.48, p=0.007). CellChat analysis predicted CD99-CD99L2 ligand-receptor signaling as a key pathway mediating SPP1+ macrophage-FAP+ fibroblast crosstalk, which was spatially confirmed by mIF in high-grade tumors (Gleason ≥8, p<0.001). The SPP1+FAP+ co-signature (SF-score) stratified patients into high- and low-risk groups, with high-risk patients exhibiting shorter PFS (HR=3.12, p<0.001), advanced T3-4 stage, and early biochemical recurrence, independent of PSA and Gleason score. High SF-score tumors displayed an immunosuppressive TME characterized by CTL exhaustion. Dual targeting with anti-SPP1 antibody and FAP-shRNA achieved synergistic tumor suppression and restored CD8+ T cell function.