Osteopontin Derived from PDE12-Driven Tumor Cells Contributes to the Immunosuppressive Niche via Triggering Inflammatory Cytokine-enriched Tumor- associated Macrophages in intrahepatic Cholangiocarcinoma

This data is the original dataset for Osteopontin Derived from PDE12-Driven Tumor Cells Contributes to the Immunosuppressive Niche via Triggering Inflammatory Cytokine-enriched Tumor- associated Macrophages in intrahepatic Cholangiocarcinoma. The complex intratumoral immune status is an important feature of intrahepatic cholangiocarcinoma（ICC）that has been closely connected with poor Immunotherapy response. Phosphodiesterase12 (PDE12) is identified as a significant target involved in negatively regulating the immune response, whereas its regulatory mechanism and roles in neoplasm progression remain indistinct. Herein, we show that PDE12 fuels ICC tumor growth by constructing an intratumoral immunosuppressive microenvironment (TIME). Mechanistically, the residue K377 of PDE12, competitively succinylation and de-succinylation modified by OGDH and SIRT7, is essential for its proteolytic activity. Osteopontin (OPN/SPP1), secreted by PDE12-driven ICC cells, mobilizes externalization of ANXA1 on the membrane of macrophages and accumulates inflammatory cytokine-enriched tumor- associated macrophages (Inflam-TAMs), which are responsible for the tumor-promoting effects. Underscoring the translational potential of the PDE12-SPP1-ANXA1 signaling axis, PDE12 inhibitors (PDE12-IN-1) or α-SPP1 both enhance the sensitivity of ICC cells to α-PD1 with improved anti-tumor benefits. Collectively, our findings highlight a link between ICC TIME and PDE12-SPP1-ANXA1 axis, suggesting a potentially valuable biomarker and promising therapy target for further development.