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
  • 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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