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Four evolutionarily connected malignant epithelial subtypes are defined, and FOSL1 is identified as a key driver of lineage plasticity via direct HMGA1 transcriptional regulation, promoting treatment resistance through proliferation, EMT, and stemness. During progression, neoadjuvant hormone therapy triggers coordinated tumor microenvironment reprogramming that enhances immunosuppressive niches, lymphoid infiltration impairment, T-cell exhaustion, and regulatory T-cell expansion. The work links epithelial plasticity to microenvironment remodeling and highlights FOSL1-HMGA1 signaling and macrophage-driven immunosuppression as therapeutic 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Molecular Cancer (2026) 25:88 Molecular Cancer  \n[https://doi.org/10.1186/s12943-026-02617-6](https://doi.org/10.1186/s12943-026-02617-6)  \nRESEARCH Open Access  \nIntegrated single-cell and spatial transcriptomic profiling decodes lineage plasticity and immune microenvironment remodeling in prostate cancer progression  \nHongyuan Yu1†, Yusong Wang2†, Mingcong He3†, Yiming Chen1, Jianbin Bi1*, Xuyong Lin4* and Xiaolu Cui1*  \nAbstract  \nThis 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), anda 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.  \nKeywords Prostate cancer, Single-cell RNA sequencing, Spatial transcriptomics, Lineage plasticity, Tumor microenvironment, Treatment resistance  \n†Hongyuan Yu, Yusong Wang and Mingcong He contributed equally to this work.  \n*Correspondence: Jianbin Bi[bijianbin@hotmail.com](bijianbin@hotmail.com)[ ](bijianbin@hotmail.com)Xuyong Lin [linxuyong@hotmail.com](linxuyong@hotmail.com)[ ](linxuyong@hotmail.com)Xiaolu Cui  \n[cui_ruby@hotmail.com](cui_ruby@hotmail.com); [xlcui@cmu.edu.cn](xlcui@cmu.edu.cn)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.)  \nYu et al. Molecular Cancer (2026) 25:88 Page 2 of 32  \nGraphical Abstract  \nSingle-Cell Atlas of Lineage Plasticity and Immunosuppressive Niche Remodeling in Advanced Prostate Cancer. Based on our study which systematically reveals the mechanisms of lineage plasticity and immune microenvi","cbCaijy7o8xSxRQg","https://ap.wps.com/l/cbCaijy7o8xSxRQg","pdf",29361736,32,"English","# Abstract\n# Graphical Abstract\n# Introduction","[{\"question\":\"What data resources does the study integrate to map prostate cancer progression?\",\"answer\":\"The work integrates 127 single-cell RNA sequencing samples and 9 spatial transcriptomics profiles spanning disease progression from healthy prostate to neuroendocrine carcinoma.\"},{\"question\":\"Which transcriptional pathway is implicated in lineage plasticity and treatment resistance?\",\"answer\":\"FOSL1 is identified as a key driver of lineage plasticity by directly regulating HMGA1 transcription, enhancing proliferation, EMT, and stemness that support treatment resistance.\"},{\"question\":\"How does neoadjuvant hormone therapy affect the tumor microenvironment in this model?\",\"answer\":\"Neoadjuvant hormone therapy induces distinct cellular responses that upregulate immunosuppressive programs, promote spatial networking between stromal and immune compartments, and increase chemokine signaling leading to functionally impaired lymphoid infiltration.\"}]","Integrated single-cell and spatial transcriptomic profiling decodes lineage plasticity and immune microenvironment remodeling in prostate cancer progression | PDF",1790149574,81]