An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer
Menée in vitro et à l'aide de modèles murins d'adénocarcinomes canalaires du pancréas ainsi que d'échantillons tumoraux et d'échantillons tissulaires adjacents prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel la kinase PYK2 favorise la différenciation des monocytes en macrophages associés à la tumeur
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic, stiff tumor microenvironment (TME), where tumor-associated macrophages (TAMs) drive ECM remodeling, 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 senses mechanical signals via Piezo1 and integrins, triggering F-actin polymerization and translocating to the nucleus to regulate mechanotransduction and differentiation genes (e.g., ACTR3, 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.
Cancer Discovery , résumé 2025