Mechanotransduction in response to ECM stiffening impairs cGAS immune signaling in tumor cells

• Published in: Cell reports (Cambridge) 2023-10, Vol.42 (10), p.113213-113213, Article 113213
• Main Authors: Liu, Yingqi, Yao, Xuemei, Zhao, Youbo, Fang, De, Shi, Lei, Yang, Li, Song, Guanbin, Cai, Kaiyong, Li, Liqi, Deng, Qin, Li, Menghuan, Luo, Zhong
• Format: Article
• Language: English
• Subjects: cGAS signaling; ECM stiffness; ROCK-myosin IIA-F-actin axis; TRIM14 protein; tumor immunity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113213

The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment. [Display omitted] •ROCK-myosin IIA-F-actin blockade in tumor cells induces DC maturation and CD8 T cell priming•Activating ROCK-myosin IIA-F-actin pathway suppresses cancer-intrinsic cGAS-cGAMP signaling•NMHC-IIA-F-actin stress fibers scavenge TRIM14 to facilitate autophagic degradation of cGAS•Blockade of ROCK-myosin IIA-F-actin potently triggers antitumor immunity Liu et al. report that the stiffened extracellular matrix-mediated ROCK-myosin IIA-F-actin mechanotransduction pathway dampens cancer cell-intrinsic cGAS-dependent immunogenicity, which is due to NMHC-IIA-F-actin stress-fiber-mediated deprivation of the cGAS stabilizer TRIM14. Treatment with specific inhibitors (blebbistatin or simvastatin) triggers potent CD8 T cell-mediated antitumor immunity for tumor elimination in vivo.