Dual Mechanism of Piezo1, a Mechanosensitive Receptor in the Cancer Microenvironment, in Tumor Suppression and Promotion
Background
Tumor tissues are continuously subjected to complex physical pressures, such as compressive forces from cell proliferation, extracellular matrix (ECM) stiffening, and shear stress from blood flow and fluids. In cancer biology, attention has been focused on mechanotransduction systems that transmit these physical stimuli into cancer cells. Piezo1, a mechanosensitive cation channel, is a representative mechanosensor protein that detects physical stimuli applied to the cell membrane and induces calcium ion influx.
Existing oncological research has tended to view Piezo1 solely from the perspective of an oncogene that promotes cancer proliferation or metastasis. However, a comprehensive analysis of clinical and basic models reveals that the expression and activity of Piezo1 exhibit opposing effects depending on the cancer type. While it promotes cancer progression in glioblastoma, pancreatic cancer, and esophageal squamous cell carcinoma, opposing results were observed in lung cancer and clear cell renal cell carcinoma (ccRCC), where it actually inhibits tumor formation. The fact that a single channel, which converts mechanical stimuli into chemical signals, performs diametrically opposite functions depending on the tissue microenvironment poses a new challenge for the development of targeted therapies.
Key Findings
This study systematically organizes the molecular pathways in which Piezo1 is involved in cancer cell proliferation, migration, epithelial-mesenchymal transition (EMT), and the maintenance of cancer stemness. A particularly noteworthy aspect is the identification of the ferroptosis pathway, a cell death mechanism induced by Piezo1 activation. When cells are subjected to continuous physical load, Piezo1-mediated calcium signaling stimulates the TfR1/DMT1/NCOA4/GPX4 axis. As a result, a vulnerability was identified where iron overload and lipid peroxidation are sequentially induced, leading to cancer cell death.
Extensive regulatory patterns were also revealed in terms of extracellular microenvironment remodeling. Piezo1 coordinates cancer-associated fibroblast (CAF) activation, angiogenesis, lymphangiogenesis, and metabolic reprogramming. Its impact on the immune system also exhibits bidirectionality. While it shows a positive aspect by enhancing the anticancer immune activity of cytotoxic T cells and natural killer (NK) cells, it also creates an immunosuppressive environment mediated by regulatory T cells, tumor-associated macrophages (TAMs), and dendritic cells.
The researchers presented the current state of targeted control technologies along with five specific clinical translational bottlenecks. The five challenges are: lack of tissue specificity, opposing functions by cancer type, low selectivity of existing small-molecule drugs, clinical application limits of mechanical stimulus application methods such as ultrasound, and tumor heterogeneity and acquired resistance. As therapeutic strategies, small-molecule modulators, ultrasound-based physical stimulation, nanoparticle delivery systems, antibody-drug conjugates (ADCs), and combination therapies are being explored from various angles.
Significance and Outlook
The Piezo1 signaling pathway is a promising entry point for next-generation anticancer therapies targeting the biophysical characteristics of tumors. The fact that the same receptor produces opposite signals depending on the cancer type and the surrounding immune environment warns that the administration of uniform inhibitors or activators could cause fatal side effects.
In the future, the key challenge will be the discovery of allosteric modulators that selectively bind only under specific physical tension states of the cancer cell membrane, based on 3D protein structures. Safe clinical translation is expected to require the integration of companion diagnostic technologies that measure tumor biomechanical properties and immune cell infiltration levels.
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, and cancer stem cell maintenance. Additionally, Piezo1-mediated ferroptosis via the TfR1/DMT1/NCOA4/GPX4 axis, which couples iron overload and lipid peroxidation to mechanical cues, is 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 discovery of allosteric modulators that selectively bind under specific physical tension states of the cancer cell membrane, and the integration of companion diagnostics measuring biomechanical properties and immune cell infiltration.
Piezo1 research contributes to the design of personalized treatments by identifying patient groups with high physical pressure, such as those with pancreatic cancer or brain tumors, to maximize therapeutic efficacy. Combining elastography imaging, which measures the physical stiffness of the tumor microenvironment, with Piezo1 expression analysis allows for precise classification of drug-responsive populations.
Drug development companies can develop localized physical stimulation combination therapies combined with focused ultrasound (FUS) or targeted nano-delivery systems to reduce cardiovascular side effects associated with systemic administration. It also provides important molecular biological evidence for designing next-generation combination immunotherapy that enhances T-cell infiltration rates and alleviates the physical barriers of the tumor stroma in combination with immune checkpoint inhibitors.