The Dual Role of Piezo1 in Cancer: Mechanotransduction, Microenvironment Remodelling, and Therapeutic Opportunities

Abstract

The mechanosensitive ion channel Piezo1 translates physical cues from the tumor microenvironment—including extracellular matrix stiffness, fluid shear stress, and compressive forces—into intracellular calcium signals and downstream cascades, playing a pivotal role in cancer. Piezo1 exhibits pronounced tumor-type dependency: it acts as an oncogene in multiple solid tumor types (eg, glioma, pancreatic cancer, esophageal squamous cell carcinoma) but exerts tumor-suppressive effects in lung cancer and clear cell renal cell carcinoma. This context-dependent duality poses fundamental challenges for clinical translation. This review systematically dissects the molecular mechanisms by which Piezo1 regulates proliferation, migration, epithelial–mesenchymal transition, cancer stem cell maintenance, and Piezo1-mediated ferroptosis via the TfR1/DMT1/NCOA4/GPX4 axis, which couples iron overload and lipid peroxidation to mechanical cues, is also discussed as a novel therapeutic vulnerability. It further analyzes its role in tumor microenvironment remodelling, including extracellular matrix stiffening, cancer-associated fibroblast activation, angiogenesis, lymphangiogenesis, and metabolic reprogramming. Moreover, the bidirectional immunomodulatory functions of Piezo1 are highlighted: it enhances T cell and natural killer cell antitumor activity but may also promote immunosuppression through regulatory T cells, tumor-associated macrophages, and dendritic cells. Regarding Piezo1-targeted therapies, advances in small-molecule modulators, ultrasound-based physical modulation, nanotechnology, combination regimens, and antibody–drug conjugates are summarized. Five translational bottlenecks are critically appraised: tissue specificity, cancer type-dependent functional differences, limitations of pharmacological tools, clinical translation barriers of mechanical force stimulation and drug resistance and tumor heterogeneity. Finally, future directions are discussed, including structure-guided drug design, organ-on-a-chip screening, CRISPR-based editing, and emerging modalities. As a critical hub linking mechanical cues to tumor biology, precise Piezo1 modulation promises to establish a new “mechanomedicine” paradigm—an emerging field that leverages mechanical force-based diagnostics and therapeutics for disease management. Future efforts should focus on highly selective modulators, patient stratification based on Piezo1 expression and mechanical signatures, and spatiotemporally synergistic strategies combining Piezo1 targeting with chemotherapy, immunotherapy, and metabolic interventions.

Introduction

Notably, tumor development involves not only the accumulation of genetic mutations but also the remodeling of the mechanical microenvironment, manifested by increased extracellular matrix (ECM) stiffness, elevated interstitial fluid pressure, and altered fluid shear stress.1 These abnormal physical signals can be converted into intracellular biochemical signals through mechanotransduction mechanisms, thereby regulating the malignant phenotype of tumor cells. Normal tissues typically exhibit elastic moduli ranging from 0.1 to 10 kPa (eg, brain, breast adipose tissue), whereas tumor tissues often display significantly increased stiffness, ranging from 10 to over 100 kPa (eg, pancreatic ductal adenocarcinoma, hepatocellular carcinoma).2,3 Shear stresses in the tumor microenvironment, particularly in the vascular and interstitial compartments, range from approximately 0.1 to 10 dyn/cm², while compressive forces generated by proliferating tumors can reach up to several hundred mmHg.4 Clinically, targeting the mechanical tumor microenvironment holds particular promise because mechanical abnormalities—such as increased stiffness and interstitial pressure—are associated with poor prognosis, therapy resistance, and immune evasion across multiple cancer types. Unlike genetic mutations, which are often tumor-specific and heterogeneous, mechanical aberrations represent a common and actionable feature of solid malignancies, making mechanosensors such as Piezo1 attractive targets for broad-spectrum therapeutic intervention. Therefore, understanding how cells sense and respond to mechanical signals has become a critical scientific question in elucidating the mechanisms of tumor progression.

Piezo1 was discovered in 2010 as the first identified mammalian mechanically activated, non-selective cation channel.5 Its unique propeller-shaped trimeric structure endows it with high membrane tension sensitivity.6,7 Activation of Piezo1 mediates calcium ion (Ca²⁺) influx, which in turn triggers a cascade of downstream signalling events, playing important roles in vascular development, bone metabolism, immune regulation and tumor progression.8 Importantly, Piezo1 is not only expressed in tumor cells but is also widely distributed in components of the tumor microenvironment (TME), including immune cells, fibroblasts and endothelial cells, where its function exhibits complex, network-like regulatory features.9 It is precisely this broad distribution and functional diversity that positions Piezo1 as a potential core hub linking tumor cells to mechanical signals from their microenvironment. In this review, we focus specifically on Piezo1 rather than the entire Piezo family, owing to its established and mechanistically diverse roles in cancer biology. While Piezo2 has been implicated in certain cancers, the current body of evidence for Piezo1 is substantially more extensive across both solid tumors and hematological malignancies. We therefore primarily discuss solid tumors, with selected examples from hematological cancers (eg, acute myeloid leukemia) where mechanistic data are available.

In recent years, Piezo1 has rapidly become a hotspot in cancer research. Pan-cancer analyses have revealed that Piezo1 is aberrantly expressed in various tumor types, and its expression level is closely correlated with patient prognosis.10 However, it is noteworthy that Piezo1 exhibits complex and even opposing functions across different cancer types and pathological stages—acting as an oncogene to promote malignant progression in some tumors while potentially exerting tumor-suppressive effects in others. For instance, in glioma, pancreatic cancer and esophageal squamous cell carcinoma, high Piezo1 expression is associated with poor prognosis and promotes tumor progression;11–13 conversely, in clear cell renal cell carcinoma and some lung cancer models, Piezo1 expression is downregulated and negatively correlates with malignancy.14,15 This context-dependent nature represents both a frontier issue in basic research and a major challenge for clinical translation. Furthermore, the dual role of Piezo1 in the tumor immune microenvironment—enhancing the antitumor function of natural killer (NK) cells and T cells on one hand, yet potentially promoting immunosuppression by modulating regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) on the other—further adds to the complexity of interpreting its functions.9,16 Consequently, systematically elucidating the functional diversity and underlying molecular mechanisms of Piezo1 across different tumor types and microenvironmental contexts is essential for developing Piezo1-based precision therapeutic strategies.

In this review, we systematically discuss the research progress on Piezo1 in cancer from five interconnected dimensions: (1) structural and molecular basis of mechanotransduction, (2) regulation of malignant phenotypes in tumor cells, (3) multifaceted roles in tumor microenvironment remodelling, (4) bidirectional immunomodulatory functions, and (5) therapeutic strategies, translational challenges, and future directions. By integrating findings from recent studies, we focus on analysing the roles of Piezo1 in regulating the malignant phenotype of tumor cells, remodeling the TME and mediating immune modulation, as well as identifying key scientific questions and technical bottlenecks that need to be addressed in this field. Through this synthesis and outlook of frontier advances, this review aims to provide a systematic reference for both fundamental research and clinical translation of Piezo1, thereby promoting a deeper integration of mechanobiology and oncology.

Unlike previous reviews that focus primarily on Piezo1’s oncogenic functions or its role in a single tumor type, the present review provides a comprehensive synthesis of its context-dependent duality across both tumor-promoting and tumor-suppressive settings. While a recent review by Qu and Zhang9 has broadly discussed Piezo1 in tumor and immune cells, the present work distinguishes itself by: (i) comprehensive integration of mechanotransduction, TME remodelling, immune modulation, and therapeutic translation within a unified framework; (ii) critical evaluation of conflicting findings across cancer types with mechanistic explanations; (iii) detailed discussion of pharmacological tools and emerging modalities including antibody–drug conjugates, PROTACs, and RNA therapeutics; and (iv) systematic identification of five translational bottlenecks and corresponding future strategies. We integrate recent advances in mechanotransduction, tumor microenvironment remodelling, immune modulation, and therapeutic translation—areas that have not been collectively addressed in prior syntheses. By critically evaluating conflicting findings and identifying key translational bottlenecks, this review aims to offer a balanced framework for guiding future mechanistic studies and precision therapeutic strategies. This narrative review was compiled through systematic searches of PubMed, Web of Science, and Scopus databases for articles published between January 2015 and June 2026, using the search terms “Piezo1”, “cancer”, “mechanotransduction”, “tumor microenvironment”, and “therapeutic targeting”. Preprint studies were included only when their findings were subsequently validated in peer-reviewed publications.

Piezo1 Structural Features and the Basis of Mechanotransduction

Piezo1 serves as a central mechanosensor that converts physical forces into biochemical signals. The following sections detail its unique structural basis for mechanosensitivity, its role as a calcium signaling hub, and its intricate crosstalk with other mechanosensitive molecules.

Structure and Mechanosensitivity

Piezo1 is a transmembrane protein composed of 2,547 amino acids that assembles into a homotrimer, adopting a distinctive “three-bladed propeller” or “bowl-shaped” conformation.17 Each subunit contains approximately 30–40 transmembrane domains, which collectively form a central ion-conducting pore. High-resolution structural studies have revealed the detailed architecture of the Piezo1 trimer, including the intricate interplay between the extracellular cap, transmembrane helices, and intracellular beam-like structures that couples force sensing to pore opening.6 This elaborate structural design endows Piezo1 with a remarkable ability to sense changes in membrane tension, with Piezo1 half-maximal activation occurring at approximately 1–3 mN/m (force per unit length)—a threshold that is exquisitely tuned to the physiological range of membrane tension fluctuations. The mechanogating mechanism, as further elucidated by Zhao et al, involves force-induced conformational transitions that propagate through the three subunits to gate the central pore.18 Upon exposure to mechanical stimuli such as shear stress, stretch, compression or alterations in membrane curvature, Piezo1 undergoes conformational changes and opens its pore, allowing the selective passage of cations including Ca²⁺ and Na⁺.19 Of note, Piezo1 not only passively perceives external forces but also actively modulates the cytoskeleton upon its activation. Indeed, Piezo1-mediated Ca²⁺ influx has been shown to regulate actin cytoskeletal remodelling through the RhoA/ROCK1 signalling pathway, thereby influencing cell migration and invasion.20 Furthermore, Piezo1 activation can generate intracellular forces via the Rho–ROCK mechanotransduction pathway, thereby promoting malignant phenotypes in tumors.1 Thus, Piezo1 functions both as a receiver of mechanical signals and as an active regulator of cellular mechanical responses.

The distribution of Piezo1 on the plasma membrane is not random but is precisely controlled by membrane curvature. Studies have revealed that Piezo1 preferentially localises to flat membrane regions and is less abundant on highly curved structures such as filopodia.21 Moreover, the composition and ordered organisation of membrane cholesterol are critical for Piezo1 clustering and function; cholesterol depletion markedly alters the pressure sensitivity of the channel, shifting the pressure–response curve rightwards and significantly slowing channel inactivation kinetics.22 These findings underscore the key role of the lipid microenvironment in fine-tuning Piezo1 function. Piezo2, a homologous mechanosensitive channel with approximately 40% sequence identity to Piezo1, is predominantly expressed in sensory neurons and proprioceptive tissues, where it mediates touch and proprioception.23 Although Piezo2 has also been implicated in certain cancers, the current evidence for Piezo1 in tumor biology is far more extensive. However, the structural and functional similarities between Piezo1 and Piezo2 pose significant challenges for the development of subtype-selective pharmacological modulators, as discussed in Limitations of Pharmacological Tools. Collectively, the unique molecular architecture of Piezo1 and its spatial organisation within the membrane constitute the molecular foundation for its function as an efficient mechanosensory (Figure 1).

Figure 1.

Structural Basis and Mechanotransduction Mechanism of Piezo1. Schematic depicting the homotrimeric, three-bladed propeller architecture of Piezo1. Upon exposure to mechanical cues—including shear stress, membrane stretch, and compressive force—the channel undergoes conformational changes to open its central pore, permitting Ca²⁺ influx. This calcium signal activates downstream effectors such as NFAT, AP-1, and the RhoA/ROCK pathway, which orchestrates actin cytoskeletal remodelling. Beyond functioning as an autonomous mechanosensor, Piezo1 engages in crosstalk with integrin β1, TRPC1/TRPV4, and ORAI1, thereby integrating into a broader mechanotransduction network. Created with BioGDP.com.24

Beyond purely elastic stiffness, the viscoelastic properties of the extracellular matrix—including stress relaxation, creep, and loss modulus—have emerged as critical determinants of Piezo1 mechanotransduction. Unlike elastic materials that store and release energy instantaneously, viscoelastic matrices exhibit time-dependent mechanical behavior, meaning that cells experience not only the magnitude of stiffness but also the rate at which forces are applied and dissipated. Recent studies have demonstrated that soft but highly viscous matrices can elicit Piezo1 activation comparable to stiff elastic substrates, suggesting that the temporal dynamics of force application (the “mechanical rate”) are as important as the absolute stiffness value. For example, Matrongolo et al showed that Piezo1-mediated cerebrospinal fluid flow regulation depends on both the amplitude and frequency of mechanical stimuli.25 These findings have profound implications for cancer biology, as tumor tissues exhibit substantial heterogeneity in both elastic and viscous properties, and viscoelasticity modulates tumor cell migration, invasion, and immune cell infiltration in ways that cannot be captured by stiffness measurements alone. Future studies should incorporate viscoelastic characterization (eg, via atomic force microscopy nanoindentation with stress-relaxation protocols) alongside stiffness measurements to provide a more comprehensive mechanical portrait of the tumor microenvironment (Table 1).

Table 1.

Representative Mechanical Loading Modes in the Tumor Microenvironment: Magnitude, Timescale, and Measurement Techniques

Loading Mode	Magnitude Range	Timescale	Measurement Method
ECM stiffness (elastic modulus)	0.1–10 kPa (normal tissues); 10–>100 kPa (tumors; PDAC/HCC >100 kPa)	Steady-state	Atomic force microscopy (AFM), rheometry, magnetic resonance elastography (MRE)
Fluid shear stress	0.1–10 dyn/cm2 (interstitial); 1–50 dyn/cm2 (vascular)	Seconds to minutes	Parallel-plate flow chamber, microfluidic devices, computational fluid dynamics
Compressive force	0–>200 mmHg (solid tumors; up to several hundred mmHg)	Minutes to hours	Mechanical compression devices, hydraulic pressure systems
Membrane stretch	1–15% strain (physiological); up to 30% (pathological)	Milliseconds to seconds	Stretch chambers (Flexcell), micropipette aspiration, optical tweezers
Ultrasound (LIPUS)	Frequency: 0.02–3 MHz; Intensity: 0.1–3 W/cm2 (100–3000 mW/cm2); Duty cycle: 10–100%	Minutes to hours (cumulative)	Ultrasound transducers, hydrophone calibration, acoustic pressure measurement
Viscoelasticity (stress relaxation)	Relaxation time constant: 1–100 s; Loss tangent (tan δ): 0.1–1.0	Seconds to minutes	AFM stress-relaxation nanoindentation, creep tests, bulk rheometry

Calcium Signaling Hub

Piezo1-mediated Ca²⁺ influx represents the central event in its signal transduction. As a mechanosensitive, non-selective cation channel, Piezo1 is activated by various mechanical stimuli—such as shear stress, stretching, or compression—triggering Ca²⁺ influx and thereby converting extracellular physical signals into intracellular biochemical responses.17 The resultant local increase in Ca²⁺ concentration activates a series of downstream effectors, including calmodulin, calpain, calcineurin, and multiple protein kinases (eg, CaMKII, PKC).26 These downstream molecules further regulate the activation and nuclear translocation of transcription factors such as NFAT, NF-κB, and AP-1, profoundly influencing cellular gene expression profiles. For instance, in hepatocellular carcinoma, Piezo1 activation upregulates the expression of the chemokine CXCL8 via the ERK1/2 and AKT signaling pathways, thereby mediating pro-inflammatory responses and facilitating crosstalk with the TME.27 Moreover, Ca²⁺ influx triggered by Piezo1 activation also engages multiple signaling cascades, including the WNK1-OSR1/SPAK pathway, further expanding the complexity of its downstream signaling network.28 Of note, Piezo1 activation not only mediates extracellular Ca²⁺ influx but may also amplify the initial calcium signal through calcium-induced calcium release (CICR).17 Furthermore, Piezo1 has been shown to mediate Mg²⁺ influx in leukemia cells, strongly suggesting that its ion selectivity and functional diversity may far exceed conventional understanding. Future investigations are warranted to explore the distinct contribution of Mg²⁺ influx to tumor cell metabolism and signal transduction.29 Importantly, Piezo1-mediated Ca²⁺ signaling exhibits remarkable context dependence: in pancreatic stellate cells, Piezo1-induced directional migration relies on the cooperative action of TRPC1 and TRPV4 channels; whereas in cancer cells, Piezo1 forms a positive feedback loop with integrin β1 to collectively respond to changes in extracellular matrix stiffness.30,31 In summary, by initiating a complex calcium signaling network that converts mechanical stimuli into diverse intracellular events, Piezo1 serves as a critical hub linking the extracellular mechanical environment to intracellular biochemical responses.

Interactions with Other Mechanosensors

Piezo1 does not function in isolation; rather, it engages in a complex interaction network with integrins, focal adhesions, and members of the TRP channel family.32 For instance, in pancreatic stellate cells, Piezo1 activation depends on the cooperative function of TRPC1 and TRPV4, with all three channels jointly mediating durotaxis—the directed migration toward stiffer matrices.30 In lymphatic endothelial cells, Piezo1 forms a functional coupling with ORAI1 to jointly regulate fluid shear stress-induced lymphangiogenesis.33 Notably, the synergistic interplay between Piezo1 and integrin β1 (ITGB1) has been shown to establish a positive feedback loop in multiple tumors: ECM stiffness triggers Ca²⁺ influx via the Piezo1/ITGB1 complex, which in turn promotes YAP nuclear translocation and upregulates target genes such as CTGF, α-SMA and COL1A1, ultimately exacerbating collagen deposition and matrix stiffening. This creates a vicious cycle of “matrix stiffening – Piezo1/ITGB1–YAP – further matrix stiffening”.31 Furthermore, in T cells, Piezo1 and ORAI1 orchestrate stiffness-dependent rapid and long-term responses, respectively: Piezo1 primarily mediates the reorientation of the microtubule-organizing centre (MTOC), whereas ORAI1 regulates NFAT1 nuclear translocation. This indicates that distinct mechanosensitive channels execute finely divided temporal roles in cellular function.34 Collectively, these studies clearly demonstrate that Piezo1 serves as a critical hub within the mechanotransduction network rather than acting as an isolated sensor. Therefore, a deep understanding of the dynamic regulatory network between Piezo1 and its interacting partners holds significant theoretical importance and clinical translational value for the development of anticancer strategies targeting mechanotransduction.

Regulatory Mechanisms of Piezo1 in Malignant Phenotypes of Tumor Cells

The mechanosensitive ion channel Piezo1 has emerged as a critical player in cancer biology, yet its functions are remarkably context-dependent across malignancies. From prognostic significance to regulation of proliferation, metastasis, stemness, and cell death, Piezo1 exhibits both tumor-promoting and tumor-suppressing roles. The following sections systematically dissect the expression landscape, prognostic value, and mechanistic involvement of Piezo1 in key hallmarks of cancer, including proliferation, migration, EMT, cancer stem cell maintenance, and programmed cell death pathways such as ferroptosis and apoptosis.

Expression Profile and Prognostic Value of Piezo1 in Tumor Tissues

Piezo1 expression is dysregulated in a broad spectrum of human malignancies, and its expression levels are closely correlated with tumor type, disease stage, and patient prognosis. Specifically, large-scale pan-cancer analyses have revealed that PIEZO1 is significantly upregulated in multiple tumor types, including breast invasive carcinoma, glioblastoma, hepatocellular carcinoma, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer, and cervical cancer.10 For instance, in gastric cancer, the mRNA levels of both Piezo1 and Piezo2 are markedly higher than those in normal tissues, and their high expression is significantly associated with poor patient prognosis.35 Similarly, in esophageal squamous cell carcinoma, Piezo1 expression is significantly elevated in tumor tissues compared with adjacent non-cancerous tissues, where it promotes tumor progression by regulating the p53-Bax-Caspase 3 axis.36 Furthermore, in bladder cancer, the expression of Piezo1 and Piezo2 is markedly increased in both human and mouse tumor tissues, suggesting an important role in bladder carcinogenesis.37 These findings collectively highlight that dysregulated Piezo1 expression serves as a potential pan-cancer biomarker and therapeutic target across diverse malignancies.

Nevertheless, it is worth noting that this upregulation trend is not universal, as the expression regulation of Piezo1 exhibits pronounced tumor type specificity. For example, in clear cell renal cell carcinoma, the protein expression level of Piezo1 in tumor tissues is significantly lower than that in adjacent normal tissues. Interestingly, however, its high expression still predicts worse overall survival and has been identified as an independent poor prognostic factor.15 This apparent contradiction may reflect the complex, context-dependent nature of Piezo1 in renal cell carcinoma. Piezo1 expression may be heterogeneous within the tumor—downregulated in the bulk mass but elevated in aggressive subsets or stromal components that drive poor outcomes. Alternatively, Piezo1 may act as a tumor suppressor in early stages but be co-opted as an oncogene in advanced, therapy-resistant clones. These observations underscore the need for single-cell and spatial transcriptomic analyses to delineate Piezo1’s cell-type- and stage-specific functions. In contrast, Piezo1 may act as a tumor suppressor in lung adenocarcinoma, where it inhibits tumor cell migration and epithelial-mesenchymal transition (EMT) through the regulation of the ROS/Wnt/β-catenin axis.38 These seemingly contradictory expression patterns precisely underscore the functional complexity of Piezo1 in different TMEs.

From a prognostic perspective, high PIEZO1 expression is generally associated with significantly poorer overall survival and disease-free survival. In glioma, Piezo1 expression levels increase with higher WHO grade, and patients with high expression exhibit markedly shortened overall survival; moreover, multivariate Cox regression analysis has confirmed Piezo1 as an independent poor prognostic factor.11,39 In hormone receptor-negative breast cancer patients, particularly in the triple-negative breast cancer subtype, high Piezo1 expression likewise predicts worse clinical outcomes, a phenomenon closely linked to the enrichment of signalling pathways associated with aggressive phenotypes such as EMT and hypoxia.40 Additionally, in hepatocellular carcinoma, upregulation of Piezo1 is also tightly correlated with aggressive clinicopathological features and poor prognosis, further supporting its potential as a prognostic marker.41 Collectively, although Piezo1 may be downregulated in certain specific tumor types, its high expression in the vast majority of solid tumors is closely associated with malignant progression and poor prognosis. These data strongly support the considerable potential of Piezo1 as a pan-cancer prognostic biomarker.

Promotion of Proliferation and Survival

As a key mechanosensitive ion channel, Piezo1 plays a central role in promoting cell proliferation and sustaining cell survival across multiple malignancies, primarily through the activation of various intracellular signalling pathways. For instance, in prostate cancer, Piezo1 accelerates the cell cycle transition from the G0/G1 to S phase by activating the Akt/mTOR signalling pathway, thereby effectively driving tumor cell proliferation.42 Similarly, in melanoma, Piezo1 relies on the same Akt/mTOR axis to maintain its malignant phenotype, suggesting a conserved pro-tumorigenic function of this signalling cascade across several solid tumors.43 Moreover, in hepatocellular carcinoma, Piezo1 promotes cell proliferation through the regulation of the MAPK/YAP signalling axis, further revealing tumor type-specific pathway utilisation.27 Notably, the impact of Piezo1 on tumor cell survival exhibits marked cell type specificity. In acute myeloid leukaemia cells, knockdown of Piezo1 induces cell cycle arrest at the G0/G1 phase and triggers the extrinsic apoptotic pathway, indicating that Piezo1 is an essential molecule for the survival of these leukaemia cells.44 Likewise, Piezo1 knockdown significantly reduces cell viability in synovial sarcoma, further supporting its pro-survival role in sarcomas.45 Beyond directly regulating the cell cycle and apoptotic pathways, Piezo1 also indirectly promotes tumor cell survival by mediating cellular sensing of the mechanical microenvironment. For example, in glioblastoma, Piezo1 senses changes in extracellular matrix stiffness and activates the integrin–FAK signalling pathway, thereby establishing a positive feedback loop that facilitates tumor progression.46 Furthermore, in pancreatic ductal adenocarcinoma, increased three-dimensional matrix stiffness induces chemoresistance through Piezo1-mediated upregulation of glycolysis, highlighting a novel role for Piezo1 in therapy resistance.47 Collectively, these findings indicate that Piezo1 plays a critical role in the proliferation and survival of diverse tumor types. Consequently, targeting Piezo1 and its downstream key signalling molecules may represent an effective therapeutic strategy for both specific haematological malignancies and solid tumors.

Regulation of Migration, Invasion and EMT

The role of Piezo1 in regulating tumor metastasis is one of the most extensively studied areas in current research; however, its effects exhibit marked tumor-type dependence and can even manifest as diametrically opposite functions. On the one hand, pro-metastatic effects have been reported in multiple cancer types. For instance, in cervical cancer, Piezo1 remodels the actin cytoskeleton via the RhoA/ROCK1/PIP2 signaling pathway, thereby driving epithelial–mesenchymal transition (EMT).20 Notably, increased ECM stiffness can activate Piezo1 through upregulation of LOXL2, thereby promoting cervical cancer cell migration and invasion.48 Similarly, in colorectal cancer, Piezo1 modulates the EMT process by regulating the PHLPP2-PI3K/Akt axis;49 in hepatocellular carcinoma, Piezo1 activates TGF-β signaling by recruiting Rab5c, thereby promoting EMT.41 Moreover, in gastric cancer, Piezo1 maintains cell morphology and motility through regulation of the Rho GTPase family.50 Furthermore, fluid shear stress, as an important mechanical signal, promotes prostate cancer metastasis via the Piezo1–Src–YAP axis;51 in pancreatic cancer, Piezo1 enhances neural invasion by activating YAP1 in the Hippo signaling pathway and is closely associated with poor prognosis.52 In uveal melanoma, ECM stiffness regulates cancer stem cell properties through the PIEZO1–DOT1L axis, thereby driving tumor progression;53 in clear cell renal cell carcinoma, Piezo1 mediates stiffness-induced tumor progression via the Ca²⁺/Calpain/YAP pathway;54 in melanoma, Piezo1 promotes malignant progression through the AKT/mTOR signaling pathway;43 in ovarian cancer, Piezo1 facilitates tumor metastasis via the Hippo/YAP signaling axis.55 Additionally, in glioma, compressive force promotes tumor progression through the Piezo1–GDF15–CTLA4 axis;56 in bladder cancer, Piezo1 cooperates with integrin β1 to form a positive feedback loop via Ca²⁺/YAP signaling, driving ECM stiffness-mediated tumor progression;31 in rhabdomyosarcoma, ECM density regulates tumor invasion through the YAP–PIEZO1 signaling axis.57 On the other hand, several studies have also reported a metastasis-suppressing role for Piezo1. For example, in lung cancer A549 cells, stiff substrates downregulate Piezo1 expression and reduce calcium influx, which instead promotes filopodia formation and cell migration.58 Similarly, in breast cancer cells, Piezo1 knockdown promotes cell migration under unconfined conditions but inhibits migration under confined conditions.59 These seemingly contradictory findings suggest that the regulation of cell migration by Piezo1 is highly dependent on cell type, matrix stiffness, spatial confinement, and the nature of the mechanical stimulus. Beyond matrix stiffness, compressive force generated by solid tumor growth represents another critical mechanical signal within the TME. Studies have shown that compressive force activates Piezo1 and its downstream Rho–ROCK signaling pathway, inducing an epigenetic “mechanical memory” that promotes breast tumor progression;1 meanwhile, in glioma, compressive force promotes tumor progression through the Piezo1–GDF15–CTLA4 axis.56 Collectively, these findings profoundly reveal the complexity and differential regulation of Piezo1 signal transduction under distinct mechanical modalities, highlighting the need for future research to explore the spatiotemporally specific mechanisms of Piezo1 action in the diverse mechanical microenvironments of different tumors. Furthermore, in clear cell renal cell carcinoma, while Piezo1 is downregulated in tumor tissues, functional studies suggest that Piezo1 re-expression can suppress invasive phenotypes through the Ca²⁺/Calpain/YAP pathway, though this effect may be counterbalanced by other oncogenic signals.54,60 Collectively, these findings underscore that the metastatic role of Piezo1 is not intrinsically pro- or anti-tumorigenic, but rather is dictated by cell type, substrate stiffness, spatial confinement, and the nature of the mechanical stimulus.

Regulation of Cancer Stem Cell Properties

The role of Piezo1 in maintaining the stemness of cancer stem cells (CSCs) has attracted increasing attention and has become a frontier topic in cancer research. CSCs represent a key subpopulation of cells that drive tumor initiation, recurrence, metastasis, and therapeutic resistance, and the maintenance of their stemness properties is finely regulated by diverse signals from the TME. In recent years, accumulating evidence has indicated that mechanical signals, acting through the Piezo1 channel, play a critical role in regulating CSC fate. For instance, in uveal melanoma, ECM stiffness regulates CSC stemness via the Piezo1–DOT1L signaling axis.53 Specifically, increased ECM stiffness upregulates Piezo1 expression, which in turn promotes DOT1L-mediated histone methylation, ultimately enhancing the self-renewal capacity and therapeutic resistance of tumor cells. Furthermore, in colon cancer, Piezo1 is markedly overexpressed in the CD133⁺/CD44⁺ CSC subpopulation and sustains CSC self-renewal by activating the Ca²⁺/NFAT1 signaling pathway; conversely, Piezo1 knockout significantly suppresses tumorigenicity and sphere-forming capacity.61 Together, these studies reveal a conserved mechanism by which Piezo1 regulates CSC stemness across different tumor types. More strikingly, a groundbreaking study has shown that physical compression of tumor cells at capillary constrictions in the circulatory system rapidly reprograms melanoma cells into a more tumorigenic, stem-like state within minutes by activating Piezo1 channels.62 Using a microfluidic device that mimics physiological blood flow rates and progressive capillary narrowing, this study demonstrated for the first time that mechanical compressive forces induce nuclear deformation, chromatin remodeling, and upregulation of transcripts associated with metabolic reprogramming, ultimately leading to the stable acquisition of a CSC phenotype. This is reflected by elevated expression of melanoma stem cell markers, enhanced transendothelial invasion capacity, and significantly increased tumorigenicity both in vitro and in vivo. This milestone discovery reveals a novel mechanism by which physical forces in the circulation act as “metastasis-initiating factors”, providing major theoretical insights into the fate determination of tumor cells during hematogenous metastasis. In summary, by sensing and transducing diverse mechanical signals within the TME, Piezo1 plays a central role in maintaining CSC stemness, regulating plasticity, and conferring metastatic potential. Therefore, therapeutic strategies targeting Piezo1 and its downstream signaling pathways hold promise as novel approaches to eradicate CSCs and overcome therapeutic resistance.

Regulation of Ferroptosis and Apoptosis

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Recent studies have established Piezo1 as a critical hub linking mechanical signals to the ferroptosis execution machinery, by coordinating intracellular iron metabolism and lipid peroxidation reactions. For instance, in cervical cancer, the natural product matrine exerts anti‑tumor effects by activating Piezo1 to induce ferroptosis.63 Conversely, in ovarian cancer, the E3 ubiquitin ligase TRIM25 promotes tumor growth by facilitating K63-linked ubiquitination and degradation of PIEZO1, thereby suppressing ferroptosis, indicating that the regulation of Piezo1 stability itself is a critical determinant of tumor cell fate.64 The detailed mechanistic cascade of Piezo1‑mediated ferroptosis, including the TfR1/DMT1/NCOA4/GPX4 axis, is discussed in depth in Piezo1-Mediated Ferroptosis.

Beyond ferroptosis, Piezo1 activation also contributes to apoptosis regulation. Activation of Piezo1 can significantly enhance TRAIL‑induced apoptosis by inducing mitochondrial outer membrane permeabilization, a process involving calpain activation and Bax activation.65 Furthermore, ultrasound microbubble technology, as a non-invasive mechanical stimulation approach, can effectively promote apoptosis in breast cancer cells by activating Piezo1 and subsequently inducing endoplasmic reticulum stress and mitochondrial dysfunction, showcasing the clinical potential of using physical factors to trigger Piezo1-mediated cell death.66 Collectively, these findings establish Piezo1 as a key molecular switch connecting mechanosensing to tumor cell fate determination. Precisely targeting Piezo1 to induce ferroptosis or apoptosis may represent a novel strategy to overcome therapy resistance and improve patient outcomes in cancer (Figure 2). The context-dependent expression and functional roles of Piezo1 across different cancer types are systematically summarized in Table 2.

Figure 2.

Multifaceted Regulation of Malignant Phenotypes by Piezo1 in Cancer Cells. (A) Oncogenic functions: Piezo1 promotes proliferation, migration, epithelial–mesenchymal transition (EMT), cancer stem cell (CSC) maintenance, and survival through the Akt/mTOR, RhoA/ROCK/TGF‑β/YAP, and Ca²⁺/NFAT/DOT1L signalling axes. (B) Tumour‑suppressive functions: Piezo1 inhibits migration and EMT via the ROS/Wnt/β‑catenin pathway, while its activation can induce ferroptosis and apoptosis. (C) Mechanistic cascade for cell death: Ca²⁺ influx upregulates TfR1‑dependent iron uptake, DMT1‑mediated transport, and NCOA4‑regulated ferritinophagy, leading to iron overload, ROS production, lipid peroxidation, and GPX4 inhibition (ferroptosis); alternatively, calpain activation and Bax‑mediated mitochondrial outer membrane permeabilization (MOMP) drive apoptosis. Created with BioGDP.com.24

Table 2.

Summary of Piezo1 Expression, Functional Role, Key Pathways, Model Systems, Therapeutic Implication, and References Across Cancer Types

Cancer Type	Piezo1 Expression (Tumor vs Normal)	Functional Role	Mechanical Context	Key Pathways/Mechanisms	Model Systems	Therapeutic Implication	References
Glioma	Upregulated	Oncogenic	Compression; stiffness	Integrin–FAK; GDF15–CTLA4; Myosin 1b–VEGF	Cell lines, xenografts	Piezo1 inhibitor; anti-CTLA4 combination	[11,39,46,56,67]
Pancreatic cancer	Upregulated	Oncogenic	3D stiffness; pressure	YAP1; glycolysis; neurotropism	Cell lines, 3D models, PSCs	Piezo1 inhibitor + gemcitabine; LIPUS + oridonin	[12,30,47,52,68]
Esophageal SCC	Upregulated	Oncogenic	Not well defined	p53–Bax–Caspase 3; ADC target	Cell lines, xenografts, patient samples	Anti-PIEZO1–MMAE ADC	[13,36]
Hepatocellular carcinoma	Upregulated	Oncogenic	Stiff ECM	MAPK/YAP; TGF-β/Rab5c; HIF-1α/VEGF; MTHFD2	Cell lines, xenografts	Piezo1 inhibitor; Jianpi Huayu + doxorubicin	[27,41,69]
Gastric cancer	Upregulated	Oncogenic	H. pylori/NF-κB; stiffening	Rho GTPases; NF-κB–YAP1–CTGF–CAF	Cell lines, organoids	Piezo1 inhibitor; CAF targeting	[35,50,70]
Colorectal cancer	Upregulated	Oncogenic	Not well defined	PHLPP2–PI3K/AKT; Ca2⁺/NFAT1	Cell lines, CSC models	Piezo1 inhibitor; Changyong Decoction	[49,63,71]
Cervical cancer	Upregulated	Oncogenic	Stiffness; LOXL2	RhoA/ROCK1/PIP2; LOXL2–stiffness; ferroptosis	Cell lines, xenografts	Matrine activates Piezo1 to induce ferroptosis	[20,48,65]
Bladder cancer	Upregulated	Oncogenic	Stiffness	Integrin β1–YAP feedback; mechano-chemotherapy	Cell lines, xenografts	Programmed pressure + intravesical chemotherapy; R11 delivery	[31,37,72,73]
Prostate cancer	Upregulated	Oncogenic	Stiffness; high-fat diet; shear stress	Akt/mTOR; Piezo1–Src–YAP; MERC; EMT	Cell lines, xenografts	Piezo1 inhibitor + statin or chemotherapy	[42,51,74,75]
Breast cancer	Upregulated	Oncogenic, context-dependent	Compression; 3D stiffness	Rho–ROCK; integrin–FAK; USMB-induced apoptosis	Cell lines, 3D structures	USMB-induced apoptosis; photothermal + Yoda1	[1,40,59,76–78]
Melanoma	Upregulated	Oncogenic	Confined space; cholesterol	AKT/mTOR; DOT1L; cholesterol-dependent migration	Cell lines, microfluidics	Statins; Piezo1 inhibitor	[43,53,64,79]
Ovarian cancer	Upregulated, context-dependent	Context-dependent; TRIM25-mediated Piezo1 degradation modulates ferroptosis	Not well defined	Hippo/YAP; MMP-1/10; TRIM25–Piezo1; ferroptosis	Cell lines, xenografts	Context-dependent; Piezo1 activation to induce ferroptosis requires validation	[55,66,80]
Lung cancer	Downregulated	Tumor suppressive in primary; context-dependent in metastasis	Stiffness downregulates Piezo1	ROS/Wnt/β-catenin; YAP–PD-L1/CXCL10	Cell lines, xenografts, metastasis models	Context-dependent; Piezo1 agonist + anti-PD-1 in selected models	[14,38,58,81,82]
Clear cell renal cell carcinoma	Downregulated at protein level	Tumor suppressive, but high expression predicts poor survival	Stiffness	Ca2⁺/Calpain/YAP	Cell lines, patient samples	Context-dependent; single-cell and spatial studies needed	[15,54]
Acute myeloid leukemia	Functional dependence	Pro-survival	Not well defined	Cell cycle; extrinsic apoptosis; Mg2⁺ influx	Leukemia cell lines	Piezo1 inhibition may reduce AML survival; requires validation	[29,44]

The Multifaceted Roles of Piezo1 in the TME

The TME is not merely the “soil” in which cancer cells thrive, but rather a complex network interwoven with mechanical, biochemical and immunological signals. As a key mechanosensor within the TME, Piezo1 integrates diverse physical cues—including ECM stiffness, fluid shear stress and compressive forces—and subsequently orchestrates angiogenesis, metabolic reprogramming, fibrosis and immune evasion. Through these processes, Piezo1 remodels the TME in a comprehensive manner, thereby profoundly influencing tumor initiation, progression and therapeutic response.

ECM Stiffness and the Positive Feedback Loop

One of the most characteristic mechanical features of tumor tissues is a marked increase in ECM stiffness. Importantly, this stiffening is not a passive epiphenomenon but an active driver of malignant progression.83 Accumulating evidence indicates that a stiff matrix exerts pro-tumorigenic effects by activating the mechanosensitive ion channel Piezo1 across multiple solid tumor types. For instance, in hepatocellular carcinoma (HCC), a stiff matrix upregulates Piezo1 expression by downregulating miR-625-5p, which in turn suppresses HIF-1α ubiquitination and enhances the expression of pro-angiogenic factors such as VEGF, CXCL16 and IGFBP2.76 In clear cell renal cell carcinoma, Piezo1 mediates matrix stiffness-induced tumor progression through the Ca²⁺/Calpain/YAP pathway.54 Furthermore, in squamous cell carcinoma (SCC), a stiff matrix promotes tumor proliferation and invasion via the Piezo1–RCC2–YAP non-canonical Hippo pathway.83 In prostate cancer cells, increased matrix stiffness induces EMT through Piezo1-regulated calcium influx.84 Similarly, in cervical cancer, LOXL2-mediated ECM crosslinking augments matrix stiffness, thereby activating Piezo1 to promote cancer cell migration and invasion.48 In osteosarcoma, substrate stiffness modulates osteogenic and adipogenic differentiation through PIEZO1-mediated signalling, and PIEZO1 cooperates with integrin β1 to facilitate YAP nuclear translocation, thus influencing the differentiation fate of tumor cells.85 In uveal melanoma, ECM stiffness regulates cancer stem cell properties via the PIEZO1–DOT1L axis.53 In fusion-negative rhabdomyosarcoma, a high-density ECM promotes tumor invasion through the YAP–PIEZO1 signalling axis.57

Notably, Piezo1 can exert divergent functions depending on tumor type. For example, in lung cancer cells, a stiff matrix paradoxically downregulates Piezo1 expression, which promotes cofilin phosphorylation and filopodia formation by inhibiting calcium influx, thereby enhancing cell migration—a mechanism that distinguishes lung cancer from most other solid tumors.58 Likewise, in esophageal squamous cell carcinoma, high Piezo1 expression correlates with malignant progression, and its downregulation suppresses tumor development.36 Collectively, these findings establish Piezo1 as a central mechanosensor that exhibits complex and context-dependent functions, underscoring its pivotal role in the mechanical TME.

More importantly, Piezo1 activation can in turn promote ECM remodelling, thereby generating a self-reinforcing malignant positive feedback loop. In SCC, Piezo1 activation induces TGFβ1 secretion, driving fibroblast-to-myofibroblast conversion and collagen deposition, which further reinforces matrix stiffness—creating a vicious cycle of “stiffness → Piezo1 → fibrosis → greater stiffness”.83 In bladder cancer, Piezo1 cooperates with integrin β1 (ITGB1) to activate Ca²⁺/YAP signalling, upregulating CTGF, α-SMA and COL1A1 expression, thereby similarly establishing a positive feedback loop that promotes matrix stiffening.31 In gastric cancer, Helicobacter pylori infection upregulates Piezo1 via NF-κB, which subsequently activates the YAP1–CTGF axis, promoting cancer-associated fibroblast (CAF) infiltration and ECM stiffening.74 In prostate cancer, a high-fat diet induces ECM remodelling that activates Piezo1-dependent mitochondria–ER contacts to promote chemoresistance; conversely, dual targeting of lipid metabolism and mechanotransduction restores chemosensitivity.86 In three-dimensional epithelial structures of breast cancer, matrix stiffening activates Piezo1 through integrin–FAK signalling, modulating ECM composition and remodelling to create an invasive microenvironment.70 Moreover, in glioma, Piezo1 localises to focal adhesions and activates integrin–FAK signalling, modulating the ECM and enhancing tissue stiffening; the resultant stiffer mechanical microenvironment in turn upregulates Piezo1 expression, forming a positive feedback loop that facilitates tumor invasion.46 Similarly, in HCC, collagen I-reinforced tissue stiffening upregulates Piezo1 expression via the miR-625-5p axis, while Piezo1 activation promotes HIF-1α-mediated expression of pro-angiogenic factors, constituting a positive feedback loop of “stiff matrix/integrin β1/miR-625-5p/Piezo1 and COL1/stiffer matrix”.76 Thus, Piezo1 functions both as a sensor of stiffness signals and as an amplifier of stiffness changes—a dual role that positions it as an unequivocal central regulatory node in the mechanical TME.

Notably, the role of Piezo1 in ECM stiffness sensing is not uniformly pro-tumorigenic. In lung adenocarcinoma, increased matrix stiffness was found to downregulate Piezo1 expression via a mechanism involving promoter hypermethylation, and the subsequent loss of Piezo1-mediated Ca²⁺ signaling relieved its inhibitory effect on the ROS/Wnt/β-catenin pathway, thereby promoting EMT and migration.75 In this context, Piezo1 functions as a tumor suppressor whose downregulation is required for stiffness-induced malignancy—a mechanism that directly opposes the pro-tumorigenic Piezo1/stiffness axis observed in bladder, cervical, and hepatocellular carcinomas.77,81 This tumor-type specificity may arise from differences in the downstream effectors coupled to Piezo1: in some cancers, Piezo1 preferentially engages YAP/TAZ to drive transcription of pro-invasive genes; in others, it activates tumor-suppressive pathways such as ROS/Wnt/β-catenin or promotes ferroptosis through iron-dependent lipid peroxidation.38,87 Understanding the molecular determinants that dictate these divergent outcomes—whether they are cell-intrinsic (eg, mutational background, epigenetic landscape) or microenvironmental (eg, matrix composition, oxygen tension)—represents a critical unmet need in the field.

Regulation of Cancer-Associated Fibroblasts (CAFs)

CAFs represent one of the most abundant stromal cell types within the TME, and their activation state is closely linked to tumor progression, tissue fibrosis, and therapeutic resistance. Recent studies have revealed that the mechanosensitive ion channel Piezo1 plays a critical role in regulating CAF activation and function. In pancreatic stellate cells (PSCs), Piezo1 has been established as a key mediator of pressure-induced pancreatic fibrosis.38 Its activation not only promotes PSC migration but also significantly enhances cellular traction forces on the ECM.88 Notably, in microenvironments that mimic the stiffness gradient of pancreatic ductal adenocarcinoma (PDAC), PSCs sense changes in ECM stiffness via the Piezo1-TRPC1-TRPV4 signalling axis and undergo durotaxis toward stiffer regions—a process with important pathological implications for the directional recruitment of PSCs to tumor sites and the formation of fibrotic foci.30 Furthermore, in models of liver fibrosis and radiotherapy-induced hepatic fibrosis, Piezo1 may broadly participate in various stages of fibrogenesis by regulating fibroblast activation protein (FAP)-positive fibroblasts.89 Concurrently, activation of Piezo1 in fibroblasts induced by mechanical overload has been shown to be closely associated with scar tissue formation, suggesting the existence of analogous mechanotransduction mechanisms in tumor-associated fibrosis.90 More importantly, Piezo1 activation in fibroblasts not only directly promotes ECM deposition and remodelling but also indirectly enhances the malignant phenotype of tumor cells through paracrine signalling, thereby establishing a vicious cycle that fuels tumor progression. Collectively, these findings suggest that targeting the Piezo1 signalling axis in CAFs may represent a potential therapeutic strategy to reverse tumor-associated fibrosis, overcome chemoresistance, and improve patient outcomes.

Angiogenesis and Lymphangiogenesis

Piezo1 plays a complex and critical role in tumor angiogenesis, with its effects exhibiting marked tumor-type dependence. In glioblastoma, aberrant overexpression of myosin 1b promotes angiogenesis via the VEGF–myc–Piezo1 axis, suggesting that Piezo1 serves as a key downstream effector molecule in the abnormal vascular hyperplasia of this tumor.91 Meanwhile, studies have also revealed that Piezo1 can influence the collective detachment and peritoneal dissemination of ovarian cancer cell clusters by modulating the expression of MMP-1 and MMP-10, thereby indirectly regulating the perivascular TME.92 Collectively, these findings reveal a complex network through which Piezo1 regulates angiogenesis via diverse molecular mechanisms in different tumor types, and targeting this channel may provide a new entry point for anti-angiogenic therapy.

With regard to lymphangiogenesis, Piezo1 has been established as an upstream mechanosensor that mediates fluid shear stress-induced lymphatic vessel growth.33 Specifically, Piezo1 senses oscillatory shear stress and integrates this signal into the genetic programme governing lymphatic valve development and maintenance; upon activation, it promotes lymphatic endothelial cell sprouting through modulation of NOTCH signalling, whereas Piezo1 deficiency leads to lymphatic vessel regression and lymphoedema.67 Further studies have shown that the Piezo1 agonist Yoda1 markedly accelerates lymphatic valve formation in vivo; moreover, even in the absence of fluid shear stress, it upregulates the expression of lymphatic valve-related genes, thereby offering a novel strategy for treating congenital or surgery-related lymphoedema.67 In addition, in a UV-induced cutaneous squamous cell carcinoma model, the YAP1/Piezo1 signalling axis has been implicated in the dynamic changes of lymphatic vessels, hinting at a potential role for Piezo1 in tumor lymphatic metastasis.80 Given that lymphangiogenesis constitutes a major route for tumor metastasis, further elucidation of the specific mechanisms by which Piezo1 contributes to tumor-associated lymphangiogenesis will provide highly promising new targets for developing anti-lymphatic metastasis therapeutic strategies.

Metabolic Reprogramming

A close relationship exists between Piezo1 signalling and tumor metabolism, and the key role of Piezo1 as a “mechano–metabolic” coupling node is receiving increasing attention. For example, in hepatocellular carcinoma, Piezo1 activation mediates mitochondrial stress and metabolic reprogramming by upregulating the metabolic checkpoint enzyme MTHFD2, thereby potently promoting tumor progression.27 Similarly, in pancreatic cancer, three-dimensional matrix stiffness significantly promotes gemcitabine resistance through Piezo1-mediated glycolysis, and inhibiting Piezo1 reverses this effect, suggesting that targeting the Piezo1–glycolysis axis may represent a novel strategy to overcome chemoresistance.47 Furthermore, in a high-fat diet-induced model of prostate cancer chemoresistance, extracellular matrix stiffness activates mitochondria–endoplasmic reticulum contacts (MERCs) via Piezo1, leading to metabolic reprogramming, and combined targeting of lipid metabolism and mechanotransduction effectively restores chemosensitivity.86 Notably, Piezo1 not only regulates metabolism in tumor cells but is also deeply involved in the metabolic reprogramming of immune cells. For instance, in CAR-T cells, Piezo1 couples cytoskeletal dynamics with metabolic remodelling through the Ca²⁺–Wnt–Rac1 signalling axis, and its activity follows the “goldilocks principle”: only a moderate level of Piezo1 activity maximizes cytotoxicity, whereas either too low or too high activity impairs the mechano–metabolic fitness of the cells.93 Collectively, these findings indicate that Piezo1 acts as a metabolic hub in various malignancies and immune cells, translating physical microenvironmental cues into functional metabolic outputs.

Beyond glycolysis and mitochondrial metabolism, Piezo1 has also been identified as a key regulator of cholesterol metabolism. In neural stem cells, loss of Piezo1 leads to widespread downregulation of cholesterol synthesis pathways, severely affecting cell proliferation and differentiation, suggesting that Piezo1 influences cell fate decisions by modulating cholesterol metabolism.94 In melanoma cells, cholesterol is an essential lipid molecule required for Piezo1 to sense confined spaces and mediate amoeboid migration, and statins effectively suppress Piezo1-mediated migration by lowering cholesterol levels, implying that targeting cholesterol metabolism may be an effective approach to inhibit Piezo1-dependent tumor metastasis.95 At the same time, the activation function of the Piezo1 channel itself is tightly regulated by membrane cholesterol organization and lipid raft integrity, and cholesterol depletion significantly impairs its channel function.22 Together, these discoveries reveal a complex bidirectional regulatory relationship between Piezo1 and cholesterol metabolism, in which the metabolic microenvironment modulates Piezo1 function, and Piezo1 in turn remodels the metabolic network.

In summary, Piezo1 integrates multiple metabolic pathways—including glycolysis, mitochondrial homeostasis and cholesterol metabolism—to construct a sophisticated and interconnected regulatory network. A deep understanding of the central role of Piezo1 in tumor metabolic reprogramming not only provides new insights into how mechanical signals drive malignant tumor progression but also lays a solid theoretical foundation for developing innovative therapeutic strategies targeting “mechano–metabolic” coupling (Figure 3).

Figure 3.

Piezo1 as a Central Hub in Tumour Microenvironment Remodelling. Piezo1 integrates and amplifies mechanical signals within the tumour microenvironment (TME), driving four interconnected programmes: (1) ECM stiffness positive feedback via the Piezo1/integrin β1/YAP axis, which upregulates CTGF, α‑SMA, and COL1A1; (2) cancer‑associated fibroblast (CAF) activation and durotaxis, mediated by TGF‑β1 secretion and cooperative signalling with TRPC1/TRPV4; (3) angiogenesis and lymphangiogenesis through HIF‑1α/VEGF and NOTCH pathways, respectively; and (4) metabolic reprogramming, encompassing glycolysis, mitochondria–endoplasmic reticulum contacts (MERCs), and cholesterol synthesis. Created with BioGDP.com.24

Bidirectional Immunomodulatory Roles of Piezo1 in the TME

The function of Piezo1 in immune cells represents an emerging frontier, and its role in antitumor immunity exhibits a complex bidirectional nature—encompassing both the promotion of effective immune responses and the potential construction of immunosuppressive networks. This dual action profoundly influences tumor progression and therapeutic outcomes.

T Cells

Piezo1 plays a critical role in initiating and regulating T cell activation. Studies have shown that Piezo1 mediates Ca²⁺ influx to activate calpain, thereby promoting cortical actin cytoskeleton rearrangement and optimizing T cell receptor (TCR) signaling—a prerequisite for efficient T cell activation.96 In tumor challenge models, Piezo1-deficient T cells exhibit functional defects in CD4⁺ helper T cells, leading to significantly impaired antitumor immune responses.79 Furthermore, Piezo1 modulates T cell mechanosensitivity, influencing their traction force and target cell killing efficiency; blocking Piezo1 can enhance T cell cytotoxicity.97 Notably, target cell stiffness plays a key regulatory role in T cell polarization and NFAT activation, wherein microtubule-organizing center (MTOC) reorientation depends on Piezo1, whereas NFAT1 nuclear translocation relies primarily on the ORAI1 channel. This suggests that rapid and long-term T cell responses regulated by stiffness can be functionally uncoupled through distinct calcium channels.34 Collectively, these findings establish Piezo1 as a central node in T cell mechanotransduction.

However, Piezo1 exerts an inhibitory effect on regulatory T cells (Tregs), representing a key example of its immunoregulatory duality. In the experimental autoimmune encephalomyelitis (EAE) model, T cell-specific Piezo1 deletion leads to enhanced TGFβ signaling and expansion of the Treg pool, thereby reducing disease severity.98 Collectively, these findings indicate that Piezo1 primarily acts as a negative regulator of Treg differentiation, and its loss-of-function, rather than hyperactivation, promotes the expansion of the immunosuppressive Treg pool. Within the TME, Piezo1 in dendritic cells (DCs) fine-tunes the reciprocal differentiation of T helper 1 (TH1) cells and Tregs by integrating SIRT1–HIF1α-dependent metabolic pathways and calcium–calcineurin–NFAT signaling, thereby influencing the antitumor immune balance.99 Moreover, Piezo1 suppresses pro-inflammatory differentiation in CD4⁺ T cells while being essential for the maintenance of effector memory T cells, further underscoring the complexity of its functions.100 Additionally, Piezo1 deficiency impairs TH9 cell differentiation, and TH9 cells play an important role in antitumor immunity, further highlighting the multifaceted nature of Piezo1 in differentially regulating immune responses across T cell subsets.101 Therefore, the differential regulation of Piezo1 across T cell subsets positions it as a highly promising yet finely tunable target for cancer immunotherapy.

This apparent paradox may be reconciled by considering the differential roles of Piezo1 across T cell subsets and activation states. Liu et al demonstrated that Piezo1 is required for optimal TCR signaling in naive CD4⁺ T cells, primarily through its role in organizing the immunological synapse and facilitating sustained Ca²⁺ influx via ORAI1 crosstalk.96 By contrast, Pang et al showed that in already activated or effector T cells, Piezo1 blockade enhances cytotoxicity—potentially by reducing Piezo1-mediated negative feedback on the actin cytoskeleton, thereby improving the mechanical coupling between T cells and target tumor cells.97 Furthermore, the temporal dimension may be critical: Piezo1 is necessary for early TCR signaling but becomes dispensable or even inhibitory during sustained effector phases. Future studies employing conditional knockouts with temporal control (eg, inducible Cre systems) are warranted to dissect these stage-specific functions.

Recent studies have uncovered novel mechanisms of Piezo1 in chimeric antigen receptor T (CAR-T) cells. Through the Ca²⁺–Wnt–Rac1 signaling axis, Piezo1 couples cytoskeletal dynamics with metabolic reprogramming, and its activity follows the “Goldilocks principle”—optimal at intermediate levels, whereas either excessive or insufficient activity compromises CAR-T cell effector function and metabolic fitness.93 This discovery offers a new mechano–metabolic regulatory perspective for optimizing CAR-T cell therapy design. Given the multiple regulatory roles of Piezo1 in T cell activation, differentiation, and metabolic adaptation, precisely modulating Piezo1 activity may represent an innovative strategy to enhance the efficacy of cancer immunotherapy.

Natural Killer (NK) Cells

The physical stiffness of the ECM within the TME not only constitutes a critical factor modulating tumor cell behaviour but has also increasingly been recognised as a core mechanical signal that regulates antitumor immune responses. Consequently, deciphering how immune cells perceive and respond to these physical cues is of paramount importance for the development of novel therapeutic strategies. Emerging evidence indicates that matrix stiffness exerts a bidirectional regulatory effect on the function of natural killer (NK) cells, wherein the mechanosensitive ion channel Piezo1 plays a pivotal role. For instance, increased ECM stiffness can activate Piezo1 channels on the NK cell membrane, inducing substantial Ca²⁺ influx, which in turn enhances the release of cytotoxic granules, cytokine secretion, and the ability of NK cells to infiltrate into solid tumors.16 This finding reveals a novel mechanism by which mechanical signals directly potentiate innate immune effector functions, suggesting that Piezo1 may serve as a key molecular switch linking the physical properties of the TME to NK cell effector activity. Collectively, elucidating the Piezo1-mediated mechanotransduction pathway provides a fresh biophysical perspective for understanding the functional regulation of NK cells within solid tumors.

However, the impact of Piezo1 activation on NK cell function is likely time-dependent. Current research has primarily focused on the beneficial effects of short-term activation, whereas whether prolonged or sustained mechanical stimulation leads to NK cell exhaustion, reduced expression of effector molecules, or a dysfunctional state induced by metabolic reprogramming remains to be thoroughly investigated.16 Notably, such a “double-edged sword” effect has been reported in other immune cells, such as T cells, where moderate Piezo1 activation optimises T-cell receptor signalling, whereas excessive or persistent mechanical stress impairs immune function by altering cytoskeletal dynamics and calcium signalling.34 Therefore, precise regulation of both the intensity and duration of Piezo1 activation is essential for harnessing its potential to enhance NK cell-based therapies. In summary, an in-depth understanding of the time-dependent kinetic characteristics of Piezo1 signalling represents a core prerequisite for its safe and effective translation into clinical applications.

Building on these findings, emerging studies offer novel mechano-regulatory strategies for NK cell-based immunotherapy. For example, transient activation of Piezo1 via short-term mechanical stimulation (such as fluid shear stress or ultrasound-mediated mechanical waves) or using specific pharmacological agents (eg, Yoda1) holds promise for markedly enhancing the antitumor efficacy of NK cells without inducing functional exhaustion. Future research should be dedicated to developing temporally controlled Piezo1-targeting technologies and validating their safety and efficacy in in vivo models, thereby translating this mechano-immunological target into clinically feasible therapeutic regimens. Looking ahead, the integration of nanotechnology and materials science to develop novel mechano-responsive drug delivery systems will be a key direction for achieving precise spatiotemporal control over Piezo1 and for driving its clinical translation.

Macrophages and TAMs

The function of Piezo1 in macrophages is highly plastic, and as such, it profoundly influences the polarization status of tumor-associated macrophages (TAMs). Notably, Piezo1 serves as a “mechano-immunological switch”: its downregulation in large tumors promotes M2-like polarization, whereas its upregulation in small tumors drives M1-mediated antitumor immunity.102 This plasticity is governed by intricate signaling cascades, including the cGAS-STING pathway,103 and therefore underscores the role of Piezo1 as an upstream mechanical sensor that integrates physical cues to dictate the functional outcome of TAMs.103,104 Indeed, this phenomenon highlights the bidirectional regulatory nature of Piezo1 expression, since its function is highly dependent on the physical properties of the tumor microenvironment (TME). For instance, by modulating nanoparticle elasticity—soft nanoparticles activate Piezo1, while hard nanoparticles do the opposite—mechanical reprogramming of TAMs from an M2 to an M1 phenotype can be achieved, thereby enhancing antitumor immune responses.102,104 Moreover, Piezo1 also participates in inflammatory responses in macrophages by regulating aerobic glycolysis, thus linking mechanical signaling to metabolic reprogramming.105 Taken together, these findings indicate that Piezo1 in macrophages not only senses the physical microenvironment but also deeply shapes the tumor immune landscape through the coupling of metabolism and polarization status. Consequently, targeting Piezo1 to remodel TAM function has emerged as a highly promising novel immunotherapeutic strategy.

In non-tumor pathological models, myeloid-specific Piezo1 deletion protects renal function by reducing macrophage infiltration and activation via inhibition of the CCL2/CCR2 pathway and Notch signaling, suggesting that Piezo1 inhibition may exert anti-fibrotic effects.106 In an acute hyperglycemia model, Piezo1 inhibition similarly protects microglia from damage.107 Moreover, in a subarachnoid hemorrhage model, engineered nanomedicines targeting Piezo1 promote the transition of microglia from an M1 to an M2 phenotype, suppress inflammatory responses and reduce neuronal injury.108 In liver fibrosis, Piezo1-mediated mechanotransduction is thought to drive the HIF-1α/TGF-β pathway, thereby activating CAFs and exacerbating both fibrosis and hepatocarcinogenesis.89 Collectively, these results underscore that the function of Piezo1 in macrophages/microglia is markedly context-dependent, and its regulatory roles exhibit complex and diverse pathophysiological implications in fibrosis, inflammation and the TME. In summary, Piezo1 acts as a “double-edged sword” in myeloid cells, with its specific function depending on the pathophysiological context; precise modulation of this channel may provide novel therapeutic targets for fibrosis, inflammation and cancer.

Dendritic Cells (DCs)

As a critical class of antigen-presenting cells, the function of dendritic cells (DCs) within the TME is finely regulated by mechanical signals, wherein the mechanosensitive ion channel Piezo1 plays a central role. Studies have shown that Piezo1 in DCs governs the secretion of IL-12 and TGFβ1, thereby directing the differentiation of naïve T cells towards TH1 and Treg cell lineages, thus exerting a dual regulatory function in antitumor immunity.99 However, the function of Piezo1 exhibits marked cell-subset and tissue dependence. For instance, in a rhabdomyosarcoma model, loss of Piezo1 in CD11b⁺ DCs unexpectedly enhances the cross-priming capacity of CD8⁺ T cells and suppresses tumor progression, strongly suggesting that Piezo1 may play an inhibitory role in antigen cross-presentation within specific DC subsets.109 Consequently, the function of Piezo1 in DCs is highly context-dependent, with its effect direction dictated by the specific immune subset and tumor background.

This seemingly paradoxical phenomenon deeply reflects the functional complexity of Piezo1 across different DC subsets (eg, cDC2A) and distinct tumor mechano-microenvironments. The underlying mechanisms may originate from the differential response of Piezo1 to various mechanical signals (such as matrix stiffness and fluid shear stress), which, through modulating calcium influx and downstream signalling pathways, remodels the metabolic and transcriptional programmes of DCs.99,109 Notably, matrix stiffness not only regulates DC function via Piezo1 but also influences the cargo composition of their secreted extracellular vesicles, further transmitting mechanical signals.110 Therefore, an in-depth understanding of the spatiotemporal specificity with which Piezo1 senses and transduces mechanical forces in distinct DC subsets is crucial for precisely modulating antitumor immunity and developing mechano-based immunotherapeutic strategies. In summary, targeting Piezo1 to reshape mechanical signal perception in DCs holds promise as a novel breakthrough for breaking immune suppression and enhancing antitumor responses.

Immune Checkpoints and Inflammatory Regulation

Notably, Piezo1 is closely associated with the expression of immune checkpoint molecules, thereby establishing a novel mechanism underlying tumor immune evasion. Specifically, in glioma, compressive forces upregulate the expression of growth differentiation factor 15 (GDF15) through Piezo1 activation, which in turn enhances CTLA4 levels and suppresses anti-tumor immune responses.56 Furthermore, in a liver metastasis model of non-small cell lung cancer, Piezo1 activation promotes PD-L1 expression by facilitating YAP nuclear translocation; this effect synergizes with anti-PD-1 therapy, suggesting that combined use of Piezo1 agonists may augment the efficacy of immune checkpoint inhibitors.111 Similarly, Piezo1 drives PD-L1 expression in multiple tumor types via the YAP signaling pathway, further underscoring its potential as a sensitizer for immunotherapy.111 However, the function of Piezo1 in immune cells is notably complex: in CD4+ T cells, Piezo1 deficiency promotes the production of IFNγ and IL-17 but paradoxically impairs the formation of effector memory T cells and their in vivo pathogenicity.100 By contrast, in CD11b+ dendritic cells, loss of Piezo1 enhances the cross-priming capacity of CD8+ T cells, thereby inhibiting tumor growth.109 Collectively, these findings reveal that Piezo1-mediated immune regulation is highly context-dependent, with its functional outcome dictated by specific cell types and the mechanical microenvironment.

In summary, Piezo1 acts as a “double-edged sword” in tumor immunity, with its function critically dependent on cell type, the mechanical features of the TME, and the intensity and duration of activation. A deeper understanding of the bidirectional regulatory mechanisms of Piezo1 in T cells, NK cells, macrophages, and dendritic cells is essential for the development of precision immunotherapeutic strategies harnessing mechanical signals. Future research should focus on deciphering the molecular switches governing these cell-type-specific functions, aiming to translate Piezo1 from a promising target into clinically actionable immunotherapies (Figure 4).

Figure 4.

Bidirectional Immunomodulatory Roles of Piezo1 in the Tumour Microenvironment. Piezo1 exerts cell‑type‑specific and context‑dependent effects on tumour immunity: (A) In T cells, moderate Piezo1 activity enhances cytotoxicity, whereas Piezo1 deficiency or inhibition relieves its restraint on TGF-β signaling, leading to FoxP3+ regulatory T cell (Treg) expansion. (B) In natural killer (NK) cells, Piezo1 potentiates cytotoxic granule release and tumour infiltration. (C) In macrophages, soft nanoparticles activate Piezo1 to drive M1‑like polarization, whereas stiff matrix or Piezo1 loss favours M2‑like tumour‑associated macrophages (TAMs). (D) In dendritic cells (DCs), Piezo1 balances TH1/Treg differentiation via IL‑12 and TGF‑β1; DC‑specific Piezo1 deletion enhances CD8⁺ T cell cross‑priming. (E) Piezo1 upregulates immune checkpoints, including PD‑L1 through YAP signalling and CTLA‑4 via the GDF15 axis. Created with BioGDP.com.24

Piezo1-Mediated Ferroptosis

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has recently emerged as a promising avenue in cancer therapy. As an upstream sensor of mechanical forces, Piezo1 has garnered considerable interest for its ability to couple physical microenvironmental signals to the ferroptotic execution program through a distinct signalling cascade.

Current evidence indicates that Piezo1-mediated ferroptosis proceeds via the following cascade of events: first, mechanical stimuli—such as increased extracellular matrix stiffness, shear stress or compressive force—activate the Piezo1 channel;5 subsequently, extracellular Ca²⁺ influx through open Piezo1 channels triggers iron metabolic reprogramming. This process includes upregulation of transferrin receptor 1 (TfR1)-dependent iron uptake, divalent metal transporter 1 (DMT1)-mediated iron transport and nuclear receptor coactivator 4 (NCOA4)-regulated ferritinophagy.112 Consequently, iron overload generates reactive oxygen species (ROS) via the Fenton reaction, which attack membrane lipids to initiate lipid peroxidation.82 Finally, ferroptosis is irreversibly induced through inhibition of glutathione peroxidase 4 (GPX4) activity.113 This iron-dependent lipid peroxidation, culminating in GPX4 inactivation, represents the core molecular machinery of ferroptosis—a conserved execution programme extensively characterised in pathological settings such as ischemia-reperfusion injury and neurological disorders.114–116 Thus, the “mechanical force–Ca²⁺–iron/lipid metabolism” axis mediated by Piezo1 represents a novel therapeutic paradigm in mechanosensitive diseases. Accordingly, a deep understanding of the fine-tuned regulatory network of this molecular axis under various pathological conditions holds substantial theoretical value for developing targeted therapeutic strategies.

The strategy of targeting Piezo1 to induce ferroptosis has been preliminarily validated in multiple malignancies. For instance, in pancreatic cancer, low-intensity pulsed ultrasound (LIPUS) combined with oridonin synergistically induces ferroptosis via the Nrf2/HO-1/GPX4 pathway by activating Piezo1.117 In cervical cancer, matrine effectively induces ferroptosis and exerts anti-tumor effects through Piezo1 activation.63 Conversely, in ovarian cancer, TRIM25 promotes K63-linked ubiquitination and degradation of Piezo1 to suppress ferroptosis, thereby facilitating tumor progression.64 Similarly, in colorectal cancer, the traditional Chinese medicine Changyong Decoction induces ferroptosis by downregulating the Piezo1–PI3K/AKT axis.118 Notably, these findings collectively suggest that the regulatory network of Piezo1-mediated ferroptosis is highly heterogeneous across different cancer types, and the underlying molecular mechanisms warrant further investigation.

Based on the above mechanisms, intervention strategies currently under exploration include direct pharmacological agonists or inhibitors of the Piezo1 channel, modulation of downstream Ca²⁺ signalling, iron chelation, inhibition of lipid peroxidation, and protection of the GPX4/coenzyme Q10 (CoQ10) axis. Nevertheless, it must be recognised that ferroptosis induction has a distinct “double-edged sword” effect: while effectively killing tumor cells, it may also damage normal tissues, particularly those with high metabolic activity. Therefore, achieving spatiotemporally precise regulation of Piezo1—amplifying ferroptotic effects in tumor cells while maximally protecting normal tissues—remains a central challenge for clinical translation in this field. In summary, future research urgently requires the development of novel delivery systems and tissue-specific intervention strategies to overcome this challenge of precise regulation, thereby facilitating the clinical implementation of Piezo1-targeted approaches.

Therapeutic Strategies Targeting Piezo1

Given the critical role of Piezo1 in the progression of various malignancies, this channel has emerged as a promising antitumor therapeutic target in preclinical studies. Current strategies targeting Piezo1 span multiple dimensions, including small-molecule drugs, physical modulation, nanotechnologies, combination therapies and antibody–drug conjugates, each of which is detailed below.

Small-Molecule Agonists and Inhibitors

The development of small-molecule tool compounds has laid a solid foundation for pharmacological interventions targeting Piezo1. Available pharmacological tools for Piezo1 can be broadly classified into agonists and inhibitors. Among the agonists, Yoda1 is the first identified specific small-molecule agonist of Piezo1. It binds to the “blade” domain of the channel, thereby reducing the mechanical threshold for channel activation and inducing channel opening even in the absence of mechanical stimulation.68 However, Yoda1 suffers from poor solubility, which severely limits its in vivo application. To address this challenge, researchers have developed a novel agonist, Yaddle1, through systematic structure–activity relationship analysis. Owing to the presence of a trifluoromethyl group, Yaddle1 exhibits approximately 10-fold higher kinetic solubility (26.72 ± 1.8 μM) compared with Yoda1 (1.22 ± 0.11 μM), while retaining potent agonistic activity.68 Furthermore, other chemically distinct agonists, including Jedi1 and Jedi2, have further enriched the Piezo1 pharmacological toolbox, offering additional options for various experimental settings.97 With respect to inhibitors, currently used Piezo1 inhibitors mainly fall into the following categories. GsMTx4 is a peptide toxin derived from spider venom, but its action is relatively broad-spectrum, inhibiting multiple mechanosensitive channels including Piezo1.71 Dooku1, in contrast, is a competitive antagonist of Yoda1 and exhibits relatively higher specificity.71 Ruthenium red and gadolinium, as non-selective cation channel inhibitors, can block Piezo1 but lack specificity, warranting caution when interpreting experimental results. Notably, in recent years, various natural products have also been identified as Piezo1 inhibitors, including tubeimoside I, salvianolic acid B, jatrorrhizine and escin. These naturally derived inhibitors provide valuable lead compounds for the development of novel antitumor agents.71 In summary, although existing small-molecule tool compounds have provided important means for studying Piezo1 function, their specificity, pharmacokinetic properties and in vivo safety profiles still require further optimisation to facilitate clinical translation. Consequently, the development of next-generation Piezo1 modulators with improved selectivity and drug-like properties remains a key scientific challenge that needs to be addressed in this field, which is essential for ultimately achieving Piezo1-targeted cancer therapy (Table 3).

Table 3.

Summary of Pharmacological Tools Targeting Piezo1

Tool	Type	Selectivity	Mechanism	Bioavailability/Solubility	Limitations	Development STAGE
Yoda1	Agonist	Piezo1-selective tool agonist	Binds to “blade” domain; reduces mechanical activation threshold	Poor aqueous solubility (1.22 ± 0.11 μM in PBS, pH 7.4; kinetic solubility)	Limited in vivo application; off-target effects	Tool compound; preclinical only
Yaddle1	Agonist	Piezo1-selective	Similar to Yoda1; structural optimization	~10-fold higher solubility than Yoda1 (26.72 ± 1.8 μM)	In vivo activity and long-term safety need validation	Next-generation preclinical agonist
Jedi1/Jedi2	Agonist	Piezo1-selective tool agonists	Chemically distinct from Yoda series	Not fully characterized	Less widely used; in vivo data limited	Tool compounds; preclinical
GsMTx4	Inhibitor	Broad-spectrum (Piezo1, TRPC1/6, etc).	Peptide toxin; binds outer leaflet and modulates gating via lipid-mediated membrane interaction, not direct protein–protein interaction	Extremely low oral bioavailability	Poor selectivity; limited to local or in vitro use	Tool peptide; preclinical
Dooku1	Antagonist	Competitive antagonist of Yoda1	Blocks Yoda1-induced activation	Not fully characterized	Ineffective against mechanically evoked Piezo1 opening	Tool compound; preclinical
Ruthenium Red	Inhibitor	Non-selective cation channel blocker	Pore blocker	N/A	Lacks specificity; multiple off-target effects	Non-selective tool; not suitable for clinical translation
Gadolinium (Gd3⁺)	Inhibitor	Non-selective cation channel blocker	Pore blocker	N/A	Lacks specificity; multiple off-target effects	Non-selective tool; not suitable for clinical translation
Tubeimoside I	Inhibitor	Natural product; selectivity not fully established	Not fully elucidated; likely allosteric	Moderate	Selectivity and potency need optimization	Preclinical lead compound
Salvianolic Acid B	Inhibitor	Natural product; selectivity not fully established	Not fully elucidated; likely allosteric	Moderate	Selectivity and potency need optimization	Preclinical lead compound
Jatrorrhizine	Inhibitor	Natural product; selectivity not fully established	Not fully elucidated; likely allosteric	Moderate	Selectivity and potency need optimization	Preclinical lead compound
Escin	Inhibitor	Natural product; selectivity not fully established	Not fully elucidated; likely allosteric	Moderate	Selectivity and potency need optimization	Preclinical lead compound

Recent advances in understanding the high-resolution cryo-EM structures of Piezo1 in closed, open, and intermediate conformations have opened new avenues for rational drug design. The Yoda1-binding site has been mapped to the distal blade domain, specifically involving residues from the extracellular loops of the transmembrane helices. Structure–activity relationship (SAR) studies have revealed that the trifluoromethyl group in Yaddle1 enhances kinetic solubility by approximately 10-fold while maintaining agonistic potency, highlighting the critical role of halogenated substituents in improving drug-like properties.119 For inhibitor development, the peptide toxin GsMTx4 binds to the outer leaflet of the membrane and modulates Piezo1 gating through a lipid-mediated mechanism rather than direct protein–protein interaction, which explains its broad-spectrum activity across multiple mechanosensitive channels.120 This mechanistic insight suggests that improving selectivity may require targeting protein-specific pockets rather than lipid-interacting regions. Computational approaches, including molecular dynamics simulations and free-energy perturbation (FEP) calculations, are currently being employed to identify cryptic binding sites on the Piezo1 protein that could accommodate small-molecule inhibitors with enhanced specificity. Importantly, given the structural homology between Piezo1 and Piezo2 (∼40% sequence identity in the pore-forming region), achieving >100-fold selectivity remains a major challenge that will likely require targeting non-conserved regions such as the extracellular cap domain or the beam-like intracellular structures.

Ultrasound and Mechanical Regulation

In recent years, physical modulation of Piezo1 activity has garnered increasing attention as a non-invasive therapeutic strategy. Among these approaches, low-intensity pulsed ultrasound (LIPUS) has demonstrated unique advantages in cancer therapy by activating Piezo1 through mechanical effects. For instance, in pancreatic cancer research, LIPUS combined with oridonin synergistically induces ferroptosis in tumor cells, a process involving the accumulation of lipid peroxides via the Nrf2/HO-1/GPX4 pathway following LIPUS-mediated Piezo1 activation.117 Furthermore, in bladder cancer, programmed mechanical pressure triggers a calcium cascade by activating Piezo1, reversibly enhancing cell membrane permeability and thereby increasing the intracellular accumulation of chemotherapeutic agents (eg, doxorubicin and mitomycin C), achieving a “mechano-chemotherapy” synergistic effect.121 Of note, in keloids—benign fibroproliferative tumors—low-frequency ultrasound not only inhibits fibroblast proliferation through Piezo1 activation but also remodels fibrotic tissue via cavitation effects, effectively alleviating the pain associated with injection therapy.72,122 On the other hand, ultrasound microbubble (USMB) technology has been shown to induce endoplasmic reticulum stress and mitochondrial dysfunction through Piezo1 activation, thereby effectively promoting apoptosis in breast cancer cells.66 Collectively, these findings suggest that ultrasound-based physical intervention strategies possess broad-spectrum antitumor potential and may serve as a standardized adjuvant therapeutic approach.

Concurrently, cyclic stretching has been explored as a novel method for selectively killing mesenchymal-like tumor cells.123 The core mechanism involves membrane bending, focal adhesion disruption, and intracellular calcium homeostasis imbalance. Owing to the marked differences in membrane viscoelastic properties between mesenchymal-like tumor cells and normal epithelial cells, cyclic stretching selectively induces apoptosis in the former while minimally affecting the migration and proliferation of healthy epithelial cells.123 From a biophysical perspective, this selectivity arises from inherent differences between the two cell types in terms of membrane lipid bilayer bending stiffness, cytoskeleton-matrix coupling strength, and the mechanogating response of the Piezo1 channel.123 These studies not only enrich our understanding of the mechanical phenotypic heterogeneity of tumor cells but also lay a theoretical foundation for developing precision therapeutic strategies based on mechanical differences. In summary, mechanical regulation strategies hold promise as non-invasive or minimally invasive approaches for precisely targeting the mechanical phenotype of tumors, and their substantial potential in combination therapy and physical immunotherapy warrants further preclinical and clinical exploration.

Nanotechnology and Targeted Delivery

Significant progress has recently been made in Piezo1-based nanomechanical modulation strategies, with the core concept being the precise engineering of the physicochemical properties of nanomaterials to effectively intervene in Piezo1-mediated mechanotransduction. This approach expands the function of nanomaterials from conventional “drug delivery vehicles” to “biomechanical signal modulators”. For instance, in the context of nanoparticle elasticity modulation, researchers have synthesized mesoporous silica nanoparticles with tunable elastic moduli (ranging from 81 MPa to 837 MPa). They found that nanoparticles with a relatively lower elastic modulus (approximately 81 MPa)—which, although considerably stiffer than biological tissues (typically ranging from 0.1 to 100 kPa), are considered “soft” in the context of nanoparticle engineering compared with their rigid counterparts (837 MPa)— can reprogramme TAMs from an immunosuppressive M2 phenotype to an antitumor M1 phenotype by activating Piezo1 channels, thereby inhibiting tumor growth and activating adaptive immune responses.104 Notably, this discovery not only reveals the critical role of nanoparticle elasticity in immune regulation, but also provides a new paradigm for developing mechano-signalling-based cancer immunotherapy, highlighting the broad potential of modulating cell fate through physical properties.

Meanwhile, in terms of targeted delivery strategies, an undecarginine peptide (R11) designed on the basis of the Piezo1/integrin β1 positive-feedback loop has demonstrated efficient targeted delivery capacity in the treatment of bladder cancer. This peptide specifically binds to integrin β1 through hydrogen bonding, while concurrently activating Piezo1 channels to promote membrane fusion and calcium release, thereby establishing a positive-feedback cycle that enhances endocytosis and significantly improves the intracellular delivery efficiency of drugs.124 Furthermore, for central nervous system disorders, researchers have developed CAQKERM@GsMTx4 engineered endoplasmic reticulum membrane nanomedicines. These agents can target acute haemorrhagic areas and successfully treat subarachnoid haemorrhage by inhibiting Piezo1 channels, opening new avenues for the application of mechano-signal intervention in central nervous system diseases.108 Collectively, these advances indicate that nanotechnology-based Piezo1 modulation strategies not only hold great promise for cancer therapy, but also exhibit broad application prospects in non-neoplastic diseases (such as cerebrovascular disorders), laying a solid foundation for the further development of precision mechanomedicine.

Combination Therapeutic Strategies

Given the central role of Piezo1 in tumor mechanotransduction, the combination of its modulators with existing therapeutic regimens holds considerable promise, with synergistic effects observed across multiple cancer types.9 In the context of combination with chemotherapeutic agents, modulation of Piezo1 can significantly influence the drug sensitivity of tumor cells. Studies have shown that Piezo1 agonists or antagonists can enhance or reverse the efficacy of specific chemotherapies, respectively. For instance, in hepatocellular carcinoma, the Jianpi Huayu formula combined with doxorubicin significantly enhances antitumor effects by downregulating Piezo1 expression and inhibiting the PI3K/AKT/mTOR pathway to induce autophagy.125 Furthermore, activation of Piezo1 can synergize with oxaliplatin via CXCL8-mediated inflammatory responses to suppress tumor progression.27 Notably, in pancreatic ductal adenocarcinoma, three-dimensional matrix stiffness promotes gemcitabine resistance through Piezo1-mediated glycolysis, whereas inhibition of Piezo1 effectively reverses this resistant phenotype, offering a novel strategy to overcome chemoresistance in solid tumors.47 Collectively, these findings indicate that targeting Piezo1 may serve as an effective means to enhance conventional chemotherapy sensitivity, opening new avenues for reversing drug resistance.

In combination with immunotherapy, Piezo1 also demonstrates substantial potential. Specifically, in a liver metastasis model of non-small cell lung cancer, the Piezo1 agonist Yoda1 combined with anti-PD-1 therapy significantly improved immune responses, with the mechanism involving YAP-mediated upregulation of PD-L1 expression and increased CXCL10 secretion, thereby promoting CD8+ T cell infiltration into tumors and converting “cold” tumors into “hot” ones.111 Moreover, Piezo1 plays a critical role in cellular immunotherapy: studies have revealed that moderate expression of Piezo1 in CAR-T cells through genetic engineering enhances their mechano-metabolic coupling efficiency and thus boosts their cytotoxic function, whereas hyperactivation or inactivation leads to T cell exhaustion, suggesting a “golden window” for Piezo1 activity.93 Concurrently, in tumor-associated macrophages, activation of Piezo1 using nanoparticles of specific stiffness promotes their polarization and reprogramming from the M2 to the M1 phenotype, mediated by exosome-driven immune amplification, providing a new paradigm for nanomechanical immunoengineering.102 Together, these studies underscore Piezo1 as a key node linking the physical microenvironment to immune responses, offering multiple potential intervention targets for improving cancer immunotherapy outcomes.

Furthermore, the combination of Piezo1 modulators with various physical and targeted therapeutic strategies has yielded notable progress. In combination with photothermal therapy, Yoda1 significantly enhances the sensitivity of TiCN nanomaterial-mediated photothermal therapy in breast cancer by augmenting reactive oxygen species production.73 In combination with TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), activation of Piezo1 promotes calcium influx and subsequent calpain activation, leading to increased mitochondrial outer membrane permeabilization, thereby synergistically enhancing TRAIL-induced apoptosis in glioma cells and offering a new approach to overcome TRAIL resistance.69 In the field of mechanochemotherapy, programmed mechanical pressure activates Piezo1 in bladder cancer cells, transiently increasing cell membrane permeability and thereby significantly enhancing intracellular accumulation of chemotherapeutic drugs, which augments antitumor efficacy while reducing mucosal toxicity.121 In summary, combination strategies involving Piezo1 modulators with chemotherapy, immunotherapy, physical therapies and targeted apoptosis-inducing agents, through multi-mechanistic and multi-pathway synergistic actions, provide a rich array of options to overcome tumor resistance and enhance therapeutic sensitivity, representing a highly promising direction for future personalized cancer therapy.

Antibody–Drug Conjugates (ADCs)

Given the aberrantly high expression of Piezo1 on the plasma membrane of various solid tumor cells, its extracellular domain can be recognized by specific antibodies, making it an ideal target for the development of antibody–drug conjugates (ADCs). For instance, in a study on esophageal squamous cell carcinoma, the researchers employed high-throughput membrane-anchored proteomics screening and identified PIEZO1 as being specifically overexpressed in tumor tissues. Based on this finding, they successfully developed a novel ADC by conjugating an anti-PIEZO1 antibody with the microtubule inhibitor monomethyl auristatin E (MMAE). Notably, this ADC selectively killed PIEZO1-high esophageal squamous cell carcinoma cells, significantly suppressed tumor progression in xenograft models, and exhibited no obvious toxicity.13 This study provides the first proof-of-concept for targeting Piezo1 with ADCs, opening up a new direction for drug development in this field. Moreover, given the aberrant expression and favourable internalization properties of Piezo1 across multiple solid tumor types, Piezo1-based ADC strategies hold promise for extension to a broader range of cancers, offering new options for targeted therapy. In summary, Piezo1-targeted therapeutic strategies are at a critical stage of accelerating translation from basic research to clinical application. The development of precision-targeted therapies such as ADCs, along with the exploration of multimodal and multi-mechanism combination intervention strategies, will represent major future directions (Figure 5).

Figure 5.

Therapeutic Strategies Targeting Piezo1 and Major Clinical Challenges. Left: Piezo1‑targeted intervention modalities, including small‑molecule modulators (agonists/inhibitors), physical regulation (low‑intensity pulsed ultrasound, cyclic stretch, programmed pressure), nanotechnology‑based approaches (elasticity‑tunable nanoparticles, R11 peptide‑mediated delivery), antibody–drug conjugates (anti‑Piezo1–MMAE), and rational combinations (chemotherapy, immunotherapy, photothermal therapy). Right: Key translational hurdles, comprising tissue‑specific toxicity due to widespread physiological expression, context‑dependent and cancer‑type‑specific functionality, suboptimal pharmacological properties of current tools, and drug resistance driven by mechanical microenvironmental heterogeneity. The central balance scale highlights the critical challenge of striking an efficacy‑safety equilibrium for Piezo1‑based therapies. Created with BioGDP.com.24

The extracellular accessibility of Piezo1’s large cap domain, which contains multiple surface-exposed epitopes, makes it an attractive target for antibody-based therapeutics. However, several technical challenges must be addressed: (i) the cap domain undergoes conformational changes upon channel opening, potentially affecting antibody binding affinity in a mechano-dependent manner; (ii) the internalization rate of Piezo1 after antibody binding needs to be characterized to ensure efficient intracellular delivery of the payload; (iii) the density of Piezo1 on the cell surface varies considerably across cancer types and even within tumors, necessitating careful patient selection strategies. The proof-of-concept study by Qin et al demonstrated that an anti-PIEZO1 antibody conjugated to MMAE exhibited potent cytotoxicity in PIEZO1-high esophageal squamous cell carcinoma xenografts, with an IC₅₀ in the low nanomolar range and acceptable in vivo toxicity.13 However, it should be emphasized that this is currently the only published Piezo1-targeted ADC study, and its findings await independent validation. Future ADC development efforts should focus on: (i) identifying antibodies with high specificity for tumor-associated PIEZO1 epitopes over the native protein expressed in normal tissues; (ii) optimizing the drug-to-antibody ratio (DAR) to maximize efficacy while minimizing off-target effects; and (iii) evaluating the therapeutic window in preclinical models that recapitulate human tissue expression patterns.

Drug Development Pipeline and Clinical Translation Roadmap

The development of Piezo1-targeted therapeutics is currently at an early stage, with no agents having entered clinical trials. The translational pipeline can be conceptualized in three phases:

Tool compounds for mechanistic studies (current status): Yoda1, GsMTx4, Dooku1, and Yaddle1 serve as valuable research tools for dissecting Piezo1 biology. However, their poor pharmacokinetic properties, limited selectivity, and suboptimal bioavailability preclude clinical development.

Lead optimization and preclinical validation (next 2–5 years): Key activities in this phase include: (a) medicinal chemistry optimization of Yaddle1 and related scaffolds to improve potency, selectivity, and in vivo half-life; (b) development of allosteric modulators targeting non-conserved domains; (c) preclinical efficacy and toxicity studies in immunocompetent animal models and patient-derived xenografts; and (d) formulation development for tumor-targeted delivery (eg, nanoparticles, liposomal encapsulation, or ADC conjugation).

Clinical development (5–10+ years): The first-in-human trials would likely target biomarker-selected patient populations with high Piezo1 expression and well-characterized mechanical microenvironments. Potential clinical indications include: (a) Piezo1-high solid tumors (eg, esophageal squamous cell carcinoma, glioblastoma, pancreatic cancer) treated with Piezo1 inhibitors or ADCs; (b) lung adenocarcinoma and clear cell renal cell carcinoma where Piezo1 functions as a tumor suppressor, potentially treated with Piezo1 agonists; and (c) combination strategies with immune checkpoint inhibitors based on the mechano-immune synergy observed in preclinical studies.

Importantly, the regulatory pathway for Piezo1 modulators will require careful consideration of tissue-specific toxicity due to the channel’s broad physiological expression. Regulatory agencies (eg, FDA, EMA) may require extensive safety pharmacology studies beyond standard ICH guidelines, including assessment of cardiovascular, hematopoietic, and lymphatic system effects.

Challenges in Clinical Translation

Although Piezo1 holds considerable promise as a therapeutic target in cancer, its clinical translation is confronted with multiple challenges that span tissue specificity, cancer type dependency, pharmacological tools, physical modulation strategies, and tumor heterogeneity.

The Dilemma of Tissue Specificity

Piezo1 is widely expressed in human tissues and participates in diverse physiological processes, including blood pressure regulation, erythrocyte volume homeostasis, and lymphatic development.78 Foundational studies from 2015–2020 established these physiological roles: Piezo1 was shown to mediate shear stress-induced endothelial cell alignment and vascular tone regulation, to govern erythrocyte volume homeostasis in response to osmotic and mechanical challenges, and to be essential for lymphatic valve development and maintenance.67,126,127 As a result, systemic activation or inhibition of Piezo1 may lead to severe adverse effects, such as cardiovascular events, anaemia, or lymphoedema. For instance, gain-of-function mutations in Piezo1 cause hereditary xerocytosis,128 whereas loss-of-function mutations are closely associated with lymphatic malformations.129 Moreover, Piezo1 plays a critical role in ventricular remodelling after myocardial infarction, where Piezo1-mediated neurogenic inflammatory cascades markedly exacerbate cardiac injury.130 Given these broad and essential physiological functions and the associated pathological risks, the development of tissue-specific delivery systems (eg, nanoparticles, antibody–drug conjugates) or local administration routes (eg, intravesical instillation, intratumoral injection) has become a core strategy for the clinical translation of Piezo1-based therapies.

Cancer Type-Dependent Functional Differences

As noted above, Piezo1 exhibits diametrically opposite functional phenotypes across different cancer types. Of particular note, in most solid tumors including breast cancer, gastric cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer and glioma, Piezo1 acts as an oncogene promoting malignant progression. By contrast, in lung cancer and clear cell renal cell carcinoma, Piezo1 is expressed at low levels or exerts tumor-suppressive functions.15,38 This strong context dependency implies that Piezo1-based therapeutic strategies must be tailored on a case-by-case basis: inhibitors (eg, GsMTx4, Dooku1) should be used in tumors with high Piezo1 expression and oncogenic activity, whereas agonists (eg, Yoda1, Yaddle1) are indicated in tumors where Piezo1 is downregulated or functions as a tumor suppressor. Therefore, precise identification of responsive patient populations and the design of interventions based on the specific mechanical microenvironment of each tumor type are essential prerequisites for the successful clinical translation of Piezo1-targeted therapies.

Limitations of Pharmacological Tools

Existing pharmacological modulators of Piezo1 have notable shortcomings that severely restrict their potential for clinical translation.78 For instance, although the first-generation agonist Yoda1 is widely used, it exhibits poor water solubility (1.22 ± 0.11 μM in phosphate‑buffered saline at pH 7.4, as determined by kinetic solubility assays), unfavourable pharmacokinetic properties in vivo, and clear off-target effects.68 Nevertheless, Yoda1 has shown non-negligible therapeutic potential in vivo; for example, in mouse models of craniosynostosis and ageing, Yoda1 treatment effectively reduced intracranial pressure, restored cerebrospinal fluid flow, and improved brain–cerebrospinal fluid perfusion, thereby demonstrating the therapeutic feasibility of Piezo1 agonists.25 Therefore, the development of improved agonists represents a key direction for overcoming current bottlenecks. By contrast, the broad-spectrum inhibitor GsMTx4, a peptide, has extremely low oral bioavailability and limited selectivity for Piezo1 (it also inhibits TRPC1/6 and other ion channels). To overcome this obstacle, engineered endoplasmic reticulum membrane vesicles have been used to deliver GsMTx4, aiming to achieve targeted inhibition of Piezo1 and thereby improve its therapeutic window.108 Furthermore, the antagonist Dooku1 only competitively blocks Yoda1-induced activation and may be ineffective against Piezo1 opening directly triggered by mechanical stimulation, which limits its widespread application in mechanotransduction studies. Hence, there is an urgent need in the field to develop highly selective inhibitors with distinct mechanisms of action. Of note, the next-generation agonist Yaddle1 has achieved marked improvements in solubility, but its in vivo activity and long-term safety still require comprehensive validation.68 Additionally, natural products such as tubeimoside I, salvianolic acid B, jatrorrhizine, and escin have also shown Piezo1 inhibitory activity, offering novel chemotypes for drug discovery, although their selectivity and potency need further optimisation.71 In summary, the development of highly selective, bioavailable, orally available small-molecule modulators of Piezo1 is an urgent requirement and a central challenge for clinical translation in this field.

Clinical Translation Barriers of Mechanical Force Stimulation

Although physical manipulation methods such as ultrasound and cyclic stretching offer non-invasive advantages, their clinical translation remains hampered by multiple challenges, as detailed below. First, there is a notable lack of standardization in equipment parameters. The ultrasound parameters employed across different studies—such as frequency, intensity, and duty cycle—vary considerably, which complicates cross-study comparisons and consequently impedes clinical adoption. For instance, low-intensity pulsed ultrasound combined with oridonin can induce ferroptosis in pancreatic cancer cells via Piezo1 activation,117 whereas low-frequency ultrasound suppresses the malignant phenotypes of keloid fibroblasts through Piezo1 activation.72 Second, accessibility to deep-seated tumors is limited. Low-intensity ultrasound exhibits restricted penetration depth for tumors located deep within the body (eg, pancreatic and liver cancers), thereby undermining its therapeutic efficacy to some extent. Moreover, the risk of damage to normal tissues cannot be overlooked. Mechanical stimulation may non-specifically activate Piezo1 channels in healthy tissues, potentially triggering unintended side effects such as pain and inflammation. Notably, cyclic stretching exerts a selective cytotoxic effect on mesenchymal-like cancer cells, while promoting migration and proliferation in normal epithelial cells—a differential response that may provide a potential safety window for physical therapy.123 Collectively, overcoming device parameter heterogeneity, improving deep-tissue penetration, and precisely distinguishing the mechanical responses of malignant versus normal cells represent critical bottlenecks that must be addressed to advance Piezo1-based mechanotherapy towards clinical application.

The heterogeneity in ultrasound parameters across studies—including frequency (ranging from 20 kHz to 3 MHz), intensity (0.1–3 W/cm²), duty cycle (10–100%), and treatment duration (minutes to hours)—severely complicates cross-study comparisons and hinders the establishment of standardized clinical protocols. For instance, low-intensity pulsed ultrasound (LIPUS) at 1.5 MHz and 30 mW/cm² combined with oridonin induces ferroptosis in pancreatic cancer cells, whereas low-frequency ultrasound at 40 kHz with higher intensity suppresses keloid fibroblast proliferation through mechanistically distinct pathways.25 Similarly, cyclic stretch parameters—including strain amplitude (typically 5–20%), frequency (0.1–2 Hz), and total number of cycles—vary widely across studies, making it difficult to determine the optimal “mechano-dose” for therapeutic efficacy. The lack of standardized parameters represents a major barrier to clinical translation, as device settings cannot be directly compared or optimized. To address this, we propose that future studies should (i) adopt standardized reporting guidelines for mechanical stimulation parameters, (ii) systematically investigate the dose–response relationship between mechanical parameters and Piezo1 activation, and (iii) develop closed-loop feedback systems that monitor real-time tissue deformation and adjust stimulus parameters accordingly.

Drug Resistance and Tumor Heterogeneity

Tumor heterogeneity has emerged as a common cause of targeted therapy failure. Notably, the expression level of Piezo1 can differ significantly between primary tumors and their metastatic lesions. For instance, the mechanical compression experienced by circulating tumor cells when passing through narrow capillaries is sufficient to induce stem cell-like reprogramming via Piezo1.62 This finding suggests that even if primary tumors are sensitive to Piezo1-targeted therapies, circulating tumor cells or established metastases may acquire adaptive resistance due to their distinct mechanical microenvironment. Furthermore, high-fat diet-induced extracellular matrix remodeling markedly promotes chemoresistance in prostate cancer by activating Piezo1-dependent mitochondria–endoplasmic reticulum contacts.86 Thus, heterogeneity within the tumor and the metastatic microenvironment directly confers differential pro-tumorigenic and drug-resistant functions on Piezo1 signaling pathways. In addition, Piezo1 engages in complex crosstalk with multiple key signaling pathways (eg, YAP, PI3K/AKT, MAPK, and Wnt), which can readily lead to compensatory pathway activation and thereby compromise the efficacy of single-agent targeted therapy. For example, increased three-dimensional matrix stiffness promotes gemcitabine resistance in pancreatic cancer through Piezo1-mediated glycolysis,47 whereas matrix stiffness drives angiogenesis and therapy resistance via the Piezo1/HIF-1α axis in hepatocellular carcinoma.76 Consequently, co-targeting Piezo1 and its downstream effectors—for instance, combining Piezo1 inhibitors with standard chemotherapeutic agents—may represent an effective strategy to overcome the above-mentioned resistance. In support of this, the Jianpi Huayu decoction has been shown to enhance chemosensitivity to doxorubicin in liver cancer cells by downregulating Piezo1 expression.125 Collectively, these lines of evidence highlight the substantial potential of Piezo1-centered combination regimens in reversing tumor resistance. In summary, the clinical translation of Piezo1-targeted therapies necessitates a comprehensive consideration of multiple complex factors, including tissue specificity, cancer type, the properties of available pharmacological tools, the precision of physical modulation parameters, and tumor heterogeneity, in order to develop truly individualized precision treatment strategies.

Future Perspectives and Potential Strategies

Emerging evidence positions Piezo1 as a central mechanotransducer in cancer, yet translating this knowledge into clinical practice remains challenging. The following six sections systematically outline key translational avenues—from biomarker development and structure-guided drug design to combination therapies, gene editing, organoid models, and novel targeting modalities—providing a roadmap to harness Piezo1 biology for precision oncology and mechanomedicine.

Biomarker Development from a Precision Medicine Perspective

In summary, Piezo1 functions as a key sensor and transducer of the mechanical microenvironment, exerting complex and central regulatory effects across multiple stages of cancer initiation and progression. However, translating these fundamental insights into clinical practice faces substantial challenges, including the functional heterogeneity of Piezo1 across different cancer types and disease stages, the selectivity and delivery issues associated with existing pharmacological tools, and the lack of reliable predictive biomarkers of therapeutic response. Addressing these bottlenecks will require systematic exploration and innovation along several dimensions. Indeed, the value of Piezo1 as a pan-cancer prognostic marker has been corroborated by multiple studies, showing that its expression levels significantly correlate with patient survival in various malignancies, including glioma, gastric cancer, and breast cancer.10,11,35,131 These findings establish the potential of Piezo1 as a pan-cancer prognostic biomarker; nevertheless, its translation into a clinically applicable companion diagnostic tool still necessitates resolution of several critical issues. For instance, with regard to predictive biomarkers, future research should systematically assess whether the expression level, activation status, or specific splicing variants of Piezo1 in tumor tissues or peripheral blood can effectively predict patient responses to different therapeutic strategies, particularly Piezo1-targeted agents combined with chemotherapy or immunotherapy. In a model of non-small cell lung cancer liver metastasis, the activation level of Piezo1 was found to be closely associated with the response rate to anti-PD-1 therapy,111 strongly suggesting that Piezo1 expression profiles may serve as a screening indicator for immunotherapy benefit. Consequently, establishing a causal relationship between Piezo1 status and the efficacy of specific therapies represents a critical step towards its clinical translation as a predictive biomarker.

Moreover, liquid biopsy applications represent a highly promising direction: exploring whether Piezo1 mRNA or protein levels in serum exosomes can serve as non-invasive diagnostic or treatment monitoring biomarkers. Research has demonstrated that matrix stiffness can regulate the loading of Piezo1 into exosomes released by three-dimensional tumor spheroids, and that these exosomes carry miRNA signatures characteristic of tumor progression,110 thereby providing a robust theoretical basis for developing a liquid biopsy-based Piezo1 detection system. Accordingly, exosome-based Piezo1 detection holds promise for minimally invasive, dynamic monitoring of tumor progression. Concurrently, in-depth investigation of the correlation between Piezo1 expression levels and imaging parameters—such as tissue stiffness measured by magnetic resonance elastography or perfusion parameters from conventional contrast-enhanced scans—also holds significant clinical translational value. Studies have revealed that Piezo1 overexpression in glioblastoma tissues is significantly positively correlated with the peritumoral brain oedema index,132 suggesting that specific imaging features may serve as non-invasive surrogate markers of Piezo1 activity. Integrating these imaging and molecular pathological data could provide a novel strategy for assessing Piezo1 status without the need for repeat biopsies. Collectively, integrating the above multidimensional biomarkers—including genomic, proteomic, imaging, and liquid biopsy indicators—holds the potential to establish a precise patient stratification system, thereby providing a robust foundation for individualised therapeutic decisions targeting Piezo1 signalling.

Structure-Guided Drug Design and Novel Drug Development

The elucidation of the high-resolution three-dimensional structure of Piezo1 has laid a solid molecular foundation for rational drug design.78 The channel exhibits a unique three-bladed propeller-like conformation, and the molecular basis of its mechanosensitivity is being gradually uncovered. Leveraging cutting-edge technologies such as artificial intelligence-assisted virtual screening, molecular dynamics simulations, and free-energy perturbation calculations, several classes of novel Piezo1-targeting molecules are expected to be developed: (1) Highly selective modulators: Building on existing agonists such as the Yoda series and inhibitors such as GsMTx4, structure-based optimization can substantially improve isoform selectivity and pharmacokinetic properties. For instance, a recent study has developed a novel agonist named Yaddle1, which exhibits significantly superior solubility compared to Yoda1 and shows promising vaccine adjuvant potential in T cell activation.68 (2) “Biased” ligands: Designing biased ligands that target specific domains of Piezo1 could selectively block its pathological mechanoactivation (eg, under aberrant matrix stiffness or compressive stress) while preserving its basal physiological activities (eg, maintenance of vascular tone or erythrocyte volume homeostasis). (3) Allosteric modulators: Discovering modulators that target non-conserved allosteric sites may avoid direct competition with endogenous mechano-activating ligands (such as membrane lipid components or cholesterol), thereby enhancing the selectivity and safety of the intervention. Given that membrane cholesterol organization is critical for the function of Piezo1 channel clusters,22 targeting the surrounding lipid microenvironment may represent an indirect yet sophisticated regulatory strategy. Collectively, these structure-based drug development strategies will provide a broader array of efficient chemical tools for the precision treatment of Piezo1-associated diseases.

Systematic Optimization of Combination Therapy Strategies

Piezo1-based combination therapy strategies require systematic optimization according to the functional role (pro-tumorigenic or tumor-suppressive) of Piezo1 in different cancer types, with the goal of achieving synergistic efficacy. First, with regard to spatiotemporal synergy strategies, optimizing the temporal coordination between ultrasound-mediated Piezo1 activation and chemotherapeutic drug administration is particularly critical. Studies have shown that programmed mechanical pressure can trigger a calcium ion cascade via Piezo1 activation, transiently enhancing the membrane permeability of bladder cancer cells, thereby significantly increasing intracellular chemotherapeutic drug accumulation and anti-tumor efficacy while mitigating mucosal toxicity.121 Similarly, low-intensity pulsed ultrasound combined with the natural compound oridonin can synergistically induce ferroptosis in pancreatic cancer cells through Piezo1 activation.117 Therefore, rational scheduling of physical stimulation and drug exposure represents a promising physical sensitization strategy to improve the chemotherapeutic window index.

Second, in terms of immuno-combination strategies, the co-application of Piezo1 agonists and immune checkpoint inhibitors should be actively explored, particularly the strategy of converting “cold tumors” into “hot tumors”. In a liver metastasis model of non-small cell lung cancer, Piezo1 activation upregulates PD-L1 expression and promotes the secretion of the CD8+ T cell chemokine CXCL10, thereby significantly improving the response rate to anti-PD-1 therapy.111 Moreover, modulating the elasticity of nanoparticles to activate Piezo1 on tumor-associated macrophages can reprogram these cells from a pro-tumorigenic M2-like phenotype to an anti-tumorigenic M1-like phenotype, thereby enhancing anti-tumor immunity.102,104 Collectively, targeting Piezo1 not only remodels the tumor immune microenvironment but also relieves immune suppression, offering a novel avenue for combination with immune checkpoint blockade.

Finally, with respect to metabolic intervention strategies, precise targeting of Piezo1-dependent metabolic pathways is required. Studies have revealed that statins (eg, fluvastatin and pitavastatin) can disrupt the ability of melanoma cells to sense membrane tension in confined spaces by reducing intracellular cholesterol levels, thereby inhibiting Piezo1-mediated amoeboid migration.95 Of note, in a high-fat diet-induced chemotherapy-resistant prostate cancer model, combined use of statins and a Piezo1 inhibitor restored matrix stiffness normalization and re-established mitochondria–endoplasmic reticulum contact integrity, thereby reversing chemoresistance.86 These findings highlight the central role of the “metabolic–mechanobiological” crosstalk in the development of drug resistance, and suggest that combined intervention targeting lipid metabolism and mechanotransduction may overcome therapy resistance driven by matrix stiffening.

Gene Editing and Cell Engineering

Gene editing technologies such as CRISPR-Cas9 provide powerful tools for the precise functional modulation of Piezo1, with particularly promising applications in cell-based therapies. For instance, moderate upregulation of Piezo1 in chimeric antigen receptor T cells (CAR-T) significantly enhances their cytotoxic function; studies indicate that Piezo1 activity follows the “Goldilocks principle” – intermediate levels of activation maximize the killing efficacy of CAR-T cells, whereas excessively low or high activity impairs their “mechano-metabolic fitness”, leading to functional exhaustion.93 Furthermore, in the context of improving dendritic cell (DC) vaccines, conditional knockout of Piezo1 in CD11b⁺ dendritic cells markedly enhances their antigen cross-presentation capacity, promotes CD8⁺ T cell activation, and thereby improves the efficacy of DC-based tumor vaccines.109 Going a step further, base editing technologies also show tremendous potential: using adenine or cytosine base editors, key functional domains of the PIEZO1 gene (eg, the pore region and mechanosensory domains) can be precisely modified without introducing double-strand DNA breaks, thereby mimicking or correcting gain- or loss-of-function mutations associated with human diseases.133,134 Collectively, these gene editing strategies offer unprecedented precision for developing “living drug cells” and correcting Piezo1 dysfunctions, and are expected to establish a new paradigm for cancer mechano-immunotherapy by finely tuning Piezo1 expression and function.

Construction and Application of Organoid and Organ-on-a-Chip Models

Patient-derived tumor organoids and organ-on-a-chip technologies provide a microenvironment platform that more closely resembles physiological conditions for the screening of Piezo1-targeted drugs and mechanistic studies, thereby overcoming the limitations of conventional two-dimensional culture models. For example, researchers have constructed microfluidic chips that recapitulate the stiffness gradient from the softer tumor edge to the stiffer tumor centre, enabling the study of Piezo1-mediated “durotaxis”. Notably, in pancreatic stellate cells, Piezo1 cooperates with TRPC1 and TRPV4 channels to collectively guide cell migration towards stiffer matrix, and this complex process can even be accurately described by mathematical models.30 Moreover, the development of tumor-on-a-chip models incorporating functional vascular networks provides a powerful tool to investigate the survival mechanisms of circulating tumor cells under fluid shear stress and the dynamic changes in Piezo1 expression. A key study has demonstrated that compressive stress at capillary constrictions can reprogramme melanoma cells into a more tumorigenic, cancer stem cell-like state through Piezo1 activation;62 using organ-on-a-chip technology, this critical metastatic initiation process can be precisely simulated in vitro and subjected to intervention assessment, highlighting the unique value of such platforms in dissecting the pro-metastatic mechanisms of mechanical signals. Finally, stratifying patient-derived tumor organoids based on Piezo1 expression levels enables individualized drug sensitivity testing, directly guiding clinical treatment choices.74 Given that these three-dimensional models better preserve the original tumor’s mechanical heterogeneity and extracellular matrix features, they hold promise for significantly improving the predictive accuracy of preclinical drug evaluation. Therefore, integrating Piezo1 expression profiling into organoid-based drug screening systems represents a crucial step towards achieving personalized cancer mechanomedicine.

Emerging Modalities for Targeting Piezo1

Beyond conventional small molecules and antibody-based drugs, a range of novel targeting modalities are emerging, opening up further possibilities for pharmacological intervention on Piezo1 that are currently at various stages of preclinical exploration. PROTAC technology: By developing proteolysis-targeting chimeras (PROTACs) directed against Piezo1, the ubiquitin-proteasome pathway can be harnessed to induce selective degradation of the Piezo1 protein – a strategy that is particularly relevant for malignancies with Piezo1 overexpression. This approach promises to overcome the limitations of traditional ion channel inhibitors and achieve more sustained signal blockade. Indeed, recent studies have demonstrated that modulating Piezo1 stability through ubiquitination holds great potential in cancer therapy.64 Accordingly, PROTAC technology offers a novel pharmacological strategy that warrants further investigation for eliminating hyperactivated Piezo1.

Cyclic Peptide Development

Designing peptide molecules with cyclic structures aims to circumvent the inherent limitations of linear peptides (eg, GsMTx4), such as low oral bioavailability and poor in vivo stability. Cyclic peptides combine the high affinity of antibodies with the favourable tissue permeability of small molecules, making them a highly promising direction for Piezo1 modulator development. In fact, a deep understanding of Piezo1’s distribution pattern on the cell membrane and its interaction with focal adhesions is crucial for designing potent and specific cyclic peptide modulators.19,32 Consequently, advances in cyclic peptide chemistry provide a solid technological foundation for translating fundamental biological discoveries on Piezo1 into clinical drug candidates.

RNA-Based Therapeutics

Developing small interfering RNAs or antisense oligonucleotides targeting the PIEZO1 gene and delivering them via advanced delivery systems such as lipid nanoparticles enables precise regulation at the gene expression level. This strategy is particularly suited for therapeutic scenarios that require long-term or systemic inhibition of Piezo1 function. Given the central role of Piezo1 in regulating the function of immune cells within the TME (eg, natural killer cells), modulating its expression level by RNA therapeutics holds promise for reshaping antitumor immune responses.9,16 Thus, RNA-based therapeutics represent a gene-level intervention strategy that tackles Piezo1 function at its source, offering broad application prospects.

Mechanoresponsive Delivery Systems

Exploiting the aberrant mechanical microenvironment of tumors (eg, elevated interstitial pressure, increased matrix stiffness), mechanoresponsive nanodrug delivery systems can be designed to achieve tumor-specific release of Piezo1 modulators. Such smart delivery strategies substantially reduce systemic toxicity while enhancing local therapeutic concentrations. For example, by precisely tuning the mechanical properties of nanoparticles, Piezo1 mechanotransduction in tumor-associated macrophages can be directly interfered with, enabling in situ immune reprogramming.102 Going a step further, using controlled mechanical forces (eg, programmed pressure) to directly activate Piezo1 can also enhance intracellular accumulation of chemotherapeutic agents, creating a unique “mechano-chemotherapy” synergistic strategy.121 In summary, these delivery systems that translate pathological mechanical signals into therapeutic opportunities represent a key technological breakthrough for achieving precision in Piezo1-targeted therapy.

Collectively, these emerging modalities expand the Piezo1-targeting toolbox but remain at preclinical stages and require further optimization and validation before clinical translation.

Conclusion

The mechanosensitive ion channel Piezo1 has emerged as a critical node that integrates physical cues from the tumor microenvironment into a vast signaling network governing cancer initiation, progression, and therapeutic response. Its influence spans the entire malignant spectrum—from cancer cell-autonomous processes such as proliferation, survival, migration, and metabolism, to the remodeling of the tumor stroma, angiogenesis, and the complex modulation of antitumor immunity. Notably, Piezo1-mediated ferroptosis via the TfR1/DMT1/NCOA4/GPX4 axis represents a distinct tumor-suppressive mechanism that couples mechanical cues to iron-dependent cell death, offering a novel vulnerability for therapeutic exploitation.

However, a central theme that permeates this rapidly expanding field is the remarkable context-dependent functionality of Piezo1. This is most starkly illustrated by its diametrically opposed roles across cancer types: it acts as a dominant oncogene in gliomas, pancreatic cancer, and esophageal squamous cell carcinoma, yet paradoxically functions as a tumor suppressor in lung adenocarcinoma and clear cell renal cell carcinoma. Beyond these classical hallmarks, Piezo1 has recently emerged as a critical regulator of ferroptosis via the TfR1/DMT1/NCOA4/GPX4 axis, coupling iron overload and lipid peroxidation to mechanical cues—a pathway that may represent a novel therapeutic vulnerability in mechanosensitive tumors. This functional duality, compounded by its broad physiological expression in normal tissues, presents the single greatest challenge to its clinical translation. It dictates that a one-size-fits-all therapeutic strategy is not merely suboptimal but may be contraindicated.

Therefore, the path forward necessitates a paradigm shift towards precision mechanomedicine. As initially articulated in our discussion of translational challenges (Cancer Type-Dependent Functional Differences), the future of Piezo1 targeting lies in a clear therapeutic stratification: Piezo1 inhibitors (eg, GsMTx4, Dooku1, or next-generation analogs) should be deployed for tumors where it is pathologically overactivated and drives oncogenic progression; conversely, Piezo1 agonists (eg, Yoda1, Yaddle1) hold promise for malignancies where its loss or downregulation contributes to a more aggressive phenotype. The success of this stratification hinges on the development and validation of robust companion diagnostics that integrate Piezo1 expression levels, the mechanical properties of the tumor (eg, stiffness, interstitial pressure), and the activation status of key downstream pathways.

Looking ahead, the translation of Piezo1 biology into clinical practice will require a multi-pronged effort. This includes: (1) the development of highly selective, bioavailable pharmacological tools through structure-guided drug design; (2) the establishment of patient stratification systems based on tumor mechano-signatures; (3) the optimization of spatiotemporally controlled delivery systems (eg, nanotechnology, ultrasound) to mitigate on-target, off-tumor toxicity; and (4) the rational design of combination regimens that integrate Piezo1 modulators with existing chemotherapies, immunotherapies, and metabolic interventions to overcome resistance and achieve synergistic efficacy.

In summary, Piezo1 holds substantial promise as a next-generation therapeutic target in oncology. However, successful bench-to-bedside translation will not be automatic. It demands a measured, evidence-based approach that rigorously addresses the complexities of its context-dependent functions and acknowledges the current limitations in our pharmacological arsenal and mechanistic understanding. Achieving this will ultimately require well-designed preclinical validation and, eventually, biomarker-driven early-phase clinical trials to realize the full potential of Piezo1-centric mechanomedicine. With continued advances in structural biology, systems mechanobiology, and precision medicine, Piezo1-centred “mechanomedicine” approaches are may emerge as a new frontier in oncology, translating physical force-based insights into tangible patient benefits.

Funding Statement

This work was funded by the National Natural Science Foundation of China (Nos. 82401633), the Natural Science Research Projects in Universities of Jiangsu Province (No. 24KJA310007, No. 24KJB310013), and Nantong Science and Technology Program (No. 20241118084).

Disclosure

The authors report no conflicts of interest in this work.