2. Academic Validation
  3. RICH1 enhances pro-inflammatory TAM infiltration in breast cancer via promoting TRIM21-mediated ubiquitination of RhoA and inhibiting STAT3 phosphorylation

RICH1 enhances pro-inflammatory TAM infiltration in breast cancer via promoting TRIM21-mediated ubiquitination of RhoA and inhibiting STAT3 phosphorylation

  • NPJ Precis Oncol. 2025 Dec 23. doi: 10.1038/s41698-025-01252-6.
Yan Zhou 1 2 3,  Huan Gao 1 2 3,  Liyu Shan 4,  Lizhe Zhu 5,  Jiao Yang 3 6,  Bo Wang 7,  Juan Zhang 1 2 3,  Ran Ran 3 6,  Qi Tian 8,  Peijun Liu 9,  Jin Yang 10 11 12 13
Affiliations

Affiliations

  • 1 Phase I Clinical Trial Ward, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Cancer Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 4 Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, China.
  • 5 Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 6 Department of Medical Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 7 Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 8 Department of Radiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 9 Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 10 Phase I Clinical Trial Ward, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 11 Cancer Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 12 Precision Medicine Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 13 Department of Medical Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
PMID: 41436617 DOI: 10.1038/s41698-025-01252-6
Abstract

Immunotherapy has emerged as an effective treatment for breast Cancer, making the exploration of novel immune-related biomarkers of paramount importance. A vital aspect of this exploration is the investigation into the subtyping of tumor-associated macrophages (TAMs). While polarity proteins within TAMs can shift their functional status, the impact of polarity proteins on inflammation-related signaling in tumor cells and their subsequent influence on the tumor microenvironment (TME) remains elucidated. We discovered that RICH1, functioning as a tumor suppressor molecule in breast Cancer, significantly increased the infiltration of pro-inflammatory M1-like TAMs within TME in 4T1 tumor-bearing mice. Furthermore, the conditioned medium from RICH1-overexpressing 4T1 cells promoted M1-like polarization in vitro by stimulating the secretion of IFN-γ and Other cytokines. Mechanistically, high expression of RICH1 in breast Cancer cells facilitated the ubiquitination degradation of RhoA through binding with TRIM21 and enhancing the interaction between TRIM21-RhoA, thereby inhibited the phosphorylation of STAT3, up-regulated the production and secretion of IFN-γ, consequently induced M1-like polarization of macrophages. Our findings reveal that RICH1 plays a crucial role in promoting pro-inflammatory TAMs infiltration in breast Cancer through modulation of inflammatory signaling. These results suggest that RICH1 could serve as an immune-related biomarker and a key contributor to the formation of immune-active microenvironments, with potential applications in combination immunotherapy strategies.

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