Abstract

Hepatocellular carcinoma (HCC) shows substantial biological heterogeneity and commonly develops within an immunosuppressive microenvironment. Tumor‐associated macrophages (TAMs), particularly M2‐skewed subsets, are repeatedly associated with aggressive disease and may represent a biologically meaningful phenotype for biomarker development. Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been implicated in malignant behavior, but its linkage to TAM polarization and its potential as a laboratory‐interpretable translational readout in HCC remain insufficiently clarified. ENPP2 expression was examined in paired HCC and adjacent tissues and referenced to public cohorts to provide clinical context. ENPP2 was overexpressed or silenced in HCC cells, followed by assays of proliferation, apoptosis, migration, and invasion. Macrophage polarization was evaluated using a noncontact Transwell coculture system with marker assessment and flow‐cytometric readouts. Intracellular cyclic adenosine monophosphate (cAMP) was quantified, and forskolin was used to interrogate pathway involvement. Xenograft experiments were conducted to examine in vivo tumor growth. ENPP2 was upregulated in HCC and showed an association with unfavorable outcomes in public datasets. ENPP2 increased malignant phenotypes in HCC cells and shifted cocultured macrophages toward an M2‐skewed state, whereas ENPP2 suppression produced the opposite pattern. ENPP2 modulation coincided with changes in intracellular cAMP signaling, and forskolin partially attenuated phenotypes observed after ENPP2 knockdown. These findings delineate a novel ENPP2/cAMP signaling axis that directly links tumor‐intrinsic ENPP2 overexpression in HCC cells to the induction of M2‐skewed TAM polarization, a mechanism that has not been previously characterized in HCC. This work not only identifies ENPP2 as a dual regulator of HCC cell malignancy and TAM polarization but also establishes cAMP as the critical intracellular mediator