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.

Introduction

Mechano-transduction is the process by which cells convert mechanical signals into biochemical cues that modulate cellular functions. In altered tissue mechanics, changes occur in mechano-transduction components like adhesion molecules, ion channels, and cytoskeletal proteins^[1,2]. Diseases such as atherosclerosis, pulmonary fibrosis, and peritumoral environments show increased tissue stiffness^[3,4], while others like abscesses and necrotic tumor cores exhibit softening^[5]. During carcinogenesis, changes in cell stiffness, adhesion, and tension affect tumor infiltration and metastasis^[2,6-10]. Understanding how these biophysical signals impact immune cell activation could offer insights for cancer treatments.

Immunotherapy, while changing the outlook of cancer treatment, still faces many difficulties in the clinic. Recent studies suggest that mechanical abnormalities may be a key factor in the efficacy of immunotherapy,^[11] and therefore, they may represent a new direction for enhancing the efficacy of immunotherapy. In this review, we will discuss the mechanical forces present in the tumor microenvironment and their relation to tumor immune escape. In addition, we detail how the relevant mechanical force signaling pathways regulate immune cells in the tumor microenvironment and propose the use of mechano-immunoengineering systems to regulate and explore the function of immune cells to provide new ideas for cancer immunotherapeutic approaches.

Mechanical forces in the tumor microenvironment

The tumor microenvironment (TME) is a complex ecosystem comprising immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, and the extracellular matrix (ECM). These components vary by tissue type and evolve alongside tumor development^[12-14]. Recent research indicates that, in addition to biochemical cues, physical signals significantly affect cellular behavior, including proliferation and metastasis^[15]. Key physical signals in tumors include increased stromal stiffness, solid stress, and interstitial fluid pressure. These forces interact synergistically during cancer initiation and progression, collectively influencing tumor development rather than acting in isolation^[16,17].

ECM remodeling and stiffening are hallmarks of solid tumors and have been used to detect various cancer types^[18]. Tumor ECM stiffening results from excessive ECM protein and enzyme activity, leading to collagen cross-linking and matrix reorganization^[19]. During tumorigenesis, solid stresses accumulate, and tumor growth under compressive stress can impact cancer cell proliferation and compress surrounding blood and lymphatic vessels^[20]. Additionally, fluid stresses, including microvascular and interstitial pressures, as well as shear forces from blood, lymph, and interstitial flow, affect the ECM and cancer cells. Even low levels of sustained fluid shear stress can influence epithelial cell adhesion in ovarian cancer progression^[21]. Overall, solid and fluid stresses in the TME can drive cell motility and promote tumorigenesis.

Solid tumor microenvironments are typically stiffer than healthy tissues due to abnormal ECM characteristics, with tumor progression often correlating with increased mechanical rigidity^[22]. ECM stiffness can impede cell movement and suppress immune responses^[23]. The collagen-rich, fibrous ECM surrounding tumors also hinder T-cell migration and limit their dispersal from the tumor mass^[24], with studies showing that high-collagen-density breast cancer tissues have fewer infiltrating T cells^[25]. Despite the rigid ECM, tumor cells within solid tumors are usually softer and more mechanically heterogeneous than healthy cells^[5]. As tumors are mechanically constrained by surrounding tissues, they shift from a proliferative to a metastatic phenotype, with metastatic cells displaying distinct mechanical traits – some become stiffer to cross the basement membrane, while others soften to move through gaps in the ECM^[26,27].

Few studies have investigated the response of tumor-infiltrating immune cells to the heterogeneous mechanical environment present within the tumor. However, evidence suggests that cytotoxic T cells are more effective at killing tumors when the tumor cells become mechanically stiff. This is because mechanically stiff tumor cell membranes are more prone to stretching and are more vulnerable to perforation by T cells^[28]. This difference in the ability to kill tumor cells may promote surviving cells capable of repopulating the tumor^[29]. Further research is needed to examine whether therapeutic modifications of the ECM impact tumor stiffness and related immune responses, with the potential to enhance clinical outcomes. Furthermore, mechanical stress has different effects on monocytes, macrophages, and dendritic cells themselves^[30-34]. Monocytes subjected to fluid forces during their migration to tissues exhibit enhanced adhesion, activation of CD11b integrins, enhanced phagocytosis, and increased secretion of pro-inflammatory cytokines. After entering tissues and differentiating into macrophages, macrophages are sensitive to the hardness of their phagocytic targets, which is triggered through Fcγ receptors, which in turn triggers integrin localization to the phagocytic cup, prompting the completion of the phagocytic process. Dendritic cells (DCs) are stimulated by shear stress to increase the expression of MHC I and CD86 and to enhance the functions of adherence and migration, and the high-hardness environment after entering tissues promotes the maturation of DCs and reduces the concentration threshold of antigen required for their activation of T cells. A harder matrix environment induces aggregation of DNAX-associated protein 10, which forms a complex with NKG2D and activates NK cell signaling. The hard matrix environment induces BCR aggregation, which elevates the affinity of B cells for antigen, resulting in the formation of more receptor microclusters and enhanced B cell activation. In conclusion, tumor development and therapeutic efficacy are closely related to the mechanical properties of ECM. Taking advantage of the mechanical properties of tumor cells and immune cells may be beneficial in the development of oncology therapeutic strategies; e.g. “softening” tumor cells and “stiffening” immune cells may improve therapeutic efficacy.

Tumor mechanical stress and tumor biology

Studies have made significant strides in reducing cancer cell metastasis and growth through various therapies^[35-39]. Immunotherapies, such as immune checkpoint inhibitors (ICIs), and adoptive cell transfer (ACT) have also greatly impacted cancer treatment^[40-49]. In addition, vaccines have not only shown remarkable results in the prevention and control of infectious diseases^[50,51] but also play a pivotal role in the immunotherapy of tumors^[52]. However, resistance to immunotherapy remains a major challenge, largely due to cancer cells’ ability to evade immune responses. Understanding and targeting these immune evasion mechanisms could improve treatment outcomes. Notably, processes like autophagy and epithelial-mesenchymal transition (EMT) are key to immune evasion^[53], and both are induced by mechanical stresses, including fluid shear and solid stress (Fig. 1).

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.

Fluid shear stress and solid stress induce autophagy

Shear stress is the tangential force exerted on the walls of blood vessels or cell surfaces during blood or fluid flow. It can be categorized into different types based on magnitude, direction, and temporal changes, such as laminar shear stress, oscillatory shear stress, and low shear stress. Solid stresses in organisms are mechanical stresses caused by physical contact, compression, or deformation between solid tissues or cells.

Fluid shear stress and solid stress are closely associated with tumorigenesis, invasion, and autophagy induction. In certain cancer cells, mechanical stress triggers autophagy as a survival mechanism. For example, lipid rafts act as mechanosensors^[54], facilitating protective autophagy in HeLa cells under physiological shear stress (20 dyn/cm²)^[55]. Even low shear stress (~1-2 dyn/cm²) enhances autophagic flux; specifically, shear stress of 1-1.4 dyn/cm² activates the integrin/cytoskeleton pathway in HCC cells, leading to cytoskeletal reorganization and autophagosome formation^[56,57]. While shear stress-induced autophagy is known to promote cell migration and invasion, its effects on immune response are less understood. Therefore, further research is needed to explore the relationship between shear stress and autophagy-mediated immune evasion.

Similar to shear stress, solid stress also stimulates autophagy. As tumors progress, mechanical pressure builds within the tumor and surrounding tissues due to increased cellular and ECM density, such as collagen. Studies show that solid stress in human tumors can range from 0.21 kPa to 19.0 kPa, with higher levels in cancers like pancreatic cancer characterized by dense connective tissue^[58]. This solid stress compresses blood and lymphatic vessels, restricting oxygen and nutrient transport while raising interstitial fluid pressure^[59]. Importantly, reduced oxygen delivery leads to hypoxia, which activates intracellular autophagy and aids in cancer cell survival^[60,61]. Additionally, solid stress may directly induce autophagy.

Overall, shear stress and solid stress play key roles in regulating cellular autophagy, and different levels of shear stress and solid stress have different effects on autophagy through various types of mechanical force sensing pathways^[62,63]. Laminar shear stress usually promotes cellular autophagy and the maintenance of cellular homeostasis^[64], whereas oscillatory shear stress and low shear stress may inhibit cellular autophagy, leading to cellular dysfunction and disease development^[65]. In addition, solid stress has a dual effect on autophagy^[66]. Moderate solid stress promotes the autophagic response and contributes to the maintenance of cellular homeostasis and enhancement of adaptation, whereas excessive solid stress may inhibit or aberrantize the autophagic process and cause damage to cells. However, the specific details of these influencing mechanisms still need further in-depth studies. Future studies should focus on the response mechanisms of different cell types to shear stress and solid stress under specific physiopathological conditions and how to intervene in the occurrence and development of related diseases, such as cancer and cardiovascular diseases, by regulating shear stress and solid stress.

Fluid shear stress and solid stress facilitate the activation of EMT

Mechanical stress on tumors can also increase the invasiveness and metastatic potential of cancer cells by inducing EMT. Studies have shown that when Hep-2 cells are exposed to a shear stress of 1.4 dyn/cm², they adopt a mesenchymal-like phenotype, which reverts upon the removal of stress^[67]. Shear stress has been demonstrated to activate EMT, enhancing metastasis by triggering the YAP pathway. Furthermore, shear stress can induce EMT in circulating tumor cells (CTCs), thereby promoting their survival in the bloodstream^[68].

Solid stress can directly or indirectly induce EMT in cancer cells. Like autophagy, solid stress-induced hypoxia can activate key transcriptional regulators of EMT. Under hypoxic conditions, the activation of hypoxia-inducible factor-1 alpha (HIF-1α) promotes EMT by regulating TWIST, a crucial transcriptional regulator of EMT^[69]. Solid stress, combined with IL-6 secreted by CD4 + T cells, mediates EMT activation in clear cell renal cell carcinoma (ccRCC) cells via the Akt/GSK-3β/β-catenin signaling pathway^[70]. Moreover, the responses of different cell types to solid stress are associated with their specific signaling pathways. For example, signaling molecules such as E-cadherin, β-catenin, etc., may exhibit different expressions or activity when regulated by solid stress in epithelial cells, thus affecting the EMT process^[71]. And in fibroblasts or tumor cells, activation of pathways such as YAP/TAZ, FAK^[72,73], etc., may exhibit different sensitivities in response to mechanical stress, leading to different degrees of EMT activation. In summary, while shear stress and solid stress are significant mediators of EMT, the precise mechanisms by which the immune response promotes cancer cell survival remain unclear due to the lack of direct mechanistic studies.

Tumor mechanical stress induces immune escape

Mechanical abnormalities may contribute to poor immunotherapy responses, making them potential therapeutic targets. Malignant cells are often weaker than non-malignant cells due to higher cholesterol levels in their membranes^[74]. Reducing cholesterol stiffens the ECM, enhancing cytotoxic T lymphocyte (CTL) efficacy and improving adoptive cell transfer (ACT) outcomes in mice. This soft ECM acts as a “mechanical immune checkpoint,” enabling cancer cells to evade immune surveillance. Similarly, reducing solid stress has improved immune checkpoint blockade (ICB) therapy in ICB-resistant metastatic breast cancer models^[75]. Angiotensin receptor blockers reduce solid stress by inhibiting fibroblast activation, promoting T-cell function, and reducing immunosuppression, thus overcoming immunotherapy resistance^[75]. FAK inhibitors also reduce solid stress by depleting the stroma, enhancing PD-1 immunotherapy responses in mouse models^[76]. Since cancer cells exhibit strong contraction on the ECM, macrophages can effectively target CRC cells with low metastatic potential, whereas cancer cells with high metastatic potential exhibit weak contraction on the ECM, thus evading macrophage attack and achieving immune escape^[77]. Mechanical properties like stiffness and viscoelasticity may further promote tumor immune escape^[78], but direct evidence linking mechanical stress^[79] to immune escape and its effect on immunotherapy remains limited.

The response of cancer cells to these stresses can aid in evading other immune detection mechanisms (Fig. 1). For instance, it has been demonstrated that MDA-MB-231 and BT-474 breast cancer cells, but not MCF-7 and SK-BR-3 breast cancer cells, overexpress VEGF-A due to compression force-induced downregulation of microRNA-9 (miR-9)^[80]. VEGF-A increased the expression of PD-1 in VEGFR + and CD8 + T cells, thereby demonstrating its capability to suppress anti-tumor immune responses^[81,82]. Furthermore, the application of shear stress has been shown to upregulate PLAU in breast cancer cells and activate YAP in breast and prostate cancer cells^[83,84]. Both PLAU and YAP activation have been linked to the promotion of an immunosuppressive environment. Additionally, YAP plays a role in promoting the recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs)^[85-87]. Overall, the findings from these studies suggest a connection between tumor mechanical stress and immune escape.

Mechanosensing pathways in cells

To explore the link between tumor mechanical stress and immune escape, it is essential to understand how immune cells sense external forces. Cells within tissues are subjected to various mechanical forces such as tension, compression, shear, and interstitial flow^[6,88,89]. The physical properties of the surrounding tissue, including matrix stiffness and structure, generate mechanical signals that influence cell behavior^[90,91]. Evolutionarily conserved signaling pathways allow immune cells to detect these matrix changes through mechanosensors. Immune cells not only experience these external forces but also actively respond to them, applying reciprocal or superimposed forces on the stroma and nearby cells.

Mechanical signals sensed by immune cells

Immune cells are exposed to various mechanical signals. Tensile and compressive forces stretch or compress cells, triggering cytoskeletal rearrangements and interactions between extracellular components^[90,92]. Shear forces act tangentially on cells at fluid interfaces^[93], while interstitial fluid flow refers to plasma moving through the extracellular matrix into lymphatics^[94]. Tissue biophysical properties (Fig. 2), primarily shaped by the ECM, determine how these forces affect immune cells^[95]. Tissue stiffness, measured by the modulus of elasticity, reflects resistance to deformation. While soft tissues typically have stiffness below 10 kPa, conditions like fibrosis can raise it above 20 kPa^[96-98].

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.

Immune cells sense and respond to mechanical signals through pathways involving mechanosensors such as integrins, TRPV4, PIEZO channels, and cytoskeletal components^[99-101] (Fig. 3). These pathways regulate Ca²⁺ flow, cytoskeletal reorganization, and transcription. External forces are transmitted to the nucleus via the cytoskeleton and LINC complex, affecting chromatin organization and gene expression^[102-106]. Actin filaments at adhesion sites drive morphological changes through polymerization and myosin contraction, regulated by Rho GTPases^[107-112]. Key transcriptional regulators include SRF, MRTFA, YAP, and TAZ.

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.

Mechanotransduction in immune cells

The biophysical signals can affect immune cell function and responses. Immune cells, being adhesive and contact-dependent, are sensitive to mechanical stimuli, such as changes in extracellular matrix stiffness. Macrophages, for example, respond to substrate stiffness, which influences functions like phagocytosis^[113,114], migration^[113], ROS production^[115], healing^[116], morphology^[117], and cytokine secretion^{[114,116,118,119]}. Macrophages on rigid substrates show stronger effector functions and produce more pro-inflammatory cytokines, such as TNF and IL-6, compared to those on softer substrates, which produce less IL-10 in response to LPS^{[114,116,118]}. Similarly, dendritic cells on stiff substrates release more pro-inflammatory cytokines and promote greater cell activation following LPS exposure^[120]. Inflammation in the tumor microenvironment promotes the differentiation of stromal cells into activated fibroblasts, which express more alpha-smooth muscle actin and collagen, contributing to tissue sclerosis. This stiffening impedes chemotherapy diffusion and immune cell infiltration, a key factor in cancer progression^[30].

Mechanosensing in immune cells involves detecting various mechanical stimuli, not just changes in tissue stiffness. In the circulatory system, monocytes respond to fluid shear by enhancing adhesion, phagocytosis, and secretion of pro-inflammatory cytokines^[121]. Neutrophils also show increased phagocytosis and activation under shear, with higher platelet-neutrophil aggregation and cytoplasmic Ca²⁺ levels^[122]. Similarly, macrophages display pro-inflammatory effects under cyclic hydrostatic pressure^[96]. These findings underscore the role of mechanical signals in modulating innate immune cell functions and influencing inflammation. Additionally, innate immune pathways can trigger broad immune responses and reprogram immunosuppressive cells to regain anti-tumor potential, offering therapeutic strategies to counteract the suppressive tumor microenvironment^[123].

Adaptive immune cells also respond to mechanical signals. T cells are influenced by the stiffness of DCs, with “hard” DCs requiring lower antigen concentrations for activation than “soft” DCs^[124,125]. Increased cytoskeletal stiffness in DCs enhances T cell activation^[125]. Stromal stiffness affects T-cell behavior, including spreading, migration^[126,127], gene expression, proliferation^[128], and cytotoxicity^[29]. A stiffer environment boosts T-cell proliferation and activation while lowering the antigen dose required for an effector response^[97]. B cells similarly sense mechanical cues, with substrate stiffness influencing B cell receptor aggregation, antigen uptake^[129], proliferation, and antibody production^[130]. Stiffened B cells may lose normal functions, contributing to immune suppression, tumor immune escape, and progression through abnormal cytokine production and altered tumor microenvironment interactions.

Biophysical signals and environmental forces are key in immune regulation, particularly through mechanosignaling pathways that impact immune cell activation and function. PIEZO1 and TRPV4, two mechanically gated ion channels, respond to physical stimuli at the plasma membrane, facilitating ion translocation^[131]. PIEZO1 belongs to the Piezo family of cation channels^[132], while TRPV4 is part of the TRP superfamily^[133]. These channels open due to mechanical membrane deformation, and TRPV4 can also respond to osmotic stress, temperature changes, or inflammatory mediators like arachidonic acid and histamine^[134]. Their activation increases Ca²⁺ influx, triggering Ca²⁺-regulated signaling pathways, such as the calmodulin neurophosphatase-NFAT pathway, critical for T-cell activation^[135]. Elevated intracellular Ca²⁺ activates calmodulin neurophosphatase, which dephosphorylates NFAT, allowing its nuclear translocation^[136]. Although PIEZO1-driven Ca²⁺ influx has been shown to activate NFAT in osteoblasts^[137], this mechanism remains unconfirmed in immune cells.

In bone marrow-derived macrophages stimulated by IFN-γ, activation of PIEZO1 channels on a hard matrix increases Ca2 + influx, enhancing NF-κB activation and F-actin formation, promoting an M1 inflammatory macrophage phenotype. While these macrophages also responded to IL-4 and IL-13 with increased arginase 1 (ARG1) expression, PIEZO1 activity on hard substrates suppressed IL-4/IL-13-induced ARG1 expression, indicating that mechanotransduction signaling may override other pathways^[116]. Furthermore, a hard extracellular matrix (ECM) silenced the tumor suppressor RB1 via histone deacetylation, controlling cell expansion and cytokine release in a PIEZO1-dependent manner^[138].

HIF-1α plays a key role in linking PIEZO1 activity to glycolysis-driven inflammatory responses, regulating immune cell metabolism. Activation of PIEZO1 by the agonist YODA1 in mouse dendritic cells induces glycolytic genes such as MYC, HK2, and SLC2A1, enhancing TNF production^[120]. PIEZO1 also mediates shear force-induced inflammation, promoting monocyte adhesion, MAC1 activation, phagocytosis, and pro-inflammatory cytokine release^[121]. Blocking PIEZO1 in T cells improves traction and cytotoxicity against tumors, positioning PIEZO1 as a target for enhancing cancer immunotherapy^[139]. Additionally, PIEZO1 in dendritic cells regulates Th1 and Treg cell differentiation, contributing to tumor growth inhibition^[140]. These findings highlight PIEZO1’s role in immune modulation across various tissue types and disease contexts.

The Hippo pathway, particularly YAP/TAZ, plays a critical role in mechanotransduction, linking mechanical signals like ECM stiffness, cell geometry, and fluid dynamics to cell proliferation, survival, and differentiation^[141]. Dysregulation of this pathway is frequently observed in cancers, with YAP/TAZ acting as oncogenes and MST1/2 and LATS1/2 as tumor suppressors. Hippo pathway dysregulation is linked to cancers such as uveal melanoma and meningiomas, impacting tumor progression, metastasis, and drug resistance^[142]. Furthermore, the pathway influences immunotherapy resistance by regulating immunosuppressive cells, like myeloid-derived suppressor cells and tumor-associated macrophages, through cytokines CXCL5 and CCL2^[142]. These insights suggest the Hippo pathway’s involvement in immune tolerance and tumorigenesis, offering potential strategies for overcoming immunotherapeutic resistance.

Mechano-immunoengineering in malignant tumors

Engineered systems are widely used to study how mechanical signals and matrix properties influence cell function, including tissue-level forces on immune cells^[143,144]. These biomaterials, often combined with ECM proteins like collagen or RGD peptides, provide natural adhesion sites for cells^[145]. Advances in biomaterial design aim to more accurately mimic physiological conditions for better exploration of mechanical signaling in cell function. During tumor progression, increased ECM stiffness hampers T-cell infiltration and reduces their antitumor activity^[30]. Softening the ECM has been investigated to improve drug diffusion and enhance therapies like CAR-T cells, though its impact on immune checkpoint blockade and cellular immunotherapy remains to be fully assessed. Combining ECM-targeting with strategies that modulate cellular mechanics may synergistically boost antitumor immune surveillance.

The Hippo signaling pathway involved in mechanotransduction and immune cell responses. Traditionally, this pathway is regulated by cell contact and density^[146]. Mechanical signals activate MST1/MST2 and LATS1/LATS2 kinases, leading to phosphorylation of YAP and TAZ, which are retained in the cytoplasm and degraded via the proteasome^[147,148]. When Hippo kinases are inhibited, YAP and TAZ translocate to the nucleus to drive gene expression by binding TEAD transcription factors^[149]. YAP and TAZ are also translocated in response to ECM stiffness and cell architecture changes^[150], influencing immune cell fate, metabolic reprogramming, and activation. For example, nuclear YAP/TAZ promotes M1-like macrophage activation and IL-6 production while inhibiting M2 polarization^[151]. In melanoma, YAP activation enhances Treg immunosuppressive activity and increases PD-L1 expression^[87,152], impacting T cells, tumor-associated macrophages, and myeloid-derived suppressor cells in the tumor microenvironment^[153].

In adaptive immune cells, YAP and TAZ show similar subcellular localization influenced by matrix stiffness. In T cells, phosphorylated YAP regulates activation by modulating NFAT1’s binding affinity to its scaffolding protein, IQGAP1^[97], under soft ECM conditions, thereby reducing metabolic reprogramming and activation (Fig. 4). In a stiff microenvironment, YAP moves to the nucleus, releasing NFAT1 and inducing metabolic gene expression, suppressing T-cell responses as the environment softens. YAP inhibits glycolysis, mitochondrial respiration, and amino acid uptake^[154]. YAP knockdown enhances CD8 + T cell cytotoxic cytokine production and disrupts Treg cell function by reducing TGFβ-Smad signaling^[87,155]. TAZ, independent of mechanistic signaling, inhibits Treg differentiation by interacting with RORγT and reducing FOXP3 acetylation^[156]. YAP and TAZ remain central to coordinating mechanical signals between innate and adaptive immunity.

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.

Many cells form strong connections to the ECM through integrins, transmembrane receptors composed of α- and β-subunits that interact with ECM proteins^[157]. Integrins cluster to create focal adhesions, which link to the cytoskeleton and activate intracellular signaling pathways through cytoskeletal rearrangements^[158]. Key downstream effectors like FAK and Src regulate pathways involving RhoA, Rac1, and Cdc42, influencing cell motility, survival, and inflammation^[159,160]. Tumor cells, such as glioma and hepatocellular carcinoma, proliferate faster and resist apoptosis on stiffer matrices, which also increases drug resistance^[17].

Integrins are essential for leukocyte migration and exhibit sensitivity to mechanical stimuli, regulating immune cell functions. For example, LFA1 increases its binding affinity to ICAM1 under high matrix stiffness, aiding in dendritic cell maturation and the activation of T and NK cells^[161-163]. Rigid substrates enhance macrophage phagocytosis via integrin CD11b and promote T cell actin polymerization through LFA1, leading to gene expression changes^[164,165]. Additionally, matrix stiffness activates FAK, enhancing B-cell expansion and activation^[166]. While some immune cells can function without integrins, they remain key for mechanosignal transduction in many contexts.

The MRTFA-SRF pathway, linked to mechanotransduction and cytoskeletal dynamics, is crucial for cellular functions. Mechanical stimulation leads to actin polymerization, releasing MRTFA from G-actin, allowing it to translocate to the nucleus and activate gene transcription with SRF^[167]. In myeloid cells, this influences migration, phagocytosis, and cytoskeletal gene expression^[168]. In dendritic cells, the pathway regulates cell cycle, adhesion, and lipid metabolism, with MRTFA deficiency reducing cholesterol metabolism^[165], potentially impairing immune function^[169]. In macrophages, MRTFA-SRF coordinates spatially constrained immunoregulatory signals^[124].

The nuclear LINC complex and nuclear lamina are crucial for mechanotransduction, regulating immune functions like chemotaxis, inflammation, proliferation, and activation. A-type lamins, interacting with the LINC complex, help organize the actin cytoskeleton during T-cell activation and promote ERK1/2 phosphorylation^[170,171], facilitating immune synapse formation. T cells lacking proper LINC-lamin interactions show impaired activation and proliferation. A-type lamins and the LINC complex play key roles in cytoskeletal reorganization and nuclear transcription, highlighting their importance in immune mechanotransduction. Further research is needed to explore these mechanisms in other immune cells.

Intrinsic immune cells activate by sensing danger signals in the tissue environment, linking mechanotransduction to immune function. In disease states, mechanical stress activates mechanosensors in immune cells, allowing them to integrate signals from pattern-recognition receptors and amplify immune responses (Fig. 5). When tension decreases, a dynamic equilibrium restores, raising the threshold for danger signaling and reducing immune activation. This supports a model in which tissue-level mechanotransduction directly regulates intrinsic signaling pathways involved in danger perception.

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.

While this discussion emphasizes direct mechanosensing pathways in immune cells, it is important to note that mesenchymal cells, such as fibroblasts, stromal cells, and endothelial cells, also significantly influence immunity through indirect mechanosensing. These mesenchymal cells typically exhibit more pronounced mechanosensing capabilities. For example, fibroblasts detect ECM mechanics and recruit immune cells like macrophages. In endothelial cells, low shear stress from unidirectional blood flow inhibits YAP and TAZ activity, suppressing pro-inflammatory gene expression and reducing monocyte infiltration. Additionally, TRPV4 regulates the degradation of human fibrocytes by modulating the expression of stretch-induced inflammatory factors, including IL-6, IL-8, COX2, MMP1, and MMP3. Understanding the crosstalk between the stroma and immune system, particularly how mechanical signaling connects these two cell populations, is a vital area for future research.

Immune cells encounter various forces in vivo, such as shear, pressure, and tension, which they convert into biochemical signals influencing their function^[30]. Monocytes, macrophages, dendritic cells, and lymphocytes can sense mechanical forces. Immunotherapies traditionally target biochemical cues, but “mechanical immune engineering” offers new strategies by enhancing immune cell cancer-fighting capabilities through biophysical manipulation. For T cells, passive cues like ECM stiffness can boost cytokine production, while active forces involve T-cell-generated or external mechanical forces. Disruption of these forces impairs T-cell activation^[172]. Innovative methods, such as ultrasound, magnetic forces, photostimulation, and fluid flow, can enhance T-cell activation and immunotherapy effectiveness. However, challenges like microbubble fragility during migration limit in vivo application, necessitating further advancements^[173].

Currently, CAR-T cell therapy suffers from cytokine release syndrome, neurotoxicity, and off-target effects. To mitigate these side effects, methods have been used to inhibit CAR-T cell activity through suicide switches or corticosteroids, which may reduce therapeutic efficacy. The University of California, San Diego, has developed light-controlled CAR-T technology (LINTAD), which utilizes blue light as a switch to precisely control CAR-T cell activation. Studies have shown that light-activated LINTAD CAR-T cells have a significant anti-tumor effect on mice transplanted with cancer cells and that blue light can also penetrate the skin to achieve local control in vivo^[174]. This technology provides a new direction for precision cancer immunotherapy, helping to enhance efficacy and minimize side effects.

In addition, another team of researchers at the University of California, San Diego, developed a new method for activating CAR-T cells using focused ultrasound. They injected modified CAR-T cells into mouse tumors and activated the cells by heating them to 43 ºC with short pulses of ultrasound while avoiding damage to the surrounding tissue. These CAR-T cells carry a gene that expresses the CAR protein only when exposed to heat. In the experiment, CAR-T cells activated by ultrasound only attacked the target tumor, while standard CAR-T cells affected all tissues expressing the target antigen^[175]. This technology effectively solves the problems of precision and safety of CAR-T cells in the treatment of solid tumors and provides a new direction for cancer immunotherapy.

In summary, preclinical trials on mechanical stimulation of immune cells to improve the efficacy of tumor immunotherapy have made some progress and are expected to provide new and effective means for future tumor therapy.

Conclusions and outlook

As tumors progress, changes in tissue mechanics influence immune cell behavior, offering new therapeutic opportunities to enhance immunotherapy. Despite this, the link between tumor mechanical stress, immune cell mechanosensation, and immune evasion remains underexplored. Alterations in the ECM also affect tissue mechanics, making ECM components potential therapeutic targets. While mechanoimmunology is emerging, in vivo measurement of tissue mechanics is still challenging, and many in vitro findings require validation. Advanced technologies like MRI, ultrasound, and AI hold promise for exploring tissue mechanics and informing new therapeutic strategies.

In addition, we can provide a new research direction to overcome immunotherapy resistance of malignant tumors with the help of “mechanical immune engineering system:”

1. Understanding the Mechanical Immune Engineering System: This emerging field explores how immune cells sense mechanical signals and how these signals impact immune responses. It highlights the role of biomechanics in immune regulation and provides a foundation for novel immunotherapies. A deeper understanding of this system can reveal the biomechanical causes of immunotherapy resistance.

2. Mechanisms of Immunotherapy Resistance: Tumor tissues exhibit abnormal mechanical properties, like increased stiffness and altered matrix structure, which can hinder immune cell infiltration and function, contributing to therapy resistance. Immune cells, such as T cells and NK cells, may struggle to recognize and kill tumor cells due to disrupted mechanical sensing.

3. Developing Novel Therapies: Modifying tumor tissue mechanics, enhancing immune cell sensitivity to mechanical cues, and combining these approaches with existing therapies, like checkpoint inhibitors or CAR-T cell therapy, can improve efficacy and overcome resistance.

4. Personalized Treatment: Given tumor heterogeneity and patient variability, mechanical immune engineering enables personalized strategies by tailoring treatments to individual tumor mechanics and immune profiles.

5. Interdisciplinary Collaboration: Advancing this field requires collaboration across biology, medicine, and engineering to drive innovation and improve immunotherapy outcomes.

In conclusion, the mechanical immune engineering system holds promise for developing precise and effective treatments for overcoming tumor immunotherapy resistance.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

This study was funded by the National Natural Science Foundation of China (82103653, 82303258, and 82302873), the Natural Science Foundation of Hunan Province (No. 2022JJ40659, No. 2023JJ40874, and 2022JJ40686), and the Scientific Research Launch Project for new employees of the Second Xiangya Hospital of Central South University (QH20230202).

Author’s contribution

L.Z. and X.Y.D. wrote the main manuscript text and Y.J.G. and X.Y.D prepared Figures 1-5. All authors reviewed the manuscript.

Conflicts of interest disclosures

The authors declare that they have no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Xiangying Deng.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Not applicable.