Single‐Cell Dissection of Therapy‐Induced Remodeling Uncovers a Fibroblast‐Driven Immunosuppressive Niche and Targetable Vulnerabilities in Lethal Prostate Cancer
Jul 2026· Advancement of science· 0 citations· 83 references
Medicine
TL;DR
These findings defined the DPT+‐complement‐macrophage axis as an actionable vulnerability and position TSPAN1 and NRXN1 as therapeutic entry points to disrupt ADT‐driven tumor ecosystem remodeling in prostate cancer.
Abstract
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 trajectories toward CRPC or neuroendocrine prostate cancer. Collectively, these findings defined the DPT+‐complement‐macrophage axis as an actionable vulnerability and position TSPAN1 and NRXN1 as therapeutic entry points to disrupt ADT‐driven tumor ecosystem remodeling in prostate cancer.
Bone metastases (BoMs) are a major clinical challenge across cancer types, yet mechanistic insights remain limited by small cohorts and insufficient profiling depth. Here, we present a single‐cell RNA sequencing atlas of 95 BoMs, 22 healthy bone marrows (hBMs) and 129 primary tumors (PTs) spanning 10 cancer types, comprising 895,475 high‐quality transcriptomes, to map cellular remodeling during bone metastatic colonization. Malignant cells in BoMs converged on chromosomal instability—high proliferative states with enhanced angiogenic programs and suppressed immune‐inflammatory and metabolic pathways. The BoM immune landscape featured reduced cytotoxic lymphoid populations and expanded exhausted T‐cell states, with pronounced cancer type‐specific heterogeneity. BoM‐resident myeloid cells showed marked suppression of antigen presentation and phagocytosis, indicating immunosuppressive reprogramming. Stromal remodeling was characterized by enrichment of immunosuppressive CAFs, depletion of antigen‐presenting fibroblasts, reduced mesenchymal MHC expression, and expanded angiogenic endothelial programs. Cell–cell communication analyses predicted strengthened CXCL12–CXCR4 stromal–immune signaling. In vitro, the CXCL12–CXCR4 axis recruited CD8
+
T cells and enhanced their adhesion, spatially sequestering them from the tumor parenchyma, while CXCR4 blockade or CXCL12 knockdown significantly reduced tumor‐cell migration and invasion in vitro. This atlas defines convergent hallmarks of bone metastasis and highlights shared stromal–immune dependencies as therapeutic vulnerabilities.
Yitong Pan, Zhou Yang, Junyuan Deng et al.· iMetaMed· 0 citations
Results show that NF‐tumor crosstalk is rapid, bidirectional and functionally relevant to MMC response in vitro, and NFs can rapidly acquire CAF‐like activation features following tumor‐derived stimulation and contribute to a stromal context associated with EMT‐like plasticity and reduced MMC‐induced cytotoxicity in vitro.
Jinhui Gao, Cindy Xinyu Ji, Ci Ren et al.· Journal of cell communicatio...· 0 citations
Advanced renal cell carcinoma frequently acquires resistance to immune checkpoint blockade (ICB), underscoring the pivotal influence of the tumor immune microenvironment (TME) on therapeutic efficacy. While recent studies have implicated multicellular crosstalk within the TME as a central driver of ICB resistance, the precise multicellular programs (MCPs) that orchestrate this process remain poorly defined. Here, through integrative single-cell and spatial transcriptomic profiling of clear cell RCC (ccRCC) cohorts, we delineated a previously unrecognized MCP associated with ICB resistance, distinguished by heightened lysosomal activity, adipogenic signaling, and rewired fatty acid metabolism. Within this program, we uncover a coordinated interplay among TAM_APOE, ccRCC_CXCL14, and endothelial cells, whereby ccRCC_CXCL14 recruits TAM_APOE, which subsequently promotes tumor lipid metabolic reprogramming and angiogenesis, forming a pro-tumorigenic feedforward loop. Spatial mapping revealed a malignant gene topic colocalizing with this MCP in tumor cores, which robustly predicted both unfavorable survival and resistance in ICB-treated patients. Functional assays confirmed that the CXCL14-TAM axis promotes metabolic reprogramming, while dual CXCR4 and PD-1 blockade synergistically reverses the resistant phenotype by restoring CD8⁺ T-cell cytotoxicity. Multiplex immunofluorescence further validated the enrichment of this MCP specifically in non-responders. Collectively, our study defines a spatially organized, functionally coordinated multicellular niche that drives ICB resistance in ccRCC, establishing both a predictive biomarker for patient stratification and a mechanistic framework for therapeutic intervention.
ABSTRACT Triple‐negative breast cancer (TNBC) derives limited benefit from immune checkpoint blockade, largely owing to primary resistance shaped by the tumor immune microenvironment. Here, baseline transcriptomic profiling of a neoadjuvant chemoimmunotherapy cohort identified carbohydrate sulfotransferase 1 (CHST1) as a candidate resistance‐associated gene. High CHST1 expression was associated with poor immunotherapy response and inferior clinical outcome across clinical datasets. Functionally, CHST1/Chst1 had minimal effects on tumor‐cell‐intrinsic proliferation, migration, or invasion in vitro, but promoted tumor growth in an immune context–dependent manner in vivo. Mechanistic analyses support a model in which CHST1 associates with NF‐κB‐repressing factor (NKRF) and limits its nuclear accumulation, a localization change associated with increased NF‐κB‐related CCL20 expression. Tumor‐cell CCL20 perturbation and rescue experiments further supported a functional contribution of CCL20 to macrophage recruitment and M2‐like remodeling. Pharmacologic CCR6 blockade enhanced the antitumor activity of anti–PD‐1 therapy in syngeneic TNBC models. Finally, a CHST1–NKRF–CCL20 expression signature showed potential value for stratifying immunotherapy response. Collectively, this study supports a CHST1–NKRF–CCL20 regulatory model and identifies CCR6 blockade as a potential therapeutic strategy.
Shu-hao Jiang, Xiaohan Ying, Ruoqing Wang et al.· Advancement of science· 0 citations
This review synthesizes established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity and outlines an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Jia Li, Jinling Li, Yuechao Zhao et al.· Frontiers in Immunology· 0 citations
Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.
G. Dagar, M. Dagar, Ashna Gupta et al.· MedComm· 0 citations
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