Immunoreactive Microenvironment Modulator GBP5 Suppresses Ovarian Cancer Progression by Inducing Canonical Pyroptosis.

Abstract

Ovarian cancer has the highest mortality among gynecological malignancies, and exploring effective strategies to reverse the immunosuppressive tumor microenvironment in patients remains a pressing scientific challenge. In this study, we identified a pyroptosis-related protective factor, GBP5, which significantly inhibits the growth of ovarian cancer cells and patient-derived ovarian cancer organoids, impeding the invasion and migration of ovarian cancer cells. Results of immunohistochemistry and external single-cell data verification were consistent. Further research confirmed that GBP5 in ovarian cancer cell can induce canonical pyroptosis through JAK2/STAT1 pathway, thereby restraining the progression of ovarian cancer. Interestingly, in this study, we also discovered that ovarian cancer cells with high GBP5 expression exhibit increased expressions of CXCL9/10/11 in a co-culture assay. Subsequent immune cell infiltration analyses revealed the remodeling of immunosuppressive microenvironment in ovarian cancer patients, characterized by increased infiltration and polarization of M1 macrophages. External immunotherapy database analysis showed profound potential for the application of GBP5 in immunotherapy strategies for ovarian cancer. Overall, our study demonstrates that the protective factor GBP5 significantly inhibits ovarian cancer progression, triggering canonical pyroptosis through the JAK2-STAT1 pathway. Driven by its pro-inflammatory nature, it can also enhance M1 macrophages polarization and reverse immunosuppressive microenvironment, thus providing new insights for ovarian cancer treatment.