Aug 2026· Frontiers in Immunology· Vol 17· 1 citation· 110 references
Medicine
TL;DR
This review synthesizes single-cell and spatial omics evidence for metabolic-immune ecosystems in prostate cancer, emphasizing the transition from androgen dependence to castration resistance, lineage plasticity, metastatic niche adaptation, and therapy resistance.
Abstract
Prostate cancer is a hormone-driven malignancy, but its clinical behavior cannot be explained by androgen receptor (AR) signaling alone. Single-cell and spatial omics are redefining prostate cancer as an evolving metabolic-immune ecosystem in which malignant epithelial states, stromal niches, myeloid programs, T-cell exclusion, vascular remodeling, and treatment-imposed selection pressures jointly shape progression and resistance. These technologies have resolved the normal prostate epithelial hierarchy, pre-existing castration-resistant-like cells, basal-like, club-like, and hillock-like programs, neuroendocrine transformation states, immunosuppressive macrophage populations, fibroblast states, and spatial neighborhoods that are difficult to detect by bulk sequencing. Treatment-associated changes have been characterized most directly in androgen-axis and immune contexts, whereas evidence related to taxanes, DNA damage response (DDR)-targeted therapy, and radioligand therapy remains emerging or hypothesis-generating. This review synthesizes single-cell and spatial omics evidence for metabolic-immune ecosystems in prostate cancer, emphasizing the transition from androgen dependence to castration resistance, lineage plasticity, metastatic niche adaptation, and therapy resistance. We argue that the next translational step is not simply to catalog additional cell types, but to connect longitudinal cell-state maps, spatially resolved metabolic dependencies, immune-neighborhood biomarkers, and mechanism-matched combination therapies.
An integrated single-cell atlas defines a critical POSTN+ CAF–APOE+ macrophage unit that is associated with a fibrotic and immunosuppressive TME in advanced prostate cancer, and suggested conserved enrichment and adverse prognostic impact of this stromal-immune axis across diverse tumor types, though tissue-specific context should be considered.
Yangzhou Liu, Ao-Chu Liu, Xing-Lai Dai et al.· Frontiers in Immunology· 0 citations
Immune checkpoint inhibitors (ICIs) have achieved breakthroughs in various solid tumors; however, their efficacy remains limited in prostate cancer (PCa), which is closely associated with its highly immunosuppressive tumor microenvironment (TME). As the most abundant stromal component in the TME, cancer-associated fibroblasts (CAFs) exhibit remarkable heterogeneity and functional plasticity, playing a central role in orchestrating an immunologically "cold" tumor phenotype and driving resistance to immunotherapy. We have moved beyond simple marker-based classification of cancer-associated fibroblast (CAF) subtypes — a framework still widely used in routine pathological assessment — and now define these populations by their functional states and molecular profiles, enabled by advances in single-cell sequencing, spatial multi-omics, and computational biology. Such functional divergence across stromal subsets allows individual CAF populations to engage in complex, multilayered crosstalk with different immune cell types, and together they build an immunosuppressive network that drives tumor immune evasion. This review systematically catalogs the identification methods and signature gene panels for distinct CAF subtypes in prostate cancer, with particular focus on the multilayered regulatory circuits through which these stromal cells shape the immune microenvironment. We also highlight emerging CAF-targeted strategies designed to reverse immunosuppressive states. This integrated perspective frames CAF heterogeneity in prostate cancer immune evasion, and establishes theoretical underpinnings and translational pathways for next-generation precision combination immunotherapies.
Kan-Kan He, Zhi-Te Zhao, Jian-Hui Bai et al.· International Journal on Bio...· 0 citations
Benign prostatic hyperplasia (BPH) represents a highly prevalent age-related disorder, traditionally managed through androgen-driven pathways. However, the limited efficacy of conventional hormonal therapies in a substantial subset of patients necessitates the investigation of alternative pathogenic mechanisms. The emergence of single-cell RNA sequencing (scRNA-seq) has provided the necessary resolution to map cellular heterogeneity and microenvironmental dynamics within the prostate. This review synthesizes recent advancements in applying scRNA-seq to BPH research, highlighting a transition from a homogeneous, hormone-centric view toward recognizing BPH as a complex, heterogeneous process driven by multifaceted cell-immune interactions. We detail how scRNA-seq has identified distinct cellular subsets within the hyperplastic transition zone, including novel basal epithelial subtypes and activated fibroblast populations that contribute directly to nodule formation and disease progression. Furthermore, we examine the central role of chronic inflammation, mediated by immune cell infiltration and senescence-associated secretory phenotypes (SASP), in perpetuating a proliferative microenvironment. The technology also clarifies mechanisms underlying treatment resistance and identifies potential biomarkers and novel therapeutic targets beyond the androgen axis, such as the CXCL13/CD4+T cell axis and granzyme K pathways. Looking forward, integrating scRNA-seq with spatial multi-omics aims to construct a comprehensive spatiotemporal atlas of BPH, facilitating molecular subtyping and the development of precision, microenvironment-targeted therapies. In conclusion, scRNA-seq is redefining the pathophysiological landscape of BPH, offering a path toward innovative, non-androgenic therapeutic strategies aimed at achieving true disease modification.
Yihao Liao, Siyuan Jiang, Haohan Wang et al.· Frontiers in Immunology· 0 citations
Prostate cancer (PCa) is one of the most common malignant tumors, and most patients develop castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT). Metabolic plasticity, which allows cancer cells to reprogram glucose, lipid, and glutamine utilization, plays a key role. This metabolic adaptation meets the bioenergetic and biosynthetic needs of tumor cells, and it can interact with the androgen receptor (AR) signaling pathway bidirectionally to evade immune surveillance via metabolic reprogramming. Current treatments include single metabolic node inhibition and AR-guided combination therapy. However, due to intratumoral metabolic heterogeneity, compensatory pathway activation, and systemic metabolic toxicity of drugs, there is a need to explore new intervention targets and strategies. This article comprehensively discusses the metabolic network, regulatory mechanism, and current challenges of CRPC in order to provide a theoretical basis for clinical prevention and treatment.
Yanzhi Lou, Zhengda Lou, Luo He et al.· Cellular Signalling· 0 citations
Neuroendocrine prostate cancer (NEPC) is an aggressive, treatment-refractory phenotype of advanced prostate cancer. This narrative review was informed by targeted searches of PubMed, Web of Science through May 2026. We classify evidence as Level A (human NEPC samples or clinical cohorts), Level B (NEPC-specific models), Level C (prostate adenocarcinoma or CRPC without NEPC resolution), or Level D (pan-cancer or non-prostate extrapolation), and apply these levels to central claims and a study-level evidence table. Direct human data support immune depletion in most NEPC tumors, with heterogeneous macrophage, fibroblast and lymphoid remodeling in selected cohorts; model studies support context-dependent cytokine, hypoxic, extracellular-matrix and metabolic effects on lineage plasticity. By contrast, CAF-derived lactate fueling NEPC, a dense collagen drug barrier, and NEPC-specific vascular permeability remain unvalidated. Most TME-directed treatments are preclinical or extrapolated, whereas DLL3-directed therapy has shown early activity in biomarker-selected disease. Longitudinal biopsies, spatial multi-omics, humanized models and biomarker-defined trials are needed to distinguish causal vulnerabilities from correlates of treatment-emergent lineage transition.
Nan Yao, Qi-Xing Yang, Peng-Kang Chang et al.· Frontiers in Oncology· 0 citations
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