Integrated single-cell and spatial transcriptomic profiling decodes lineage plasticity and immune microenvironment remodeling in prostate cancer progression.

[UNLABELLED] This study presents a comprehensive single-cell and spatial transcriptomic atlas of prostate cancer progression, integrating 127 single-cell RNA sequencing samples and 9 spatial transcriptomics profiles spanning the disease continuum from healthy prostate to neuroendocrine carcinoma. Our analysis defines four evolutionarily connected malignant epithelial subtypes: luminal-identity (sub1), stress-adaptive luminal (sub2), neuroendocrine (sub3), and a double-negative basal-like state (sub4). We identify FOSL1 as a key driver of lineage plasticity through direct transcriptional regulation of HMGA1, promoting treatment resistance via enhanced proliferation, EMT and stemness. The tumor microenvironment undergoes coordinated reprogramming during progression, with neoadjuvant hormone therapy inducing distinct cellular responses: FOLR2 + and CX3CR1 + TAMs upregulate TGF-β signaling to establish immunosuppressive niches, while CXCL12 + iCAFs and ACTA2 + myCAFs maintain spatial co-localization and facilitate immune cell recruitment. Spatial analyses reveal enhanced chemokine signaling post-therapy, particularly in specific TAM subsets, driving increased but functionally impaired lymphoid infiltration characterized by T-cell exhaustion and regulatory T-cell expansion. This integrated analysis establishes a unified paradigm connecting epithelial plasticity with microenvironmental reprogramming, revealing FOSL1-HMGA1 signaling and macrophage-driven immunosuppression as promising therapeutic targets for advanced prostate cancer.

[GRAPHICAL ABSTRACT] [Figure: see text]

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12943-026-02617-6.