POSTN⁺ cancer-associated fibroblast-CCL3⁺ macrophage crosstalk defines the immune-excluded tumor microenvironment in clear cell renal cell carcinoma

Yingjian Wang; Bingtong Yue; Hongqiang Ni; Jinchun Chen; Run Shi; Zhe Wang; Xinglai Dai; Maolin Sheng

doi:10.1016/j.tranon.2026.102682

POSTN⁺ cancer-associated fibroblast-CCL3⁺ macrophage crosstalk defines the immune-excluded tumor microenvironment in clear cell renal cell carcinoma

Transl Oncol. 2026 Mar:65:102682. doi: 10.1016/j.tranon.2026.102682. Epub 2026 Jan 24.

Authors

Yingjian Wang¹, Bingtong Yue², Hongqiang Ni³, Jinchun Chen³, Run Shi⁴, Zhe Wang⁵, Xinglai Dai⁶, Maolin Sheng⁷

Affiliations

¹ Surgical Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing, China; Department of Urology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan 450052, China.
² Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
³ Surgical Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing, China.
⁴ Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁵ Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan 450052, China.
⁶ Department of Urology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, Henan 450052, China.
⁷ Surgical Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing, China. Electronic address: shengmaolinsy@sina.com.

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) frequently exhibits an immune-excluded tumor microenvironment (TME) that limits the efficacy of immune checkpoint blockade (ICB). However, the stromal-immune interactions responsible for this exclusion remain poorly understood.

Methods: We integrated eight single-cell RNA sequencing datasets, two spatial transcriptomic datasets, and bulk transcriptomic cohorts to construct a comprehensive ccRCC TME atlas. Fibroblast subsets were characterized using clustering, trajectory, transcription-factor regulon, and gene-network analyses. Stromal-immune signaling was assessed using CellChat and NicheNet, and spatial colocalization patterns were validated by SpaGene analysis. Prognostic and therapeutic relevance were evaluated in TCGA-KIRC and ICB-treated cohorts.

Results: Seven fibroblast subtypes were identified, among which periostin (POSTN)-positive cancer-associated fibroblasts (CAFs) were selectively enriched in tumors and exhibited strong activation of TGF-β, PI3K-AKT, and extracellular-matrix pathways. Trajectory and regulon inference revealed GATA6 as a key transcriptional regulator driving fibroblast differentiation toward this ECM-remodeling phenotype. Spatial analyses demonstrated that POSTN⁺ CAFs colocalized with CCL3-positive macrophages at the invasive front, forming a hypoxic, fibrotic niche that excluded CD8⁺ T cells. Ligand-receptor mapping identified reciprocal TGF-β, SPP1, and IL-6 signaling that reinforced fibro-myeloid activation. Activation of the POSTN⁺ CAF-CCL3⁺ macrophage axis correlated with poor survival and reduced response to ICB therapy.

Conclusions: This study defines a spatially organized stromal-immune signaling axis that drives immune exclusion and immunotherapy resistance in ccRCC. Targeting the POSTN⁺ CAF-CCL3⁺ macrophage interaction offers a promising strategy to remodel the fibrotic barrier and restore antitumor immunity.

Keywords: Clear cell renal carcinoma; Fibroblast; Immunotherapy; Macrophage; Periostin; Spatial transcriptomics; Tumor microenvironment.