Single‐Cell Dissection of Therapy‐Induced Remodeling Uncovers a Fibroblast‐Driven Immunosuppressive Niche and Targetable Vulnerabilities in Lethal Prostate Cancer

作者：Yuehua Chen, Dandan Dong, Jinling Liao, Naikai Liao, Mengqi Liu, Qin Zhang, Siting Chen, Liu Q, Ying Lu, Tianyu Li, Chunlin Zou, Qiong Song, Qiuyan Wang, Jian Liang, Qiji Xie, Chengyang Li, Mengyun Wang, J Cheng, Zengnan Mo, Gong‐Hong Wei · 发表于：Advanced Science · 年份：2026 · DOI：10.1002/advs.202521088 · 研究领域：Prostate Cancer Treatment and Research、Single-cell and spatial transcriptomics、Cancer Immunotherapy and Biomarkers

ABSTRACT Therapy resistance in prostate cancer arises from coordinated remodeling of malignant and stromal compartments, yet the mechanisms orchestrating this ecosystem adaptation remain elusive. Here, single‐cell RNA sequencing of longitudinal biopsies obtained before and after androgen‐deprivation therapy (ADT) delineated a therapy‐induced stromal lineage bifurcation toward APOD + and DPT + fibroblast states. DPT + fibroblasts activated a C3‐ITGAX/ITGB2 complement signaling axis targeting macrophages, coinciding with suppression of M1 inflammatory programs, amplification of immune‐checkpoint signaling, and a shift of CD8 + T cells from cytotoxic to exhausted phenotypes. Concomitantly, we identified pre‐existing malignant epithelial subpopulations characterized by reduced AR/KLK3 activity and heightened chromosomal instability that preferentially persisted following therapy. Integrative multi‐omic analyses nominated TSPAN1 as a functional effector of castrate resistant prostate cancer (CRPC) and NRXN1 as a regulator of neuroendocrine plasticity through calcium‐dependent signaling programs. Genetic silencing of either gene suppressed proliferation, clonogenicity, migration, and tumor growth, while attenuating neuroendocrine features in vitro and in vivo. Spatial mapping, functional perturbation, and stromal‐epithelial co‐culture experiments mechanistically established a therapy‐induced DPT + fibroblast‐complement circuit that enforced immune evasion and channels epithelial tr...