Progranulin and Inflammation‐Induced Cancer: An Important Player in the Tumor Microenvironment?

Progranulin (PGRN) is a multifunctional glycoprotein recognized as a key regulator at the intersection of tumor progression and inflammation. Originally described as a mitogenicgrowth factor within the tumor. PGRN is now known to exert a broad spectrum of biological effects within the tumor microenvironment (TME), where it functions as both an oncogenic driver and an immunomodulatory molecule. Beyond its capacity to promote tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT). PGRN critically shapes the inflammatory and stromal landscape that sustains tumor growth. This review aims to comprehensively summarize current knowledge on the multifaceted roles of PGRN within the TME, with a particular focus on its functions in immune and stromal cells that contribute to tumor progression and immune evasion. In fact, it reprograms TME toward an immunosuppressive state by activating signaling pathways such as TNFR2/STAT3 and PI3K/AKT. It promotes M2-like macrophage polarization, enhances PD-L1 expression, supports regulatory T-cell stability, and suppresses CD8⁺ T- and NK-cell cytotoxicity, and fosters immune evasion. Simultaneously, PGRN affects stromal components by activating cancer-associated fibroblasts (CAFs), remodeling the extracellular matrix, and stimulating angiogenesis. These coordinated actions position PGRN as a central orchestrator of tumor-associated inflammation. Despite these insights, its roles in myeloid-derived suppressor cells, neutrophils, and other stromal subsets remain poorly understood. Therefore, investigating PGRN's influence on these cells is crucial for understanding tumor progression and therapeutic resistance and may reveal novel strategies to disrupt PGRN-dependent inflammatory circuits and enhance anti-tumor immunity.