2. Academic Validation
  3. The extracellular-matrix-remodeling capability exposes therapeutic vulnerability in a subset of renal cell carcinomas with tumor thrombi

The extracellular-matrix-remodeling capability exposes therapeutic vulnerability in a subset of renal cell carcinomas with tumor thrombi

  • Dev Cell. 2025 Aug 5:S1534-5807(25)00448-4. doi: 10.1016/j.devcel.2025.07.010.
Qi Zhang 1,  Yezhen Tan 1,  Qiyang Liang 2,  Liangyou Gu 3,  Yue Shi 4,  Yan Huang 3,  Xiubin Li 3,  Jie Qi 5,  Cheng Peng 3,  Hanfeng Wang 3,  Yaohui Wang 3,  Kan Liu 3,  Tianwei Cai 2,  Yudan He 1,  Qingbo Huang 3,  Xu Zhang 6,  Baojun Wang 7,  Xin Ma 8,  Weimin Ci 9
Affiliations

Affiliations

  • 1 China National Center for Bioinformation, Beijing 100101, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Department of Urology, Chinese PLA General Hospital, Beijing 100039, China; Medical School of Chinese PLA, Beijing 100853, China.
  • 3 Department of Urology, Chinese PLA General Hospital, Beijing 100039, China.
  • 4 China National Center for Bioinformation, Beijing 100101, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 China National Center for Bioinformation, Beijing 100101, China; Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 6 Department of Urology, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: xzhang301@163.com.
  • 7 Department of Urology, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: baojun40009@126.com.
  • 8 Department of Urology, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: mxin301@126.com.
  • 9 Department of Urology, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: ciwm@foxmail.com.
PMID: 40774251 DOI: 10.1016/j.devcel.2025.07.010
Abstract

Preoperative downstaging of renal cell carcinoma with a tumor thrombus (RCC-TT) makes thrombectomy feasible. However, treatment resistance is common and may partly be attributed to the tumor-promoting role of the tumor microenvironment (TME). Herein, we sequenced, integrated, and comprehensively analyzed multi-center, multi-omics data from 164 RCC-TT patients and identified two clinically relevant RCC-TT subtypes. We find that the poor-prognosis subtype (TT1) exhibits enhanced extracellular-matrix (ECM) remodeling driven by epithelial LOX expression. Spatial transcriptomics (ST) shows the co-localization of GPNMB+ macrophages, THBS2+ fibroblasts, and LOX+ malignant cells around tumor nests in TT1 tumors, reinforcing tumor immune barriers (TIBs). Our extensive validations using cell lines, syngeneic mouse models, multiplex immunofluorescence staining, and large-scale RCC cohorts underscore the potential of LOX inhibition in disrupting TIBs, sensitizing RCC to immunotherapy, and overcoming treatment-induced phenotypic plasticity. This study provides insights into the biological underpinnings and prognosis assessment of RCC-TT, demonstrating targetable ECM-remodeling vulnerabilities.

Keywords

extracellular matrix; phenotypic plasticity; renal cell carcinoma with tumor thrombus; tumor immune barrier.

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