Spatial and single-cell insights into the prostate cancer microenvironment: overcoming immunotherapy resistance through multidimensional strategies
- 1Department of Urology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
- 2Department of Urology, the Second Affiliated Hospital of School of Medicine, Zhejiang University
Abstract
Despite breakthroughs in immune checkpoint inhibitors (ICIs) across various malignancies, prostate cancer (PCa), particularly metastatic castration-resistant prostate cancer (mCRPC), has shown limited responses to ICIs. This pervasive primary resistance is fundamentally driven by the canonically “immune-cold” and highly immunosuppressive tumor microenvironment (TME) of PCa. Propelled by recent advancements in single-cell RNA sequencing and spatial transcriptomics, this review comprehensively deconstructs the dynamic spatiotemporal evolution of the PCa immune landscape across localized, mCRPC, and lineage-plastic variant stages (e.g., neuroendocrine and double-negative PCa). We systematically delineate how the profound immune-excluded phenotype is sculpted not by isolated events, but by an intricate, multicellular suppressive ecosystem. Specifically, we detail the subclonal heterogeneity, spatial topography, and metabolic crosstalk of key suppressive populations, including specific tumor-associated macrophage (TAM) subsets, regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and myeloid-derived suppressor cells (MDSCs). Furthermore, we elucidate the tumor-intrinsic genetic aberrations (e.g., PTEN inactivation, TP53 mutations) and epigenetic rewiring (e.g., EZH2, CHD1, ARID1A dysregulation) that initiate and perpetually orchestrate this suppressive network. Finally, we highlight emerging therapeutic vulnerabilities and future translational directions. Dismantling the microenvironmental barriers in PCa necessitates transcending singular ICI blockade by employing novel combinatorial strategies that target chemotactic recruitment axes (e.g., CXCR2/CXCR4), reverse metabolic plasticity, and abrogate epigenetic silencing. Coupled with high-resolution liquid biopsy biomarkers (e.g., ctDNA, B7-H3+ EVs) for precise patient stratification and cutting-edge synthetic biology interventions, these multidimensional approaches hold profound promise for reversing the dual metabolic and immune suppressive state of PCa, thereby overcoming clinical immunotherapy resistance.
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BibTeX
@article{liu2026spatial,
title = {{Spatial and single-cell insights into the prostate cancer microenvironment: overcoming immunotherapy resistance through multidimensional strategies}},
author = {Dekai Liu and Junliang Tang and Yiwei Jiang and Jungang Zhao and Junxiao Shen and Lijie You and Yichun Zheng},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1979117},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979117/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Spatial and single-cell insights into the prostate cancer microenvironment: overcoming immunotherapy resistance through multidimensional strategies
AU - Dekai Liu
AU - Junliang Tang
AU - Yiwei Jiang
AU - Jungang Zhao
AU - Junxiao Shen
AU - Lijie You
AU - Yichun Zheng
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1979117
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979117/full
AB - Despite breakthroughs in immune checkpoint inhibitors (ICIs) across various malignancies, prostate cancer (PCa), particularly metastatic castration-resistant prostate cancer (mCRPC), has shown limited responses to ICIs. This pervasive primary resistance is fundamentally driven by the canonically “immune-cold” and highly immunosuppressive tumor microenvironment (TME) of PCa. Propelled by recent advancements in single-cell RNA sequencing and spatial transcriptomics, this review comprehensively deconstructs the dynamic spatiotemporal evolution of the PCa immune landscape across localized, mCRPC, and lineage-plastic variant stages (e.g., neuroendocrine and double-negative PCa). We systematically delineate how the profound immune-excluded phenotype is sculpted not by isolated events, but by an intricate, multicellular suppressive ecosystem. Specifically, we detail the subclonal heterogeneity, spatial topography, and metabolic crosstalk of key suppressive populations, including specific tumor-associated macrophage (TAM) subsets, regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and myeloid-derived suppressor cells (MDSCs). Furthermore, we elucidate the tumor-intrinsic genetic aberrations (e.g., PTEN inactivation, TP53 mutations) and epigenetic rewiring (e.g., EZH2, CHD1, ARID1A dysregulation) that initiate and perpetually orchestrate this suppressive network. Finally, we highlight emerging therapeutic vulnerabilities and future translational directions. Dismantling the microenvironmental barriers in PCa necessitates transcending singular ICI blockade by employing novel combinatorial strategies that target chemotactic recruitment axes (e.g., CXCR2/CXCR4), reverse metabolic plasticity, and abrogate epigenetic silencing. Coupled with high-resolution liquid biopsy biomarkers (e.g., ctDNA, B7-H3+ EVs) for precise patient stratification and cutting-edge synthetic biology interventions, these multidimensional approaches hold profound promise for reversing the dual metabolic and immune suppressive state of PCa, thereby overcoming clinical immunotherapy resistance.
SN - 1664-3224
ER -