Tumor cell-derived CTSZ mediates macrophage recruitment and M2 polarization to promote castration-resistant prostate cancer progression through the TRA2A/IL-32/ITGA5 axis
Castration-resistant prostate cancer (CRPC) is a lethal stage of prostate cancer after androgen deprivation therapy (ADT). However, most studies have focused on the autonomous alterations of CRPC cells, and the specific contribution of CRPC cells to the metastatic microenvironment remains less well understood. Here, we report that cathepsin Z (CTSZ) was overexpressed in CRPC cells, enhancing macrophage infiltration and promoting M2 polarization, ultimately leading  to the metastasis of CRPC. Mechanistically, CTSZ facilitates the maturation of IL-32 mRNA by directly degrading the alternative splicing factor TRA2A in CRPC cells, thereby increasing the secretion of IL-32. Subsequently, elevated IL-32 directly binds to ITGA5 in macrophages and activates the PI3K/AKT/mTOR pathway in macrophages, thus promoting the recruitment and polarization of macrophages. Furthermore, treatment with an ITGA5 inhibitor blocked the effect of CTSZ overexpression and suppressed CRPC development. These findings uncover a novel mechanism wherein CTSZ involvement in cell?cell interactions within the tumor microenvironment contributes to the progression of CRPC and provide new therapeutic strategies for CRPC. Overall design: To investigate the mechanism of CTSZ regulating cytokine secretion in prostate cancer cells, we established a stable knockdown of CTSZ in PC3 cells using shRNA. Subsequently, we collected RNA from the experimental and control groups. Compare gene expression profile analysis in the RNA-seq data.