Xie Wenyan, Yu Xin, Yang Qingxin, Ke Nengwen, Wang Ping, Kong Hao, Wu Xiangji, Ma Panpan, Chen Lang, Yang Jie, Feng Xiuqin, Wang Yuan, Shi Hubing, Chen Lu, Liu Yun-Hua, Ding Bi-Sen, Wei Qiang, Jiang Hong
Sichuan University, China.
Sichuan University, Chengdu, China.
Cancer Discov. 2025 May 9. doi: 10.1158/2159-8290.CD-24-1712.
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.
胰腺导管腺癌（PDAC）的特征是具有纤维化、僵硬的肿瘤微环境（TME），其中肿瘤相关巨噬细胞（TAM）驱动细胞外基质重塑、肿瘤进展和免疫逃逸。机械信号对单核细胞分化为TAM的作用在很大程度上仍未被探索。在这里，我们表明机械力是单核细胞向巨噬细胞分化所必需的。作为一种创新的免疫机械检查点，PYK2实际上控制着这一分化过程。我们证明PYK2通过Piezo1和整合素感知机械信号，触发F-肌动蛋白聚合并转移到细胞核以调节机械转导和分化基因（如ACTR3、RELA）。靶向删除PYK2会损害单核细胞衍生巨噬细胞的分化和极化，重塑PDAC微环境，并增强抗PD-1免疫疗法的疗效。这些发现强调了机械信号在单核细胞分化中的关键作用，并表明靶向PYK2是调节TAM功能和改善PDAC患者免疫治疗结果的一种有前景的策略。
