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

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.