Caveolae in cancer: mechanochemical signaling in tumor progression, immunity, and therapy

Abstract

Caveolae are specialized, flask-shaped invaginations of the plasma membrane enriched in cholesterol, sphingolipids, and other membrane lipids that serve as multifunctional hubs for signal transduction, endocytosis, and mechanosensing. Their formation and functions depend on the coordinated organization of lipid microdomains, caveolins (CAV1–3), cavins (CAVIN1–4), and regulatory proteins such as EHD2 and PACSIN2, which together enable caveolae to dynamically reorganize in response to mechanical and biochemical cues. Beyond their classical functions in membrane organization, caveolae influence tumor cell proliferation, invasion, and metabolic adaptation by modulating key signaling pathways and cytoskeletal dynamics. Emerging studies suggest that caveolae contribute to tumor immune regulation by affecting antigen processing, immune cell trafficking, and the trafficking and extracellular vesicle–mediated dissemination of immune checkpoint molecules such as PD-L1. Within the tumor microenvironment, caveolae act as mechanosensitive membrane reservoirs that buffer plasma membrane tension and translate extracellular stiffness, shear stress or solid pressure into intracellular signaling responses. Through these mechanisms, caveolae may shape tumor progression, immune evasion, and responses to therapy. In this review, we synthesize current advances in caveolae biology from structural, lipid-membrane, signaling, immunological, and mechanobiological perspectives, emphasizing caveolae as integrated mechanochemical organelles rather than isolated molecular components. We discuss how caveolae couple membrane tension, lipid organization, and signaling plasticity in cancer, and we highlight emerging translational opportunities and unresolved questions relevant to tumor progression, immune regulation, and therapy.

Key points

Caveolae have been redefined as integrative mechanochemical organelles that influence multiple hallmarks of cancer. We highlight emerging translational opportunities: targeting caveolae–cytoskeleton interactions to disrupt mechanotransduction, exploiting caveolae-mediated endocytosis for precision nanomedicine delivery, and leveraging caveolar biomarkers for cancer prognosis. Future research integrating mechanobiology, high-resolution imaging, and nanotechnology will establish caveolae as both mechanistic regulators and therapeutic gateways in cancer, revealing new strategies for diagnosis and treatment.

Introduction

Caveolae (Latin: “little caves”) are small, flask-shaped invaginations of the plasma membrane that were first described by Palade and Yamada through electron microscopy in the mid-twentieth century [1]. These membrane microdomains are enriched in cholesterol, sphingolipids, phosphatidylserine, and other lipid species, and their lipid environment cooperates with caveolin and cavin proteins to generate membrane curvature and stabilize caveolar identity [2–4]. They are distinct from clathrin-coated pits or other endocytic structures in morphology, molecular composition, and trafficking behavior [2]. Initially regarded as static membrane specializations, caveolae are now recognized as highly dynamic structures that participate in signal transduction, lipid regulation, endocytosis, and cellular adaptation to mechanical stress [5, 6]. Morphologically, caveolae exhibit characteristic Ω-shaped or cup-like profiles and undergo rapid, reversible structural remodeling in response to changes in membrane tension and extracellular cues [7].

The formation and stability of caveolae depend on the coordinated assembly of membrane lipids, caveolins (CAV1–3) and cavins (CAVIN1–4) [8, 9], together with regulatory proteins such as EHD2 and PACSIN2 [10, 11]. Caveolins form the membrane-embedded scaffold, while cavins and accessory factors organize the caveolar coat and link caveolae to the actin cytoskeleton [12]. This multicomponent architecture enables caveolae to act as flexible membrane reservoirs that buffer mechanical stress and spatially compartmentalize signaling molecules at the cell surface. Because the lipid biology of caveolae has been comprehensively reviewed elsewhere [3, 4], we introduce it only briefly here and focus primarily on caveolae-associated signaling, mechanotransduction, immunity, and cancer biology.

In normal physiology, caveolae are particularly abundant in endothelial cells, adipocytes, and muscle cells, where they regulate lipid homeostasis [13], nitric oxide signaling [14], transcytosis [15], and mechanosensing/mechanotransduction [8, 10]. Acute mechanical stress can trigger rapid caveolar flattening and partial disassembly, thereby buffering plasma membrane tension and initiating downstream signaling responses. These properties establish caveolae not merely as membrane invaginations, but as dynamic mechanosensors and mechanotransducers that link membrane architecture to biochemical signaling. Caveolae can internalize selected ligands and receptors through clathrin-independent pathways [16–18] and rapidly reorganize their protein composition without complete vesicle scission, distinguishing them from classical endocytic structures. Through these properties, caveolae integrate biochemical signaling with physical forces at the plasma membrane.

Alterations in caveolae structure or composition have been implicated in a wide range of pathological conditions, including cardiovascular disease [19], metabolic disorders [20], muscular dystrophies [21], and cancer [22–24]. In the tumor context, changes in extracellular matrix stiffness, interstitial pressure, and shear stress impose persistent mechanical challenges on cancer cells and the surrounding stroma. Caveolae are increasingly viewed as key sensors and modulators of these mechanical cues [25], linking the physical tumor microenvironment to intracellular signaling pathways that govern proliferation, migration, metabolism, and survival [9].

At the same time, accumulating evidence suggests that caveolae influence tumor–immune interactions. Caveolae-associated processes have been implicated in antigen uptake and presentation [26], immune cell trafficking across the endothelium [27], and the trafficking and extracellular vesicle–mediated dissemination of immune checkpoint molecules such as PD-L1 [28]. These observations place caveolae at a strategic interface between tumor cells, stromal components, and the immune system.

Despite these advances, most existing studies and reviews have focused predominantly on CAV1, often yielding context-dependent and sometimes contradictory conclusions regarding its tumor-suppressive or tumor-promoting roles [29]. Less attention has been given to the coordinated contributions of cavins, EHD2, and PACSIN2, or to how caveolae function as integrated mechanochemical platforms rather than isolated molecular components.

In this review, we synthesize current knowledge on caveolae biology in cancer, with equal emphasis on molecular architecture, signaling regulation, mechanotransduction, tumor immunity, and translational implications. By integrating findings across these domains, we aim to provide a coherent framework for understanding how caveolae couple mechanical and biochemical signals in the tumor microenvironment and to highlight key unanswered questions that will guide future research.

Molecular architecture of caveolae

Caveolae are defined by a highly organized molecular architecture that integrates membrane scaffolding, lipid sorting, curvature generation, and cytoskeletal coupling [3, 30]. Their formation and stability rely on the coordinated assembly of caveolins, cavins, membrane lipids, and regulatory proteins that together confer structural integrity and dynamic responsiveness to mechanical and biochemical stimuli [8, 31, 32] (Table 1).

Table 1.

Core caveolar proteins and their principal functions

proteins (genes/common names)	Principal function
Caveolin-1 (CAV1)	Principal structural scaffold of caveolae in most non-muscle cells; regulates membrane curvature, cholesterol homeostasis, mechanosensing, and compartmentalization of signaling molecules
Caveolin-2 (CAV2)	Forms hetero-oligomeric complexes with CAV1; contributes to caveolar stability, membrane trafficking, and signaling regulation
Caveolin-3 (CAV3)	Muscle-specific caveolin required for caveolae formation in skeletal and cardiac muscle; important for membrane integrity and mechano-adaptation in muscle cells
Cavin-1 (PTRF)	Essential for caveolae biogenesis and stabilization; promotes caveolar coat assembly and contributes to membrane tension buffering and signaling organization
Cavin-2 (SDPR)	Regulates caveolar morphology, curvature, and abundance; often linked to tumor-suppressive functions in cancer
Cavin-3 (SRBC)	Modulates caveolar signaling dynamics and stress-response pathways; implicated in tumor suppression and signal adaptation
Cavin-4 (MURC)	Muscle-enriched cavin involved in caveolae-associated signaling and membrane organization in striated muscle
EHD2 (EHD2)	ATPase is located at the caveolar neck; stabilizes caveolae at the plasma membrane and regulates caveolar dynamics under mechanical stress
PACSIN2 (Syndapin II)	F-BAR domain protein that senses membrane curvature, supports caveolar shaping, and links caveolae to actin remodeling and endocytosis

Recent structural and imaging studies have refined the classical view of caveolae as uniform flask-shaped pits assembled by a static caveolin shell [33]. Instead, caveolin complexes are now understood to form oligomeric membrane scaffolds that can be organized into bendable structural units across caveolae of different curvature states [34]. These findings support a model in which caveolae are not rigid vesicular entities but structurally plastic membrane assemblies whose curvature and coat organization can be dynamically remodeled in response to lipid composition, membrane tension, and protein stoichiometry. This updated structural view is particularly relevant to cancer, where persistent mechanical stress and altered membrane lipid environments may reshape caveolar architecture and function.

Caveolins: membrane-embedded scaffolds

The caveolin family comprises three members—CAV1, CAV2, and CAV3—of which CAV1 is essential for caveolae formation in most non-muscle cell types [35]. Caveolins are integral membrane proteins characterized by a central hydrophobic domain that inserts into the inner leaflet of the plasma membrane, generating local membrane curvature [30, 36]. CAV1 oligomerizes to form a polygonal scaffold that binds cholesterol and sphingolipids, thereby stabilizing the lipid environment required for caveolar invagination [35, 37].

Beyond their structural role, caveolins possess scaffolding domains capable of interacting with a wide range of signaling molecules, including receptor tyrosine kinases, Src family kinases, and G proteins [36, 38]. Through these interactions, caveolins contribute to the spatial organization of signaling complexes at the plasma membrane. However, caveolin-associated signaling functions are highly context dependent, varying with cell type, caveolar integrity, and microenvironmental conditions.

Cavins: caveolar coat proteins and structural organizers

Cavins (CAVIN1–4) are peripheral coat proteins recruited to the cytoplasmic face of caveolae. Among them, CAVIN1/PTRF is essential for caveolae biogenesis; loss of CAVIN1 markedly reduces caveolae formation despite preserved caveolin expression and increases caveolin mobility [39]. CAVIN2/SDPR and CAVIN3/SRBC modulate caveolar curvature, coat organization, and tissue-specific functions, whereas CAVIN4/MURC is predominantly expressed in muscle tissues [30, 40–43]. Thus, the cavin family should not be interpreted as a set of equivalent structural components: CAVIN1 provides a core requirement for caveolae formation, while other cavins tune caveolar morphology, stability, and context-specific function.

Cavins assemble into hetero-oligomeric complexes that shape the caveolar bulb and connect caveolae to the cortical actin cytoskeleton. Unlike caveolins, cavins are not embedded in the membrane and can dynamically dissociate from caveolae in response to mechanical stress [44]. This property allows cavins to act as structural adaptors that translate caveolar remodeling into downstream signaling consequences, linking membrane mechanics to intracellular pathways.

Regulatory proteins: EHD2 and PACSIN2

In addition to caveolins and cavins, caveolae function is modulated by regulatory proteins that control caveolar dynamics and membrane coupling. EHD2, an ATPase of the EHD family, localizes to the neck of caveolae and oligomerizes into ring-like structures in an ATP-dependent manner, helping confine caveolae to the plasma membrane through association with actin [45, 46]. This role supports caveolar surface stability and limits excessive caveolar mobility or internalization, but the precise relationship between EHD2 activity and the mechanical threshold for caveolar flattening remains context dependent and should not be overgeneralized [10, 47].

PACSIN2, a member of the F-BAR domain protein family, senses and induces membrane curvature and interacts with both caveolins and cavins [11]. PACSIN2 participates in clathrin-independent endocytosis and couples caveolae to actin remodeling, particularly in regions of high membrane curvature such as the leading edge of migrating cells [34]. Through these interactions, PACSIN2 links caveolar architecture to cytoskeletal dynamics and invasive behavior [48–50].

Caveolae as dynamic structural platforms

Collectively, the cooperative assembly of caveolins, cavins, and regulatory proteins endows caveolae with their defining properties: structural plasticity, mechanical responsiveness, and spatial control of signaling (Fig. 1). Rather than static membrane invaginations, caveolae function as dynamic mechanosensing and mechanotransduction platforms whose composition and organization are continuously remodeled in response to changes in membrane tension, lipid composition, and extracellular forces [8]. This architectural flexibility provides the foundation for the diverse signaling, mechanotransductive, and immunomodulatory roles of caveolae discussed in subsequent sections.

Fig. 1.

Structural organization and dynamic regulation of caveolae. Caveolae are assembled through coordinated interactions among caveolins, cavins, and regulatory proteins including EHD2 and PACSIN2. Recent structural studies support the view that caveolar coats are composed of adaptable oligomeric scaffold units rather than rigid static shells. Under increased membrane tension, caveolae can rapidly flatten and partially disassemble, releasing structural and regulatory components that contribute to mechanotransduction. Upon stress relaxation, caveolae can reassemble in a cytoskeleton- and ATP-dependent manner

Caveolae in cancer hallmarks

Caveolae participate in multiple hallmarks of cancer, including proliferation, invasion, metabolic adaptation, tumor–stroma crosstalk, and immune modulation [51]. Their effects are context dependent and vary by tumor type, disease stage, and microenvironmental conditions. Understanding caveolae as an integrated, dynamic system—rather than focusing on single components—is essential for interpreting their paradoxical functions in cancer biology.

Sustaining proliferative signaling

Sustained proliferative signaling is a central hallmark of cancer, and caveolae have been implicated in the modulation of multiple growth-related pathways in a context-dependent manner [52]. As specialized membrane microdomains, caveolae influence spatial organization, trafficking, and signal duration of growth factor receptors and downstream effectors [53], thereby shaping proliferative responses rather than acting as simple positive or negative regulators.

Among caveolar components, CAV1 has been most extensively studied, with reports describing both tumor-suppressive and tumor-promoting roles across cancer types and disease stages. In breast cancer, CAV1 has been shown to interact with EGFR, Src family kinases, MAPK, and RAS signaling pathways, with functional outcomes influenced by hormone receptor status and HER2 expression [54]. In lung cancer models, CAV1 has been reported to attenuate proliferation by limiting EGFR accumulation at the plasma membrane and reducing downstream STAT3 activation [55, 56], whereas in pancreatic cancer, CAV1 can promote proliferation and epithelial–mesenchymal transition through activation of MAPK and TGF-β/Smad signaling [57]. Similar dual roles have been observed in prostate cancer and glioblastoma, where CAV1 appears to suppress PI3K–AKT–mTOR signaling at early stages but may facilitate proliferative signaling during advanced disease progression [9, 58].

Some discrepancies in caveolae-associated proliferative signaling may arise from differences in experimental conditions. For example, early studies of EGFR internalization often used relatively high EGF concentrations [59], which may reveal stress-associated or non-canonical trafficking routes that are less prominent under physiological ligand exposure [60]. These observations suggest that caveolae may not serve as a dominant EGFR endocytic route under all conditions, but instead modulate receptor accessibility, membrane compartmentalization, and signal duration in a context-dependent manner [61].

Beyond CAV1, emerging evidence suggests that cavins contribute to proliferative control by regulating caveolar stability and signaling compartmentalization. CAVIN2 (SDPR) is frequently downregulated in several cancers, including lung [62], liver [63], breast [64], and colorectal cancers [65], and its loss has been associated with enhanced cell-cycle progression and increased activation of ERK and related mitogenic pathways. Rather than directly activating signaling cascades, cavins are thought to modulate the availability and localization of signaling complexes by maintaining caveolar architecture or by redistributing upon caveolae flattening or disassembly [66].

Collectively, these findings highlight that caveolae influence proliferative signaling through spatiotemporal regulation of receptors and signaling intermediates, rather than uniform amplification or suppression of growth signals. Apparent discrepancies in literature likely reflect differences in tumor type, disease stage, mechanical context, and caveolar integrity. Accordingly, analyses focused on individual caveolar proteins in isolation may provide an incomplete picture. Viewing caveolae as integrated and dynamic signaling platforms offers a more coherent framework for understanding how proliferative signaling is modulated in cancer.

Enabling invasion and metastasis

Tumor invasion and metastasis require coordinated changes in cell adhesion, cytoskeletal organization, membrane dynamics, and extracellular matrix (ECM) interactions [67]. Caveolae, through their unique membrane curvature and mechanical responsiveness, are increasingly recognized as important regulators of these processes. By modulating focal adhesion turnover, actin remodeling, and mechanotransductive signaling, caveolae contribute to the dynamic plasticity required for cancer cell migration and dissemination.

CAV1 has been widely implicated in the regulation of cell motility and invasive behavior [67, 68], although its effects remain highly context dependent. In breast cancer, CAV1 interacts with focal adhesion kinase (FAK) and Src family kinases to influence focal adhesion assembly and turnover [69]. During early tumor stages, CAV1 expression has been associated with reduced migratory capacity, whereas in mechanically stiffened tumor microenvironments, elevated CAV1 expression can promote invasive phenotypes. Increased matrix stiffness has been shown to drive CAV1-dependent formation of actin-rich protrusions and recruitment of curvature-sensing proteins such as PACSIN2, thereby enhancing invasive migration [29].

In lung cancer models, CAV1 depletion suppresses proliferation but paradoxically reduces invasive and migratory capacity by impairing epithelial–mesenchymal transition (EMT) programs [70]. CAV1 has been reported to regulate EMT-associated transcription factors, including Snail and Slug, and to modulate cadherin-mediated cell–cell adhesion [67]. Similar pro-invasive roles for CAV1 have been described in prostate cancer and glioblastoma, where CAV1 facilitates cytoskeletal reorganization and extracellular matrix engagement through Rho GTPase–dependent pathways [71].

Beyond caveolins, caveolae-associated proteins coordinate membrane curvature and cytoskeletal remodeling during invasion. PACSIN2, through its F-BAR domain, senses and stabilizes curved membrane regions and has been implicated in cell spreading, migration, and N-cadherin internalization [49, 50, 72]. In addition, a mechanosensitive caveolae–invadosome interplay has been shown to drive matrix remodeling during cancer cell invasion [67]. These observations support the idea that caveolae-associated curvature-sensing machinery can couple membrane tension buffering with localized actin remodeling and extracellular matrix degradation, although the precise contribution of each component is likely to vary among tumor models.

Cavins, particularly CAVIN2 (SDPR), are generally associated with suppressed invasive behavior. Reduced expression of CAVIN2 has been reported in breast, colorectal, gastric, and non–small cell lung cancers and correlates with enhanced migration, invasion, and poor prognosis [62, 65]. Mechanistically, loss of CAVIN2 may destabilize caveolae or alter caveolar remodeling under mechanical stress, leading to aberrant activation of RhoA-ROCK and MAPK signaling pathways that promote cytoskeletal contractility and motility [73].

Taken together, these findings support a model in which caveolae act as dynamic regulators of invasion and metastasis, integrating mechanical cues from the tumor microenvironment with cytoskeletal and signaling networks. The dual and sometimes opposing roles of caveolar components in invasion underscore the importance of considering tumor type, disease stage, and mechanical context when interpreting their functions. Viewing caveolae as adaptive mechanochemical platforms provides a coherent framework for understanding how cancer cells balance adhesion, force generation, and membrane remodeling during metastatic progression.

The seemingly contradictory roles of CAV1 in invasion and metastasis may, at least in part, reflect differences in epithelial differentiation state, matrix mechanics, and the mode of cell migration examined. In relatively differentiated epithelial settings, CAV1 expression has frequently been associated with membrane organization and cell–cell adhesion [74], whereas in mechanically stiff tumor microenvironments, caveolae may support mechanoadaptive remodeling of focal adhesions, actin dynamics, and cell–matrix interactions [75]. In this context, caveolae-associated regulators such as PACSIN2 and EHD2 may influence invasive behavior by controlling membrane curvature, caveolar stability, and actin-dependent membrane remodeling [32]. Thus, in the specific setting of invasion, caveolae may either stabilize epithelial organization or facilitate mechanically driven motility depending on tumor differentiation state and biomechanical context [76].

Deregulating cellular energetics

Metabolic reprogramming is a defining feature of cancer cells, enabling sustained proliferation, survival under stress, and metastatic dissemination. Caveolae have been implicated in the regulation of cellular metabolism, particularly lipid and glucose handling, although their precise roles in tumor metabolic rewiring remain incompletely understood.

CAV1 has been most frequently linked to metabolic regulation through its ability to bind cholesterol and organize lipid-rich membrane domains. Caveolae contribute to cholesterol homeostasis and fatty acid trafficking [72], processes that are essential for membrane biogenesis and energy balance in rapidly proliferating tumor cells. In several cancer models, CAV1 has been reported to modulate glucose uptake by interacting with glucose transporters (GLUTs) [77], and its expression inversely correlates with the activity of key glycolytic enzymes [78]. These observations suggest that caveolae may restrain glycolytic flux under certain conditions, although the functional consequences appear to vary across tumor types and microenvironmental contexts.

In lipid metabolism, CAV1 and caveolae have been linked to fatty acid uptake, lipid droplet organization, and oxidative metabolism in several cellular contexts [72, 79, 80]. In hormone receptor–positive breast and prostate cancer models, altered lipid-handling programs have been associated with tumor growth and therapy resistance, although the extent to which these effects depend on assembled caveolae versus caveolin-associated signaling remains context dependent [79]. By organizing lipid droplets and coordinating lipid signaling pathways, caveolae may influence the balance between anabolic and catabolic metabolism [72, 80]. However, whether these effects are directly mediated by caveolae as structural entities or reflect caveolin-dependent signaling functions remains an open question.

Compared with signaling and invasion, the role of cavins and other caveolae-associated proteins in tumor metabolism is less well characterized. Limited evidence suggests that disruption of caveolar integrity may alter cellular metabolic flexibility by affecting membrane lipid composition and mechanosensitive signaling pathways linked to mitochondrial function. Most existing studies rely on in vitro models, underscoring the need for in vivo and context-specific analyses.

Overall, current data indicate that caveolae contribute to tumor metabolism primarily by regulating lipid organization, membrane composition, and metabolic signaling interfaces, rather than acting as direct metabolic enzymes. Further work is required to define how caveolae-mediated metabolic regulation intersects with mechanical stress, nutrient availability, and immune modulation within the tumor microenvironment.

Tumor microenvironment (TME) and stromal interactions

The tumor microenvironment (TME) comprises a complex and dynamic network of cancer cells, stromal cells, immune cells, extracellular matrix (ECM), and soluble factors, all of which collectively shape tumor progression, metastasis, and therapeutic response [81, 82]. Increasing evidence indicates that caveolae contribute to multiple aspects of tumor–stroma interactions by integrating biochemical signaling with physical and mechanical cues within the TME [83, 84].

Mechanical abnormalities are a defining feature of solid tumors. Progressive extracellular matrix stiffening, elevated interstitial pressure, and abnormal fluid shear stress impose persistent physical constraints on both tumor and stromal cells [85]. Caveolae contribute to cellular adaptation within this environment by modulating plasma membrane organization and coordinating mechanotransductive signaling responses, thereby linking physical cues to intracellular pathways that govern migration, survival, and therapeutic response.

At the molecular level, caveolae interact with key mechanotransduction pathways, including integrins, focal adhesion kinase (FAK), Src family kinases, RhoA/ROCK, and the transcriptional regulators YAP and TAZ [25]. Changes in caveolae organization under mechanical stress can alter spatial distribution and activation of these pathways, influencing cytoskeletal tension and cell–matrix interactions. In tumor cells, such signaling promotes invasive adaptation to stiff microenvironments, whereas in stromal and endothelial compartments it may regulate matrix remodeling and vascular function. Beyond cancer cell–intrinsic functions, CAV1 exerts profound non-cell-autonomous effects within the TME, particularly through its expression in cancer-associated fibroblasts (CAFs) and endothelial cells. In CAFs, loss of CAV1 expression is strongly associated with poor prognosis, increased metastasis, and therapy resistance across multiple tumor types, including breast, prostate, and pancreatic cancers [29, 86]. Mechanistically, CAV1-deficient CAFs undergo metabolic reprogramming known as the “reverse Warburg effect,” whereby autophagy and aerobic glycolysis produce lactate, ketones, and nucleotides that fuel adjacent cancer cells [87]. Additionally, CAV1 loss in CAFs leads to excessive secretion of TGF-β, IL-6, and extracellular matrix components, promoting cancer cell invasion and matrix remodeling [88]. Importantly, cancer cells can actively induce CAV1 downregulation in neighboring fibroblasts through paracrine autophagy/lysosomal degradation, converting normal fibroblasts into a pro-tumor CAF phenotype [89]. These findings suggest that restoring CAV1 function in CAFs may represent a novel stroma-targeting strategy.

In contrast, endothelial CAV1 generally supports tumor progression. As a core component of caveolae in endothelial cells, CAV1 is essential for caveolae-mediated transcytosis, which contributes to the hyperpermeability of tumor blood vessels (“leaky” vasculature), thereby facilitating tumor cell extravasation and nutrient supply [90]. Endothelial CAV1 also sustains VEGFR2 signaling and angiogenesis [91]. Thus, while CAV1 loss in CAFs is pro-tumorigenic, endothelial CAV1 expression promotes tumor growth, highlighting the cell-type-specific net effect of CAV1 in the TME [92].

A particularly instructive example of CAV1’s contextual switching comes from the ITGB1-TGFβ signaling axis in prostate cancer. Integrin β1 (ITGB1)-dependent upregulation of CAV1 switches TGFβ signaling from tumor-suppressive to oncogenic, inducing SLUG and PAI-1 while repressing CDH1, DSP, and CDKN1A [93]. CAV1 knockdown in this setting leads to growth arrest and reduced invasion, indicating that CAV1 can rewire major cytokine pathways in a stage- and context-dependent manner.

Caveolae also play important roles in the tumor vasculature. Endothelial caveolae regulate transcytosis, nitric oxide signaling, and barrier function, processes that influence tumor perfusion, hypoxia, and drug delivery [94]. Mechanical forces generated by aberrant blood flow and solid stress can remodel endothelial caveolae, potentially disrupting vascular normalization and promoting hypoxic niches that favor tumor progression and therapy resistance. Through these mechanisms, caveolae may indirectly shape the metabolic and immune landscape of tumors.

In addition to mechanical regulation, caveolae-mediated endocytosis influences the uptake and intracellular distribution of therapeutic agents. Several studies have suggested that caveolae contribute to the internalization of specific drugs or nanoparticles, and that alterations in caveolar structure or abundance may affect drug sensitivity [95]. Mechanical stress–induced caveolae remodeling could therefore influence treatment efficacy by modifying endocytic pathways and intracellular drug trafficking.

Taken together, caveolae emerge as central modulators of tumor–stroma crosstalk, integrating mechanical forces with signaling, vascular function, and therapeutic response. Considering caveolae as dynamic components of the TME provides a more comprehensive framework for understanding how physical and biochemical factors converge to drive tumor progression and resistance, and highlights caveolae as potential targets for strategies aimed at modulating the tumor microenvironment.

Caveolae and tumor immunity

Tumor immunity is shaped by a coordinated interplay between cancer cells, immune cells, stromal elements, and the vascular system. Increasing evidence suggests that caveolae contribute to this interplay by regulating membrane organization, vesicular trafficking, and mechanotransductive signaling processes that influence immune recognition, immune cell infiltration, and immune escape [96]. Rather than acting as direct immune effectors, caveolae appear to modulate the spatial and mechanical context in which immune signaling occurs.

Antigen processing, cross-presentation, and dendritic cell function

Caveolae and their core component CAV1 have been implicated in dendritic cell (DC) maturation and function. During DC activation, CAV1 expression has been associated with enhanced cellular motility and migration to draining lymph nodes, thereby supporting T-cell priming [97]. Mechanistically, caveolar microdomains may organize major histocompatibility complex (MHC) molecules and costimulatory receptors into nanoscale platforms that facilitate antigen uptake, processing, and presentation [27, 98].

Caveolae mediate clathrin-independent endocytosis of selected ligands and fluid-phase cargo, delivering antigens to early endosomes and specialized antigen-processing compartments relevant for cross-presentation [99]. Although direct mechanistic evidence remains limited, current studies suggest that intact caveolae support efficient formation and surface display of peptide–MHC complexes and enhance immune synapse formation with CD8⁺ T cells [100]. Conversely, disruption or mislocalization of caveolar components in tumor-associated antigen-presenting cells may impair cross-presentation and weaken tumor-specific T-cell responses [101].

In this context, caveolae-associated trafficking should be viewed as one potential contributor to antigen processing rather than as a universal antigen-uptake pathway. Future studies using cell-type-specific perturbation of caveolar components, physiologic antigen loads, and quantitative imaging will be required to determine whether intact caveolae directly enhance peptide–MHC complex formation, cross-presentation efficiency, or immune synapse assembly in cancer.

Beyond these roles in antigen-presenting cells, CAV1 also functions as a key ‘molecular organiser’ within lymphocytes themselves, directly regulating the initiation of adaptive immunity [102]. This regulation is primarily achieved through its influence on the nanoscale clustering of T cell receptors (TCRs) and B cell receptors (BCRs) at the plasma membrane – an aspect that has often been overlooked in classical studies of the immunological synapse [103]. For example, in CD8⁺ T cells, CAV1 is necessary for the efficient clustering and polarization of TCR signaling complexes within the immunological synapse [104]. CD8⁺ T cells lacking CAV1 exhibit not only impaired signal transduction but also significantly reduced antiviral and antitumor functions in vivo [105]. In B cells, CAV1 similarly acts as a ‘guardian’ of the spatial distribution of BCR nanoclusters [106]. Src-family kinase-mediated phosphorylation of CAV1 promotes the entry of BCRs into GM1-lipid-enriched membrane microdomains upon antigen stimulation, thereby modulating signal intensity [107, 108]. This process is crucial for maintaining central B cell tolerance, and the absence of CAV1 leads to autoimmune tendencies due to disrupted BCR signaling [106, 109].

Tumor-derived extracellular vesicles and immune evasion

Beyond antigen presentation, caveolae-associated machinery has emerged as a regulator of extracellular vesicle (EV) biogenesis, cargo sorting, and secretion [110]. Tumor-derived EVs enriched in immunosuppressive molecules such as PD-L1, FasL, TGF-β, and regulatory microRNAs can suppress cytotoxic T-cell and natural killer cell function, promote T-cell exhaustion, and attenuate responses to immune checkpoint blockade [111, 112].

Caveolins and cavins are thought to influence EV cargo selection by organizing lipid raft–like microdomains and interacting with tetraspanins and ESCRT components, thereby facilitating nanoscale clustering and endosomal sorting of proteins such as PD-L1 [26, 113]. Experimental disruption of caveolar integrity, including CAV1 depletion, has been reported to alter EV composition and reduce EV-mediated immunosuppression in certain tumor models [114]. Tumor-derived EVs (TEVs) carrying CAV1 have been shown to promote pre-metastatic niche formation, immune modulation, and malignant phenotype transfer [62]. In melanoma models, Y14-phosphorylated CAV1 (pY14-CAV1) is preferentially packaged into EVs, and these CAV1(Y14E) EVs transfer β3 integrin to CAV1-negative recipient cells, enhancing their migration, invasion, and metastatic capacity – an effect that can be blocked by anti-αVβ3 antibodies [115]. Similarly, in rhabdomyosarcoma and breast cancer, CAV1-enriched EVs alter the protein cargo and recipient cell behavior, promoting tumor dissemination and extracellular matrix remodeling [116]. However, direct evidence that intact caveolae specifically control EV-associated PD-L1 sorting remains limited. Thus, caveolae should currently be viewed as potential regulators of membrane organization and EV cargo selection rather than established PD-L1-sorting machinery.

Endothelial caveolae and immune cell trafficking

Endothelial cells lining tumor vasculature are highly enriched in caveolae and play a central role in regulating immune cell trafficking [117]. Caveolae contribute to endothelial transcytosis, barrier maintenance, and the spatial organization of adhesion molecules such as ICAM-1 and VCAM-1 that are required for leukocyte arrest and transmigration [118, 119]. Perturbation of endothelial caveolae—through CAV1 knockdown, cavin depletion, or cholesterol disruption—can alter the balance between paracellular and transcellular leukocyte passage [27], thereby modulating immune cell infiltration into tumor tissue.

In inflammatory contexts, CAV1 deficiency impairs efficient Th1 cell infiltration without causing overt tight junction disruption [120], suggesting that caveolae support regulated immune cell entry rather than nonspecific vascular leakiness. Within tumors, abnormal shear stress, hypoxia, and solid pressure may remodel endothelial caveolae, biasing immune infiltration toward exclusion of effector T cells or preferential recruitment of immunosuppressive myeloid populations [46]. These findings highlight endothelial caveolae as an important mechanosensitive interface linking vascular biology to tumor immune regulation.

Collectively, these observations position caveolae as modulators of tumor immunity through their effects on membrane organization, vesicular trafficking, and immune cell migration, shaping immune surveillance and therapeutic responsiveness in a context-dependent manner (Fig. 2).

Fig. 2.

Caveolae as integrative platforms linking signaling, mechanics, and immune regulation in cancer. Caveolae and their constituent proteins, particularly CAV1, play complex and context-dependent roles in cancer progression by regulating multiple oncogenic pathways. They sustain proliferative signaling by modulating key pathways like EGFR, MAPK/ERK, and PI3K–AKT–mTOR; CAV1 can either suppress or enhance tumor growth in a manner dependent on cancer type, stage, and hormone receptor status. In invasion and metastasis, caveolae contribute to cytoskeletal remodeling and adhesion dynamics. CAV1 often promotes migration, EMT, and angiogenesis, especially under biomechanical stress like matrix stiffness, while other components like CAVIN2 frequently act as metastasis suppressors. Caveolae also deregulate cellular energetics by interacting with glucose transporters and glycolytic enzymes, influencing whether a tumor utilizes glycolysis or oxidative metabolism. Within the tumor microenvironment, caveolae act as mechanical buffers, enabling cell survival under pressure and transducing mechanical cues into biochemical signals. This mechanical role also impacts therapeutic resistance by affecting drug uptake and vascular function. Emerging evidence highlights their role in tumor immunity, where caveolae influence dendritic cell migration and T-cell priming, regulate immune cell trafficking across endothelium, and are implicated in the biogenesis of immunosuppressive extracellular vesicles. Overall, caveolae function as dynamic signaling hubs that help tumors adapt to diverse environmental challenges

Non-caveolin regulators of caveolae dynamics and cancer behavior

While CAV1 is essential for caveolae formation, the functional diversity of caveolae in cancer is critically shaped by non-caveolin regulatory proteins that control caveolar stability, membrane coupling, and curvature-dependent remodeling [121]. Among these, the cavin family, EHD2, and PACSIN2 form a regulatory layer that tunes caveolae dynamics in response to mechanical and biochemical cues, thereby influencing downstream signaling and tumor cell behavior.

Cavins (CAVIN1–4) form a peripheral coat on the cytoplasmic face of caveolae and are indispensable for caveolar maturation and maintenance. CAVIN1 (PTRF) is essential for caveolae biogenesis; its loss leads to caveolar collapse, altered membrane tension buffering, and dysregulated signaling in adipose tissue and muscle, with emerging implications in prostate and breast cancer [39, 122, 123]. CAVIN2 (SDPR) frequently functions as a tumor suppressor: its downregulation in lung, liver, colorectal, breast, and gastric cancers correlates with increased proliferation, EMT, and poor prognosis, often via modulation of ERK, NF-κB, or TGF-β pathways [43, 62, 65]. CAVIN3 (SRBC) has been linked to stress-response signaling and BRCA1 complexes, and its loss is associated with aggressive behavior in liver, gastric, and renal tumors [41, 124]. CAVIN4 (MURC), though predominantly expressed in cardiac and skeletal muscle, may influence sarcoma biology and vascular remodeling [42, 125].

Rather than directly activating oncogenic pathways, cavins appear to function primarily as structural adaptors that stabilize caveolae and constrain mechanosensitive signaling [39]. Under mechanical stress, caveolae remodeling can induce cavin dissociation, leading to reorganization of the plasma membrane and facilitating activation of signaling pathways such as ERK and RhoA, thereby promoting cytoskeletal contractility and cell motility [25]. However, recent findings challenge this unidirectional model. In migrating cells, caveolae act as spatially organized mechanosensors, and their integrity is required for proper RhoA activation at the cell rear. Notably, increased membrane tension triggers caveolae disassembly into CAV1 scaffolds, which disrupts the recruitment of RhoA-GEFs and leads to a reduction in localized RhoA activity and impaired actomyosin contractility, ultimately inhibiting directional migration [126, 127]. Together, these observations suggest that caveolae do not simply restrain or promote signaling, but instead function as dynamic regulators of mechanotransduction [8]. Depending on the spatial context and mechanical state, caveolae disassembly may either release signaling constraints or, conversely, impair the localized activation of RhoA required for contractility. This highlights a context-dependent and bidirectional role for caveolae in coordinating membrane tension, cytoskeletal dynamics, and cell migration [33].

EHD2 is an ATP-dependent regulatory protein that oligomerizes around the neck of caveolae and couples them to the cortical actin cytoskeleton [45, 128]. By restraining caveolar mobility and internalization, EHD2 helps maintain a relatively stable caveolar pool at the cell surface [129, 130]. In cancer cells, reduced EHD2 expression has been associated with increased caveolar internalization, enhanced invasive migration, and altered lipid uptake, suggesting that loosening this “collar” favors a more dynamic, motile phenotype [131]. Conversely, high EHD2 levels can enforce membrane anchoring, limit caveolae-mediated endocytosis of growth factor receptors, and dampen mechanosensitive signaling through FAK, Src, and YAP/TAZ. Although data are still emerging [132], EHD2 appears to act as a rheostat for the mechanical responsiveness of caveolae, with downstream consequences for tumor stiffness adaptation, invasion, and possibly drug uptake [47, 133, 134].

PACSIN2, an F-BAR domain protein, senses and generates membrane curvature and is a key partner of both CAV1 and EHD2 [48, 135]. At the leading edge of migrating cells, PACSIN2 accumulates at sites of high curvature and associates with actin-rich structures such as invadosomes and podosomes [136]. Recent work has shown that caveolae–PACSIN2 complexes form a mechanosensitive interface that coordinates ECM degradation with membrane tension buffering, thereby promoting efficient three-dimensional invasion [50, 67]. Loss of PACSIN2 impairs invadosome formation, reduces matrix remodeling, and attenuates metastasis in experimental models, whereas its overexpression can enhance motility and invasion. In addition, PACSIN2 regulates clathrin-independent endocytosis of EGFR and other receptors, linking curvature sensing to growth-factor signaling [49, 50]. These findings position PACSIN2 as a crucial mediator of how caveolae integrate membrane mechanics with invasive behavior.

Together, cavins, EHD2, and PACSIN2 coordinate the dynamic regulation of caveolae architecture rather than acting as independent signaling molecules. Alterations in this regulatory network can shift caveolae from stabilizing membrane organization toward permissive states that favor cytoskeletal remodeling, invasive behavior, and adaptation to mechanically challenging tumor microenvironments. Framing these proteins as integral regulators of caveolae dynamics reinforces the view of caveolae as adaptive membrane systems whose cancer-related functions emerge from coordinated structural control.

These findings argue against a simple model in which caveolae uniformly promote or suppress signaling. Instead, caveolae function as dynamic mechanochemical regulators whose effects depend on the magnitude, duration, and spatial distribution of mechanical stimuli. Mechanical stress can induce caveolar flattening and partial disassembly, leading to redistribution of caveolae-associated proteins and altered local signaling organization. Depending on cellular context, these events may either enhance signaling accessibility or disrupt localized signaling complexes, producing distinct—and sometimes opposing—biological outcomes.

Clinical and translational perspectives

Despite rapid progress in our understanding of caveolae biology, their direct clinical translation in oncology remains at an early stage. Most studies to date have focused on individual caveolar components—particularly CAV1—often yielding context-dependent and sometimes contradictory results. These observations underscore the importance of considering caveolae as integrated and dynamic membrane structures whose functions are shaped by cellular context, mechanical environment, and tissue specificity. Below, we outline potential clinical directions in which caveolae and their associated proteins may serve as therapeutic targets, biomarkers, or drug delivery gateways (Fig. 3).

Fig. 3.

Translational perspectives and open questions related to caveolae in cancer. Future clinical applications of caveolae research require viewing them not just as a collection of proteins but as dynamic, integrated organelles that adapt to the tumor's mechanical microenvironment. A more promising approach is to target caveolae as a structural unit. Given their role as mechanosensors, caveolae reorganize in response to tumor stiffness and stress, influencing pro-tumor signaling through pathways like FAK and YAP/TAZ. Potential strategies include disrupting these mechanotransduction pathways, modulating membrane cholesterol to alter caveolar stability, and exploiting caveolae-mediated endocytosis for improved drug delivery. As biomarkers, caveolae-associated proteins also show translational potential. Although CAV1's duality makes it an unreliable standalone prognostic marker, other cavin family members, like the tumor-suppressive CAVIN2, offer more consistent correlations with patient outcomes. Ultimately, a multi-faceted biomarker strategy that combines the expression profiles of several caveolar components or directly visualizes caveolae density and dynamics is likely to be more robust. Integrating the assessment of caveolae's structural state, protein composition, and the tumor's mechanical profile holds significant promise for advancing personalized cancer diagnostics and developing novel "mechanotherapeutics

Caveolae as potential therapeutic targets

The structural plasticity and mechanosensitive properties of caveolae raise the possibility that targeting caveolae-associated pathways could modulate tumor behavior. Caveolae-associated pathways intersect with clinically relevant signaling axes, including FAK, Src, RhoA/ROCK, and YAP/TAZ, many of which are already under therapeutic investigation [137, 138]. Understanding how caveolae organize and modulate these pathways may help refine patient stratification or inform combination strategies rather than serving as stand-alone therapeutic targets.

Rather than directly inhibiting caveolar proteins, which may disrupt essential physiological functions, a more feasible strategy may involve targeting caveolae–cytoskeleton interactions, membrane lipid composition, or downstream mechanotransductive signaling pathways. Interventions that alter membrane tension, cholesterol homeostasis, or caveolae stability could indirectly influence oncogenic signaling, invasion, and immune regulation. Collectively, these approaches underscore the value of caveolae as a structural regulator of both cellular biomechanics and signaling plasticity.

Caveolae-mediated endocytosis and drug delivery

Caveolae-mediated endocytosis has emerged as a promising route for targeted drug delivery, particularly for macromolecules and nanoparticle-based therapeutics. Unlike clathrin-dependent pathways, caveolae enable non-degradative internalization and transcytosis, making them especially attractive for delivering intact cargos across cellular barriers [139, 140]. The enrichment of caveolae in endothelial cells and in specific tumor types suggests that caveolar pathways can be exploited to facilitate drug transport across vascular endothelium and improve tissue penetration [140].

Preclinical studies have demonstrated that caveolae-targeting strategies—including ligand-directed nanoparticles and albumin-based carriers—can enhance tissue-specific delivery via caveolar transcytosis [141]. A notable example is the albumin-bound formulation of Paclitaxel (nab-paclitaxel), which has been proposed to utilize caveolae-associated transport mechanisms to improve intratumoral accumulation, although the precise contribution of CAV1 remains context dependent [141, 142]. More broadly, nanoparticle platforms engineered to engage caveolar pathways have shown improved endothelial transport and reduced lysosomal degradation in preclinical models [140].

Importantly, caveolae dynamics are highly sensitive to mechanical stress and microenvironmental cues. Mechanical forces such as membrane tension induce rapid caveolae flattening and disassembly, thereby modulating endocytic capacity and membrane trafficking [8]. In tumors, increased matrix stiffness, elevated interstitial pressure, and vascular abnormalities may therefore significantly influence caveolae-mediated uptake and drug distribution [8, 142]. These observations suggest that the efficiency of caveolae-targeted delivery is not solely determined by ligand–receptor interactions but is also governed by the biophysical state of the tumor microenvironment.

In this context, incorporating mechanical features—such as tissue stiffness, shear stress, and endothelial integrity—into drug delivery design may enhance therapeutic efficacy. We speculate that integrating caveolae-targeting strategies with approaches that normalize tumor vasculature or modulate mechanical stress could further improve drug penetration and distribution, representing a promising yet underexplored direction for translational oncology.

Caveolae and caveolar proteins as biomarkers

Caveolae-associated proteins have also been explored as potential biomarkers for cancer prognosis and treatment response. CAV1 expression has been evaluated in multiple tumor types; however, its dual tumor-suppressive and tumor-promoting roles limit its reliability as a standalone marker. In contrast, several cavins, particularly CAVIN2 (SDPR), exhibit more consistent associations with tumor suppression and adverse clinical outcomes when downregulated [62, 65], although validation across large, independent cohorts remains necessary.

Rather than focusing on individual proteins, composite biomarkers reflecting caveolae integrity, protein localization, or structural remodeling may offer greater predictive value. Advances in imaging, spatial proteomics, and single-cell analysis may enable more precise assessment of caveolae-related features in clinical samples.

Limitations, therapeutic relevance, and open questions

Despite growing interest in caveolae biology, several limitations currently constrain their translational exploitation in cancer. Caveolae are essential for normal physiological functions in endothelial, adipose, and muscle tissues, making direct pharmacological targeting challenging and potentially unsafe. Moreover, much of the existing literature relies on static measurements of caveolar components, whereas caveolae function is inherently dynamic and highly sensitive to mechanical and microenvironmental context.

These limitations raise important conceptual questions regarding the therapeutic relevance of caveolae. A central unresolved issue is whether caveolae primarily act as drivers of tumor progression or as adaptive modulators that enable cancer cells to tolerate mechanical stress, metabolic demand, and immune pressure. Clarifying this distinction will be critical for determining whether therapeutic strategies should aim to disrupt caveolae-associated processes or instead exploit caveolae-dependent vulnerabilities that arise under specific tumor microenvironmental conditions.

The apparent duality of CAV1 as either a tumor suppressor or a tumor promoter can be interpreted within this broader context-dependent framework. CAV1 function is likely shaped by several determinants, including cellular lineage and differentiation status, disease stage, relative expression in tumor versus stromal compartments, caveolae assembly state, and the biomechanical properties of the local microenvironment. In earlier or more differentiated contexts, intact caveolae may spatially constrain receptor signaling, preserve membrane organization, and dampen excessive proliferative signaling [9, 29, 54, 58]. In advanced tumors exposed to chronic matrix stiffening, elevated membrane tension, metabolic stress, invasive remodeling, or therapeutic pressure, CAV1 and caveolae-associated pathways may instead be repurposed to support mechanoadaptation, cytoskeletal plasticity, survival, invasion, and treatment resistance [29, 67, 83, 143]. Divergent outcomes may also depend on whether CAV1 functions within fully assembled caveolae, non-caveolar membrane domains, or stromal compartments such as fibroblasts and endothelial cells [29, 86–88, 92]. Thus, apparently contradictory findings may reflect context-specific rewiring of a mechanochemical membrane system rather than inherently opposing biological properties of CAV1 itself.

Another major open question concerns the role of caveolae in immune regulation. While accumulating evidence links caveolae to antigen handling, immune cell trafficking, and PD-L1 trafficking through extracellular vesicles, the molecular determinants and cell-type specificity of these processes remain poorly defined. It is unclear to what extent caveolae-mediated immune modulation occurs in tumor cells versus stromal or immune compartments, or how mechanical forces influence these interactions in vivo.

From a translational perspective, caveolae may be more relevant as determinants of therapeutic response rather than as direct therapeutic targets. Caveolae remodeling in response to extracellular matrix stiffness, shear stress, or treatment-induced mechanical changes could influence receptor signaling duration, drug uptake, and immune accessibility. These properties suggest that caveolae-associated features—such as protein localization, structural integrity, or dynamic remodeling—may serve as biomarkers for treatment stratification or resistance prediction.

Finally, technical challenges remain a major barrier to progress. Capturing caveolae dynamics in physiologically relevant tumor settings will require advances in live-cell and super-resolution imaging, biophysical force measurements, and spatial omics approaches. Addressing these methodological gaps will be essential to determine whether caveolae can be meaningfully leveraged in cancer therapy and to define their role at the intersection of membrane organization, mechanics, and immune regulation.

Conclusion and future directions

Caveolae have evolved from being viewed as static membrane invaginations to being recognized as dynamic plasma membrane nanodomains that integrate mechanical forces, membrane organization, and intracellular signaling. Accumulating evidence indicates that caveolae influence multiple hallmarks of cancer, including proliferative signaling, invasion and metastasis, metabolic adaptation, tumor–stromal interactions, and immune regulation. Importantly, these effects are highly context dependent and reflect the ability of caveolae to function as adaptive interfaces between the tumor microenvironment and intracellular signaling networks.

A central concept emerging from recent studies is that caveolae operate as integrated mechanochemical systems, rather than as collections of independent molecular components. The coordinated actions of caveolins, cavins, and regulatory proteins such as EHD2 and PACSIN2 allow caveolae to buffer membrane tension, organize signaling complexes, and regulate vesicular trafficking in response to extracellular cues. Disruption of this coordination—through mechanical stress, altered lipid composition, or protein mislocalization—can reprogram signaling pathways and immune interactions in ways that contribute to tumor progression and therapeutic resistance. This system-level perspective provides a framework for reconciling the seemingly contradictory roles reported for individual caveolar proteins across different cancer types and disease stages.

Looking forward, several challenges and opportunities define the future of caveolae research in cancer. A major priority will be to elucidate how caveolae dynamics vary across cell types within the tumor microenvironment, including tumor cells, endothelial cells, stromal fibroblasts, and immune cells. Equally important is understanding how mechanical forces intersect with caveolae-dependent trafficking and signaling to shape immune surveillance and treatment response. Addressing these questions will require integrative approaches that combine live-cell and super-resolution imaging, biophysical measurements, spatially resolved omics, and physiologically relevant in vivo models.

In conclusion, caveolae represent a unifying interface linking membrane architecture, mechanical forces, and cellular signaling in cancer. Continued interdisciplinary efforts at the intersection of membrane biology, mechanobiology, and tumor immunology will be essential to fully define how caveolae contribute to cancer progression and to determine how this knowledge can be leveraged to improve therapeutic strategies.

Authors’ contributions

Jiawei Zhang and Hanguang Hu conceived and designed the study. Wen Cai, Xinlei Li and Yifan Chen analyzed and interpreted data. Wen Cai and Xinlei Li acquired data and wrote the paper. All authors have approved the submitted version and are accountable for their contributions.

Funding

This work was supported by Huadong Medicine Joint Fund of Zhejiang Provincial Natural Science Foundation of China (LHDMZ26H310001), National Natural Science Foundation of China (32571449) and Zhejiang Provincial Natural Science Foundation of China (LY22H160024).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Consent for publication

Not applicable.