MORC2 Recruits Tumor-Associated Macrophages and Inhibits Pyroptosis Through Activating the Wnt/β-Catenin Pathway in Breast Cancer

Breast Cancer (BC), characterized by a high incidence specifically in women, exhibits a complex etiology. This study aims to investigate the role and underlying mechanism of microrchidia CW-type zinc finger 2 (MORC2) in BC progression. MCF-7 and MDA-MB-231 cells with MORC2 knockdown were utilized to investigate the impact of MORC2 on BC. To explore the in vivo functions of MORC2, xenograft tumor mouse model was established. In this study, we discovered that MORC2 was significantly upregulated in BC tumor tissues. Consistent with MORC2 functioning as a suppressor of Pyroptosis, MORC2 knockdown enhanced the expression of pyroptosis-related markers (Caspase-1, NLRP3, GSDMD-N, and LDH) and inflammatory factors (IL-18, IL-1β, and TNF-α), while suppressing CCL5, CCL2 levels, and macrophage migration. Furthermore, MORC2 knockdown inhibited tumor growth in vivo, decreased CD68 cell infiltration and M2 markers, and increased the M1/M2 macrophage ratio. TAMs from MORC2-knockdown tumors exhibited reduced immunosuppressive capacity, promoting T cell proliferation and IFN-γ/IL-2 production. Mechanistically, silencing of MORC2 suppressed the Wnt/β-catenin pathway, and Compound 3 f significantly reversed the effects of MORC2 knockdown on Pyroptosis and macrophage recruitment BC. In summary, MORC2 suppresses Pyroptosis and promotes TAMs recruitment in BC; MORC2 knockdown alleviated the progression of BC by reversing these effects, which was mediated by suppressing the Wnt/β-catenin signaling pathway.