Myeloid Focal Adhesion Kinase Promotes Macrophage Accumulation but Does Not Alter Tumor Progression in Hepatocellular...

Hepatocellular carcinoma (HCC) develops within an immunologically complex tumor microenvironment that is heavily shaped by infiltrating myeloid cells. Immune-based treatment strategies such as atezolizumab plus bevacizumab have shown promising therapeutic benefits, but patients do not experience durable responses. This shortfall motivates current efforts to elucidate signaling programs that sustain pro-tumor myeloid states. Focal adhesion kinase (FAK, encoded by PTK2) integrates adhesion, growth factor, proliferative, and inflammatory signaling, but the contribution of FAK in myeloid cells to HCC has not been tested. In this study, we used human HCC transcriptomic analyses and a myeloid-specific FAK knockout mouse model to investigate the role of myeloid-intrinsic FAK in HCC progression. Analysis of the PRHCCdb single-cell database showed PTK2 expression was detectable in myeloid populations. Higher PTK2 expression in myeloid-rich TCGA-LIHC tumors was associated with a significantly worse overall survival. Further analysis of the NCI-CLARITY single-cell data set localized the strongest FAK-associated transcriptional programs to a monocyte-derived macrophage state marked by VCAN and COLEC12. Specifically, this population demonstrated hypoxia-associated and inflammatory signatures. To test the functional role of FAK in myeloid cells, we generated myeloid-specific FAK knockout (LysMCre;FAK^f/f) mice. Deletion of FAK did not alter baseline liver morphology, liver-to-body weight ratio, or proliferation. When challenged with the MET/β-catenin-driven HCC model via hydrodynamic tail vein injection, myeloid-specific FAK deletion did not significantly affect survival, gross tumor burden, or tumor proliferation. However, tumors from the LysMCre;FAK^f/f mice showed significantly reduced F4/80⁺ macrophage accumulation compared with FAK^f/f controls. These findings indicate that myeloid-specific FAK promotes macrophage accumulation, but its loss alone is insufficient to alter tumor burden, proliferation, or survival in this oncogene-driven HCC model.