PGRN mediates the crosstalk between ovarian cancer cells and CAFs and reshapes tumor immune microenvironment

The tumor microenvironment (TME) serves crucial functions in ovarian cancer progression through complex interactions between tumor cells and stromal cells, particularly cancer-associated fibroblasts (CAFs). However, tumor-stroma interactions in ovarian cancer remain poorly characterized. Here, we identified progranulin (PGRN) as a key TME mediator that promotes crosstalk between tumor cells and CAFs, contributing to an immunosuppressive microenvironment. First, we discovered that PGRN deficiency in tumor cells attenuated malignant phenotypes and orthotopic tumor growth, while also suppressing CAF activation. Conversely, CAF-derived PGRN promoted tumor proliferation and invasion, while fibroblast-specific ablation of PGRN markedly suppressed tumor growth in vivo. Remarkably, PGRN in the TME rejected intratumoral CD8⁺ T cell infiltration, augmented the expression of programmed cell death 1 (PD-1), thereby fostering an immunosuppressive TME. Moreover, in human ovarian cancer tissues, PGRN expression was upregulated and positively correlated with CAFs abundance. High expression of PGRN correlated with poor overall survival in human ovarian cancer. Collectively, these findings highlight PGRN as a vital regulator of tumor-CAF interactions and a promising target for TME-directed therapies in ovarian cancer, emphasizing its therapeutic potential for clinical translation.