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

  • Cell Rep. 2023 Oct 5;42(10):113213. doi: 10.1016/j.celrep.2023.113213.
Yingqi Liu  1 ,  Xuemei Yao  1 ,  Youbo Zhao  1 ,  De Fang  1 ,  Lei Shi  1 ,  Li Yang  2 ,  Guanbin Song  2 ,  Kaiyong Cai  2 ,  Liqi Li  3 ,  Qin Deng  4 ,  Menghuan Li  5 ,  Zhong Luo  6
Affiliations
  • 1. School of Life Science, Chongqing University, Chongqing 400044, P.R. China.
  • 2. Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University, Chongqing 400044, P.R. China.
  • 3. Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P.R. China.
  • 4. Analytical and Testing Center, Chongqing University, Chongqing 400044, P.R. China.
  • 5. School of Life Science, Chongqing University, Chongqing 400044, P.R. China. Electronic address: [email protected].
  • 6. School of Life Science, Chongqing University, Chongqing 400044, P.R. China; 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, P.R. China. Electronic address: [email protected].
PMID: 37804510 DOI: 10.1016/j.celrep.2023.113213
Abstract

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.

Keywords
CP: Cancer; CP: Immunology; ECM stiffness; ROCK-myosin IIA-F-actin axis; TRIM14 protein; cGAS signaling; tumor immunity.
Products
Inhibitors & Agonists
Other Products