An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly fibrotic and stiff tumor, and tumor-associated macrophages (TAMs) are pivotal in driving ECM remodeling, PDAC progression and immune evasion. The contribution of mechanical cues to monocyte differentiation into TAMs remains largely unexplored. Here we show that mechanical force is required for monocyte-to-macrophage differentiation. PYK2, as an innovative immunomechanical checkpoint, de facto governs this differentiation process. We demonstrated that PYK2 responds to mechanical signals within the tumor microenvironment (TME) via Piezo1 and integrins, leading to its activation and subsequent F-actin polymerization. Activated PYK2 then translocates to the nucleus, where it engages with promoters of genes governing mechanotransduction and differentiation, including ACTR3 and RELA. Targeted deletion of PYK2 impairs the differentiation and polarization of monocyte-derived macrophages, reshapes the PDAC microenvironment, and enhances the efficacy of anti-PD-1 immunotherapy. These findings underscore the critical role of mechanical cues in monocyte differentiation and suggest that targeting PYK2 is a promising strategy to modulate TAM function and improve immunotherapy outcomes in patients with PDAC.