Focus on mechano-immunology: new direction in cancer treatment

Abstract

The immune response is modulated by a diverse array of signals within the tissue microenvironment, encompassing biochemical factors, mechanical forces, and pressures from adjacent tissues. Furthermore, the extracellular matrix and its constituents significantly influence the function of immune cells. In the case of carcinogenesis, changes in the biophysical properties of tissues can impact the mechanical signals received by immune cells, and these signals c1an be translated into biochemical signals through mechano-transduction pathways. These mechano-transduction pathways have a profound impact on cellular functions, influencing processes such as cell activation, metabolism, proliferation, and migration, etc. Tissue mechanics may undergo temporal changes during the process of carcinogenesis, offering the potential for novel dynamic levels of immune regulation. Here, we review advances in mechanoimmunology in malignancy studies, focusing on how mechanosignals modulate the behaviors of immune cells at the tissue level, thereby triggering an immune response that ultimately influences the development and progression of malignant tumors. Additionally, we have also focused on the development of mechano-immunoengineering systems, with the help of which could help to further understand the response of tumor cells or immune cells to alterations in the microenvironment and may provide new research directions for overcoming immunotherapeutic resistance of malignant tumors.

Figure 1.

Mechanical forces drive tumor progression by inducing EMT and autophagy, leading to immune escape. Solid stress in tumors (compression and stretching) collapses vessels, causing hypoxia and triggering EMT and autophagy via stromal and invasive pathways. Additionally, stress-induced pathways (e.g. VEGF) promote immune suppression by upregulating PD-1 and recruiting Tregs and MDSCs. In circulation, fluid shear stress enhances immune evasion by recruiting MISCs, upregulating PD-L1, and inducing EMT and autophagy through cytoskeletal changes. EMT and autophagy both contribute to immune escape by inhibiting CTL-mediated killing, degrading MHC-I, and upregulating pSTAT3.

Figure 2.

Stiffness in different parts of the human body under normal or pathological conditions. In certain tissues, stiffness increases under pathological conditions or during carcinogenesis, while in others, it decreases.

Figure 3.

Overview of mechanotransduction pathways. Bottom left: The Hippo pathway activation phosphorylates MST1/2 and LATS1/2, leading to YAP and TAZ phosphorylation and sequestration in the cytoplasm. Mechanical force (MF) inhibition of Hippo allows YAP/TAZ nuclear translocation, activating TEAD transcription factors to regulate immune genes, metabolism, proliferation, and inflammation. Bottom right: Integrins anchor cells to the ECM, forming focal adhesions that signal through FAK and SRC, influencing immune cell function, cell shape, and cytoskeletal dynamics. F-actin polymerization reduces G-actin, freeing MRTFA to enter the nucleus, where it partners with SRF to drive gene expression. Top left: The LINC complex links the nuclear scaffold to the cytoskeleton, regulating nuclear morphology, gene expression, and YAP, TAZ, and MRTFA translocation. Top right: Mechanical activation of TRPV4 and Piezo1 channels increases Ca2 + influx, affecting transcription factors, inflammation, and cytoskeleton remodeling.

Figure 4.

Mechanical regulation of T-cell activity by YAP. In soft ECM environments, YAP is phosphorylated and stays in the cytoplasm, binding to IQGAP1 and sequestering NFAT1, which suppresses T-cell metabolism and proliferation. In stiff ECM environments, YAP is dephosphorylated and moves to the nucleus, releasing NFAT1 from the cytoplasm. With help from CRAC channels, calcineurin, and calmodulin, NFAT1 translocates to the nucleus, promoting T-cell activation gene expression.

Figure 5.

Mechanotransduction pathways and natural immune cell activation. Mechanical forces combined with pattern recognition receptor (PRR) stimulation localize Piezo1 with certain toll-like receptors (TLRs). The activation of TRPV4 and Piezo1 triggers Ca²⁺ influx, promoting actin polymerization, Rho GTPase activation, and enhanced phagocytosis. MRTFA enters the nucleus upon F-actin formation, driving the transcription of immune effector genes like IL-6 and CXCL9. Ca²⁺ also boosts TLR signaling by activating EDN1 and NF-κB, stabilizing HIF-1α, and promoting inflammatory gene expression. YAP/TAZ translocates to the nucleus, activating genes involved in glycolysis and inflammation. Piezo1 further induces histone deacetylase (HDAC) activation, contributing to inflammatory cytokine production and tumor progression.