POLE2 of tumor cells promotes OPN secretion based on PCLAF to drive M2 macrophage polarization in clear cell renal cell carcinoma.

The malignant progression of renal cell carcinoma (RCC) is closely associated with the establishment of an immunosuppressive tumor microenvironment (TME). This study aims to elucidate the oncogenic functions of DNA polymerase ε subunit POLE2 in RCC and its mechanism in modulating the tumor immune microenvironment. We found that POLE2 was significantly upregulated in clear cell RCC (ccRCC) tissues and cell lines. Gain-of-function and loss-of-function experiments demonstrated that POLE2 markedly enhanced tumor cell proliferation, migration, and tumorigenicity both in vitro and in vivo. Mechanistically, POLE2 binds to the PCNA-associated factor PCLAF and stabilizes the PCLAF protein by inhibiting its ubiquitin-proteasome-mediated degradation, thereby leading to increased expression and secretion of SPP1/osteopontin (OPN) in tumor cells. OPN acts as a key cytokine that drives macrophage M2 polarization by activating the CD44/integrin receptors on macrophages and their downstream STAT6 signaling pathway. Moreover, we identified the transcription factor NFATc2 as an upstream regulator of POLE2, which directly binds to the POLE2 promoter and activates its transcription. Our study unveils a comprehensive NFATc2/POLE2/PCLAF signaling axis that promotes ccRCC progression via OPN-mediated M2 macrophage polarization, providing a solid rationale and potential therapeutic targets for developing novel immunocombination therapies.