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

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

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: menghuanli@cqu.edu.cn.
  • 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: luozhong918@cqu.edu.cn.
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.

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