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Review

Therapeutic Use of Integrin Signaling in Melanoma Cells: Physical Link with the Extracellular Matrix (ECM)

by
Katarzyna Adamiak-Nikolouzou
1,*,
Andrzej T. Słomiński
2,3,
Zofia Skalska
1 and
Iwona Inkielewicz-Stępniak
1,*
1
Department of Pharmaceutical Pathophysiology, Faculty of Pharmacy, Medical University of Gdansk, Dębinki 7 Street, 80-211 Gdansk, Poland
2
Department of Dermatology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
3
Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL 35294, USA
*
Authors to whom correspondence should be addressed.
Cancers 2025, 17(18), 3037; https://doi.org/10.3390/cancers17183037
Submission received: 28 August 2025 / Revised: 7 September 2025 / Accepted: 15 September 2025 / Published: 17 September 2025
(This article belongs to the Section Cancer Drug Development)
Browse Figures
Versions Notes

Simple Summary

Understanding how the extracellular matrix (ECM)—the network surrounding cells—regulates cell behavior through integrins is essential for developing innovative strategies to treat melanoma. Investigating the role of integrins in controlling melanoma behavior can help identify new approaches to precisely target tumor cells. This review highlights recent advances in translational research between 2021 and 2025, focusing on potential melanoma therapies based on integrin signaling. These developments may pave the way for more selective and efficient treatment of melanoma patients.

Abstract

Extracellular matrix (ECM) macromolecules play a vital role in the regulation of cellular phenotype. Ongoing interactions of the extracellular matrix and cells via surface receptors can affect the cellular behavior selectively or non-selectively. Under physiological conditions, the ECM-cell interactions are essential for ensuring balance, whereas the dysregulation of these interactions can lead to the onset of diseases. Extensive knowledge of the integrins with two non-covalently linked α and β subunits plays a vital role in cell–cell adhesion and ECM interactions. The identification of a key adhesion signaling pathway may lead to new therapeutic strategies targeting melanoma cells. This review highlights the potential role of integrins as a selective target in melanoma therapy, which would reduce side effects and increase the effects of the treatment.

1. Introduction

Melanoma, an aggressive skin tumor of melanocytic origin, significantly challenges public health due to its aggressive behavior, resistance to therapy of advanced disease, and complex biology [1]. Understanding its epidemiology, aggressive nature, and barriers to treatment is crucial for better patient outcomes.
The global incidence of melanoma continues to rise. Data from the Rochester Epidemiology Project, spanning over 50 years, demonstrate evolving patterns in the rates of primary cutaneous melanoma [1,2]. While skin exposure to UV radiation (UVR), both from the sun and tanning beds, is the biggest risk factor for the development of cutaneous melanoma [3,4], many other environmental and genetic risk factors are now recognized as the cause of this disease [1]. It must be noted that the role of UVR, especially of its UVB spectrum, is complex and context-dependent [5,6,7]. The constitutional factors affecting susceptibility to melanoma development include low eumelanin or relatively high pheomelanin content in the skin [8,9,10], the presence of moles on the skin [11], genetic predisposition [12], previous history or family history of melanoma [13], and an immunosuppressive environment [14]. Modern medicine recognizes development as a complex process, shaped by genetic predisposition, environmental exposures, and lifestyle choices to varying degrees [1,7,15].
The rapid progression of melanoma and metastases to lymph nodes and distant organs, such as lungs [16,17], brain [18], and liver [19], significantly worsens the prognosis and highlights the critical need for early detection and potent systemic therapies [20]. Notably, advanced melanomas not only can autoregulate their tissue environment but also body homeostasis through production of diverse bioregulatory molecules [21]. The key to understanding and controlling metastasis in melanoma is consideration for the lining (stroma) and the level of oxidative stress in tumor cells. Rich lipid density in the stroma promotes high oxidative phosphorylation (OXPHOS). High oxidative phosphorylation (OXPHOS) in melanoma means that the tumor cells are heavily reliant on using oxygen and the mitochondrial electron transport chain to generate energy [22]. Therefore, metabolic balance and oxidative stress in melanoma cells, dependent on the environment, determine the ability to metastasize [23]. It is also dependent on the melanogenic activity [10,24,25].
Despite recent progress, melanoma treatment, especially for advanced and metastatic forms, remains challenging. A major challenge is disease heterogeneity, where different melanoma cells react distinctly to therapies, often leading to drug resistance. These can be secondary to pathological and uncontrolled melanogenesis, generating an immunosuppressive and mutagenic environment within the tumor [10,24,26,27]. For example, while BRAF inhibitors revolutionized treatment for BRAF-mutated melanoma, resistance frequently occurs, limiting long-term efficacy [28]. Similarly, despite the impact of immunotherapy (e.g., immune checkpoint inhibitors), not all patients respond, and many of them develop primary or acquired resistance [29]. Reducing side effects of systemic therapies, like immune-related adverse events, requires careful clinical expertise [30]. The complexity of selecting therapies shown on Figure 1 and finding optimal patient-specific combinations remains an active research area and clinical challenge [1].
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Figure 1. Emerging Therapeutic Approaches to Melanoma. Created with BioRender.com.
Figure 1. Emerging Therapeutic Approaches to Melanoma. Created with BioRender.com.
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2. Integrin–Extracellular Matrix Interactions

2.1. The Role of Integrins

Integrins are a key family of cell surface receptors that mediate critical interactions between cells and their extracellular environment. Their unique biology is fundamental to various physiological and pathological processes, including oncogenesis and tumor progression, especially in melanoma [31].
Integrins are heterodimeric transmembrane glycoproteins, composed of one α (alpha) subunit and one β (beta) subunit. The human body has 18 different α and 8 β subunits. Their combinations allow the formation of 24 unique combinations of proteins, each exhibiting unique binding specificities and functional roles. These receptors link the extracellular matrix (ECM) to the actin cytoskeleton inside the cell, providing a mechanical bridge that allows cells to sense and respond to their physical surroundings [32]. Beyond this structural role, integrins play a key role in transducing signals bi-directionally across the cell membrane, affecting cell behavior [33].
Integrins play a key role in cell adhesion, enabling stable yet dynamic adhesion connecting cells to ECM components.
The adhesion is not static but dynamic, allowing cells to engage and disengage as needed for processes like migration. Beyond mechanical roles, integrins are powerful signaling agents. They mediate important signaling pathways that control various cellular functions, including cell survival, proliferation, and differentiation [34]. In a pathological context, such as cancer, these signaling functions contribute to the metastatic cascade. In cell migration, integrins regulate cell–substrate attachments, allowing cells to move across surfaces. This process involves cycles of integrin activation, binding to ECM, and later detachment, coordinated with cytoskeletal rearrangements. By translating extracellular cues into intracellular signals, integrins promote communication between the cell and its microenvironment, ultimately influencing fundamental cellular decisions [35].

2.2. Extracellular Matrix Remodeling in Melanoma

In melanoma, the expression and function of integrins are significantly altered compared to normal melanocytes, playing a crucial role in tumor progression and metastasis [36]. Melanoma cells frequently express specific integrin subtypes and promote their aggressive behavior. These integrins primarily mediate cell-ECM interaction and, to a lesser extent, intercellular adhesion. Based on their ligand specificity, integrins can be classified into collagen-binding (α1β1, α2β1, α10β1, and α11β1), laminin-binding (α3β1, α6β1, α7β1, and α6β4), leukocyte-associated integrins (αLβ2, αMβ2, αXβ2, αDβ2, αEβ7, and α4β7), and those that recognize the RGD (Arg-Gly-Asp) amino acid motif (α5β1, α8β1, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, and αIIbβ3) [37,38,39,40]. This broad diversity in integrin profiles suggests that each patient’s melanoma may exhibit a unique integrin signature.
Figure 2 illustrates how extracellular matrix (ECM) components—like collagen, fibronectin, and laminin—interact with cell surface receptors (e.g., integrins, syndecans, DDR1/2, and CD44), triggering intracellular signaling pathways (e.g., PI3K/AKT, MAPK, Rho/ROCK, and YAP/TAZ). These pathways lead to changes in gene expression, ultimately affecting cell behavior and function.
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Figure 2. Cell–ECM interactions and downstream signaling pathways.
Figure 2. Cell–ECM interactions and downstream signaling pathways.
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The extracellular matrix (ECM) also contains hydrated, gel-forming macromolecules such as hyaluronan and proteoglycans alongside integrins that transmit adhesion signals, and various other components [41,42]. Understanding the ECM characteristics of a benign melanocytic nevus provides an essential baseline for investigating the pathophysiological remodeling that occurs in melanoma progression. In melanoma, the ECM undergoes significant remodeling compared to healthy tissue. Key differences include marked membrane disruption; modified distribution and accumulation of collagen IV and laminin around large cell aggregations; and a dense surrounding of melanoma nests by dermal collagens I, III, and VI. Additionally, levels of tenascin and fibronectin are significantly elevated throughout the dermis. This modified ECM forms a highly supportive matrix that actively promotes tumor growth and invasion [43,44].

2.3. Role in Tumor Progression and Metastasis

The “inside-out” signaling happens when a signal from inside the cell activates the integrin, even without an external ligand attaching. The “outside-in” signaling happens when a ligand attaches to the integrin from outside the cell. This causes the integrin to change shape, increasing its ability to bind to the ligand and leading to integrin clustering, which initiates cell adhesion to the extracellular matrix [45,46]. In melanoma, altered ECM composition directly impairs integrin signaling, disrupting normal cell communication. Disregulation contributes to more aggressive cellular behavior, including increased proliferation, motility, and resistance to therapy [47].
Integrins are key players in melanoma tumor progression and metastasis due to their modified expression in tumor cells. They also play a major role in the metastasis cascade, affecting fundamental processes such as cell adhesion, signaling, epithelial–mesenchymal transition (EMT), and the formation of new blood vessels (angiogenesis) [48]. Certain integrin subtypes can even direct melanoma cells to specific organs, promoting specific metastasis. As such, integrin-ECM signaling is a fundamental force behind the aggressive spread of melanoma [49].

2.4. Integrins and Therapy Resistance

Integrin-ECM signaling plays a pivotal role in therapeutic resistance, enabling tumor cells to survive under the pressure of treatment. In melanoma with BRAF mutations, resistance to targeted therapy, including dual treatment with MAPK and PI3K/AKT inhibitors, is a common challenge despite early efficacy [50].
Studies have shown that this resistance is mediated by ECM integrins α3β1 and α11β1. Once connected to the ECM, integrins activate Src kinase, a main mechanism driving resistance. The blockage of α3β1 and α11β1 integrins significantly inhibits the proliferation of resistant melanoma cells [51,52]. Due to their critical role in resistance mechanisms, integrins on melanoma cells can be targeted for selective treatment. This can be achieved through various strategies, such as blocking integrin–ligand interactions, inhibiting specific signaling pathways, or integrin-targeted therapies (e.g., antibodies or peptides) [53]. This work investigates why integrins are crucial in melanoma and highlights the role of the tumor microenvironment.
By examining their role in tumor growth, spread, and resistance to therapy, this research aims to understand how targeting integrin–extracellular matrix signaling can lead to new treatments.

3. Current Translational Research on Integrin Signaling in Melanoma Treatment

Integrins as transmembrane receptors play an essential role in cell migration, adhesion, and signaling in cancer growth [54,55,56,57,58,59,60,61,62,63,64,65,66]. In recent years, translational research has increasingly focused on integrin signaling pathways as potential therapeutic targets, especially in malignant melanoma, a highly aggressive form of skin cancer resistant to conventional therapies.
Translational research in the years 2021–2025 led to the potential integrin-targeted treatments and biomarkers [67,68,69,70,71,72,73,74,75,76,77,78,79,80].
Table 1 summarizes advances on integrin signaling in melanoma treatment in the past five years (2021–2025) based on in vivo models, whereas Table 2 presents in vitro studies. Table 3 presents research performed in both levels of evidence.
Table 1. In vitro studies on integrin signaling in melanoma treatment (2021–2025).
Table 1. In vitro studies on integrin signaling in melanoma treatment (2021–2025).
YearStudy ModelKey FindingsMechanism of
Intervention		Reference
20252D model/A 375,
G-361,MeWo, MM127, MM370, RPMI-7951, SH-4, SK-MEL-1, A431, MCC13		The expression of integrin α1 (ITGA1) was elevated at both the mRNA and protein levels in drug-treated melanoma cellsITGA1 may serve as a senescent melanoma cell biomarker[81]
20242D model/
WM115,
WM266-4		Melanoma-derived ectosomes are mediated by αvβ5 integrinαvβ5 integrin present in melanoma ectosomes is a key driver of tumor-induced angiogenesis and may serve as a more effective target[82]
20242D model/
SK-MEL-2, HEMn-MP		CYR61 increases melanoma cell proliferation and survival rateBlockage of CYR61–integrin β3 may serve as a potential therapeutic target[83]
20232D model/
A375, 1205Lu		SERPINB8 and furin regulate the expression of ITGAX, which promotes the proliferation of melanomaITGAX Knockout and SERPINB8 both inhibited the proliferation and invasion of melanoma cells[84]
20232D model/
MDA- MB-435S		KANK2 interacts with talin2, resulting in increased sensitivity to PTXThe talin2 knockdown led to increased sensitivity to PTX and also reduced migration[85]
20232D model/
A375P, K029A, SKMEL3		Possible targeted therapy for BRAF inhibitor–resistant melanoma characterized by epigenetically repressed PGC1αStatin treatment blocks cell growth by lowering RAB6B and RAB27A prenylation and affects integrin localization and downstream signaling required for melanoma cell growth[86]
20222D model/
SK-Mel-147		Knockdown of integrin α3β1 in SK-Mel-147 human melanoma cells led to a marked increase in cellular senescence of melanoma cellsIntegrin α3β1 plays a protective role against cellular senescence in melanoma cells[87]
20222D model/
16F10		Silencing of STAT3 after treatment with anti-STAT3 siRNA-loaded liposomes triggers apoptotic activity in B16F10 melanoma cancer cells. C-RGD peptide targeted liposomal siRNA delivery system was able to induce apoptosis in a greater amount than non-targeted liposomes on overexpressed integrin αvβ3 receptor cellsC-RGD peptide targeted liposomal siRNA delivery system was able to induce apoptosis more than non-targeted liposomes on overexpressed integrin αvβ3 receptor cells[88]
20222D model/
A375		NECTIN1 loss activates integrin-dependent matrix adhesionKnockdown of integrins: β3, β4 and β5 results in reduced migration of NECTIN1-deficient cells[89]
20212D model/
SK-Mel-147		Integrin α2β1 helps prevent senescence in SK-Mel-147 melanoma cellsThe silencing of integrin α2β1 reduced cell proliferation and enhanced the percentage of SA-β-Gal-positive cells, a phenotypic feature of cellular senescence[90]
20212D model/
WM793		ILK knockdown by siRNA suppresses melanoma cell growth by inducing autophagy through AMPK activation, and simultaneously initiates apoptosisCombinatorial treatment of melanoma cells with CQ and siILK has a stronger antitumor effect than monotherapy[91]
20212D model/
C32, SK-MEL-28		CD36 facilitates melanoma cell adhesion to the extracellular matrix (ECM)CD36 as a regulator of VM by melanoma cancer cells that is facilitated via integrin-α3[92]
20213D mouse model/
B16		Regulatory T (Treg) cells expressing the β8 chain of αvβ8 integrin (Itgβ8)—the main cell type in the tumorsTargeting the integrin αvβ8–TGF-β activation axis on Tregs may represent a promising therapeutic strategy[93]
Table 2. In vivo research on integrin signaling in melanoma treatment (2021–2025).
Table 2. In vivo research on integrin signaling in melanoma treatment (2021–2025).
YearStudy ModelKey FindingsMechanism of
Intervention		Reference
20253D mouse model/
B16F10		Inclusion of αvβ3 integrin into extracellular vesicles and subsequent transfer to recipient melanoma cells promotes migration, invasion, and metastasisCAV1 phosphorylated on Y14 intrinsically promotes migration, invasion, and metastasis of cells[94]
20253D mouse model/
B16-BL6		Carnosic acid significantly inhibits the expression of integrins: α4 (ITGA4) and α9 integrin (ITGA9)Downregulating α4 (ITGA4) and α9 (ITGA9) integrins, carnosic acid effectively reduces the ability of melanoma cells to adhere to the extracellular matrix and proliferate[95]
Table 3. In vitro and in vivo research models on integrin signaling in melanoma treatment (2021–2025).
Table 3. In vitro and in vivo research models on integrin signaling in melanoma treatment (2021–2025).
YearLevel of EvidenceStudy ModelKey FindingsMechanism of
Intervention		Reference
2025In vitro
In vivo		2D model/A2058, A375
3D mouse model/C57BL/
BALB/c		4S5NG-PE24 induced cell pyroptosis in integrin α6 melanoma cells by caspase 3/gasdermin E (GSDME) signaling pathway with lack of histological alterationsThe usage of 4S5NG to deliver PE24 for selective elimination of melanoma cells through integrin α6[49]
2024In vitro
In vivo		2D model/B16BL6
3D mouse model/B16BL6, CT26		EVs with 5-FU, DEAP-DOCA, and cRGD peptide targets αvβ3 integrin receptors on melanoma cellsEV-based drug-delivery platform capable of tumor targeting via integrin αvβ3, controlled pH-sensitive release[96]
This section synthesizes recent research developments across six key axes that define the future of integrin-targeted melanoma therapies.

3.1. Peptide–Toxin Conjugates for Tumor-Selective Cytotoxicity via Integrin α6

A notable advancement in targeted melanoma therapy involves the development of the multifunctional peptide 4S5NG, which integrates an α6-specific ligand (S5), an intracellular delivery sequence (N), and an endosomal escape domain (G). When conjugated to a de-immunized Pseudomonas exotoxin (PE24), construct—4S5NG–PE24—exhibits highly selective uptake in integrin α6+ melanoma cells and induces pyroptotic cell death via the caspase-3/GSDME pathway.
In vivo studies confirm both selective tumor accumulation and limited off-target toxicity. Importantly, co-treatment with immune checkpoint inhibitors (anti–PD-1) leads to a synergistic anti-tumor response, supporting the dual functionality of this system in direct cytotoxicity and immune activation. This strategy establishes a promising blueprint for next-generation peptide-based therapeutics in precision oncology [49].

3.2. Extracellular Vesicle-Mediated Nanotherapies Targeting Integrin αvβ3 and αvβ5

Integrin-targeted extracellular vesicles (EVs) represent a versatile platform for drug delivery and intercellular communication in melanoma. EVs functionalized with the cyclic RGD peptide (cRGD) enable selective binding to αvβ3-expressing melanoma cells, while a pH-sensitive polymer (DEAP-DOCA) facilitates controlled drug release (e.g., 5-fluorouracil) in the acidic tumor microenvironment. This design enhances therapeutic selectivity and efficacy in vivo [96].
Parallel studies show that melanoma-derived ectosomes enriched with αvβ3 and αvβ5 integrins can transfer these proteins to endothelial cells, promoting angiogenesis through integrin-specific pathways. Notably, αvβ5 plays a dominant role via VEGF signaling, highlighting it as a priority target for anti-angiogenic interventions [82]. These findings confirm the utility of EVs and ectosomes in both therapy and tumor microenvironment modulation.

3.3. Intracellular Regulators of Integrin Expression and Chemotherapy Sensitization

Beyond extracellular targeting, emerging studies emphasize the importance of regulatory pathways modulating integrin expression and function. The SERPINB8–furin–ITGAX axis, for example, influences integrin αXβ2 expression, which contributes to melanoma cell proliferation. Targeting this axis disrupts integrin-mediated growth signals [84].
Similarly, the talin2–KANK2 module plays a pivotal role in regulating microtubule dynamics and paclitaxel sensitivity in integrin αvβ5-positive melanoma cells. Talin2 knockdown destabilizes focal adhesions and enhances chemotherapeutic response, suggesting that structural integrin interactors represent viable co-targets to improve drug efficacy [85].
Inhibition of integrin-linked kinase (ILK)—a central node in integrin signaling—combined with chloroquine, further demonstrates that translation and autophagy regulation intersect with integrin-mediated survival pathways. These regulatory insights open new ways for rational combination therapies targeting both adhesion and signaling nodes [91].

3.4. Integrin-Mediated Control of Angiogenesis and Metastasis

Integrins also play critical roles in tumor-induced angiogenesis and metastatic dissemination. Ectosome-mediated transfer of αvβ5 to endothelial cells promotes tube formation and migration, essential features of tumor neovascularization. Blocking αvβ5 function significantly impairs these processes, establishing it as a central effector of melanoma-associated angiogenesis [82].
On the metastatic front, carnosic acid has been shown to downregulate integrins α4 (ITGA4) and α9 (ITGA9), reducing melanoma cell adhesion and lung metastasis in vivo [95]. Meanwhile, CD36, a non-integrin membrane receptor, facilitates vasculogenic mimicry (VM) by enhancing ECM adhesion, thereby mimicking vascular channels. Together, these findings support integrin-focused anti-angiogenic and anti-metastatic strategies, especially in targeting lung dissemination and neovascular remodeling [92].

3.5. Integrins and Cell Fate: Senescence, Survival, and Adhesion

Recent research uncovers the roles of integrins in cellular senescence and survival, particularly through the Akt1–mTOR–p53/p21 axis. Depletion of integrin α3β1 or α2β1 in melanoma cells leads to growth arrest and senescence, accompanied by increased p53 and mTOR activity. This suggests a protective role for these integrins against premature senescence and highlights pro-senescence therapy as a potential therapeutic angle [87].
In contrast, NECTIN1, an adherens junction component, suppresses metastasis by promoting cell–cell over cell–matrix adhesion. Loss of NECTIN1 causes a phenotypic switch that facilitates matrix-dependent migration, particularly under low IGF1 conditions. These findings reveal how integrin and adhesion proteins affect melanoma cell plasticity, dissemination, and dormancy escape [89].

3.6. Integrins as Immunomodulators and Immunotherapy Enablers

Integrins also regulate immune responses within the tumor microenvironment. The αvβ8 integrin, expressed on regulatory T cells (Tregs), activates latent TGF-β, contributing to immune evasion. Blocking this pathway enhances anti-tumor immunity and could improve checkpoint blockade efficacy [93].
Conversely, integrin-targeted therapies can augment immune responses. The 4S5NG–PE24 conjugate, beyond inducing pyroptosis, enhances PD-1 checkpoint blockade [49], while cRGD-functionalized liposomes improve siRNA delivery against STAT3, a key immune evasion mediator [88]. These studies suggest that integrin-directed approaches can be used to recondition the immune landscape in melanoma.
The integration of integrin expression profiling into clinical diagnostics has opened new avenues for patient stratification and personalized therapy. Concentrating on particular integrin subunits may lead to early tumor detection and treatment response monitoring.
The translational research regarding integrin signaling in melanoma emphasizes its relevance to tumor biology and innovative clinical targets development. Future perspectives should elucidate heterogeneity of integrin in melanoma subtypes and combine synergistic therapeutic approaches that utilize integrin signaling vulnerabilities.

4. Discussion

Studies from 2021 to 2025 highlight the crucial role of integrins in melanoma progression, drug resistance, and the development of targeted therapies.
The first axis—peptide 4S5NG-PE24—selectively targets integrin α6+ melanoma cells, inducing pyroptosis via caspase-3/GSDME activation and enhancing anti–PD-1 immunotherapy offers tumor-specific cytotoxicity, minimal off-target toxicity, and immunogenic cell death—a rare trifecta in targeted cancer therapy. However, there are some methodological and translational limitations—like in vivo selectivity claims are based on murine models, not patient-derived xenografts (PDXs) or clinical samples—limiting predictive value for human tumors. Despite the immune-stimulatory potential of pyroptosis, clinical pyroptotic therapies remain experimental. There is a possible risk of cytokine release syndrome or immune overstimulation [49].
The extracellular vesicle-mediated nanotherapies, like melanoma-derived ectosomes, transfer αvβ3/αvβ5 integrins to endothelial cells, promoting angiogenesis by blocking αvβ5, not αvβ3, which most significantly impairs angiogenesis. This idea shifts the therapeutic focus from αvβ3 to αvβ5, challenging long-held assumptions in anti-angiogenic therapy [82]. The past literature emphasized αvβ3 as the key proangiogenic driver [97,98,99,100,101,102]. These new findings contradict prior VEGF-centric models, necessitating reassessment of cilengitide and similar compounds that primarily target αvβ3 integrin. Additionally, most studies use HUVECs and HDMECs as endothelial models, which do not fully represent tumor vasculature heterogeneity in vivo. Targeting EVs remains technically difficult—issues in delivery, tracking, and clearance are unresolved. Integrin transfer via EVs introduces off-tumor risks—altered endothelial function outside the tumor site has not been studied.
The third axis, based on targeting regulatory elements of integrin function (e.g., SERPINB8, talin2, ILK), provides a more dynamic and indirect therapeutic approach, especially for enhancing chemotherapy sensitivity and overcoming drug resistance. Some regulators (e.g., SERPINB8) have context-dependent roles: while it acts as a tumor promoter in melanoma, it functions as a suppressor in other cancers, raising concerns about off-target effects or conflicting biological roles in multi-tumor patients. ILK inhibition has systemic implications due to its pleiotropic roles in multiple cell types (cardiac, vascular, immune), and combining it with chloroquine, an autophagy inhibitor, may result in unpredictable toxicity. Chemotherapy sensitization via talin2–KANK2 or ILK pathways is largely studied in 2D monolayer cultures. These models do not replicate 3D ECM context or stromal interactions critical for integrin behavior [84,85,91]. Lack of biomarker strategies to stratify patients based on integrin regulator expression undermines the translational path for personalized medicine.
The integrin-mediated control of angiogenesis and metastasis axis confirms the role of integrins (especially αvβ5) and non-integrin adhesion receptors (e.g., CD36) in tumor angiogenesis, vasculogenic mimicry, and metastatic dissemination, particularly to the lungs. While targeting αvβ5 shows promise, blocking angiogenesis due to the tumor adaptation via alternative vascular pathways (e.g., VM) is a challenging matter [82]. CD36 inhibition could interfere with fatty acid metabolism and immune cell function, suggesting possible metabolic side effects. The anti-metastatic effects of carnosic acid, a plant-derived compound, are promising but may not be reproducible in humans due to limited bioavailability, fast metabolism, and variability in integrin expression among patient tumors. Metastatic models often use tail vein injection, which bypasses the natural steps of metastasis (e.g., intravasation and immune escape), limiting the predictive power of such findings. CD36 and integrin expression are spatiotemporally dynamic, and static expression analysis may misrepresent their actual role during metastasis [92].
The fifth axis, based on the connection of integrins and cell fate, reveals that integrins α3β1 and α2β1 are shown to prevent premature senescence, supporting a pro-survival role in melanoma [87]. Meanwhile, NECTIN1 governs the adhesion mode switch, revealing how adhesion molecules influence dormancy escape and dissemination. While promoting senescence via integrin inhibition is therapeutic in principle, senescent cells often secrete pro-inflammatory SASP factors, which can paradoxically promote tumor progression and resistance. NECTIN1 loss is associated with enhanced invasion, yet in some cancers, low NECTIN1 expression correlates with better outcomes, indicating tumor-type–specific roles that complicate generalization. Senescence is often inferred via SA β Gal activity, which lacks specificity and may not reliably indicate a stable, irreversible growth arrest. The NECTIN1 study lacks mechanistic depth on how IGF1 deficiency integrates with cell–matrix adhesion, and in vivo models (e.g., zebrafish) have limited immune context compared to human tumors [89].
Integrins as immunomodulators and immunotherapy enablers show that integrins like αvβ8 on Tregs activate TGF-β, supporting immune evasion, while integrin-targeted platforms (e.g., 4S5NG–PE24 and cRGD-siSTAT3) enhance immune checkpoint therapy and gene silencing. This axis aligns integrin biology with modern immuno-oncology paradigms. αvβ8 is not consistently expressed across melanoma subtypes, and targeting it may have limited applicability. Moreover, Tregs are essential for immune homeostasis, and systemic αvβ8 blockade could trigger autoimmune responses. Delivery platforms like cRGD liposomes face challenges in nuclease resistance, endosomal escape, and scalability for clinical use. Combining pyroptotic agents (e.g., PE24) with PD-1 inhibitors can cause excessive immune activation, raising the possibility of cytokine release syndromes or tissue damage in patients. Studies often rely on subcutaneous tumor models, which lack the complex immune architecture of human melanoma and cannot predict immune-related adverse events accurately. Absence of patient-derived melanoma models or syngeneic immunocompetent models hinders the translation of immunomodulatory findings [49,88,93].
The expanding landscape of integrin research in melanoma reflects a transition from static structural roles to dynamic regulatory and therapeutic functions. The described six axes—ranging from precision peptide–toxin delivery to immune and microenvironmental modulation—highlight integrins as multidimensional therapeutic targets.
Integrin-focused strategies are particularly promising due to their: tumor specificity (e.g., α6, αvβ3, and αvβ5), therapeutic synergy (e.g., immunotherapy and chemotherapy), delivery flexibility (e.g., EVs and liposomes), and regulatory depth (e.g., protease networks and actin-MT crosstalk). Future work should focus on enhancing clinical translatability of integrin-targeted platforms, developing isoform-specific inhibitors or ligands, exploring biomarker-guided patient stratification, and integrating multi-omic profiling to uncover novel integrin regulatory circuits.
Together, these integrin-directed innovations position themselves at the forefront of next-generation melanoma therapy.
The challenging question is whether the natural products such as vitamin D derivatives and melatonin with its metabolites [103,104], known for their anti-cancer activity [105,106,107], can sufficiently affect integrin expression and composition to attenuate melanogenesis and tumor progression, including metastatic disease. Vitamin D derivatives and melatonin with its derivatives are excellent candidates as adjuvants in melanoma therapy [1,105]. Interestingly, vitamin D hydroxymelabolites can affect fibroblast activities and composition of the ECM [108,109,110], raising the possibility that these agents could alter tumor–stroma interactions in melanoma. Their role as adjuvants in melanoma therapy warrants further investigation, particularly regarding their ability to modulate integrin composition in metastatic disease.
It is worth mentioning that acral melanoma is a distinct and rare subtype of melanoma that arises on the palms, soles, and nail beds. Unlike cutaneous melanoma, acral melanoma is not associated with ultraviolet (UV) radiation exposure, suggesting alternative mechanisms drive its initiation and progression. Recent studies indicate that integrins—transmembrane receptors involved in cell adhesion, migration, and signaling—play a pivotal role in acral melanoma biology. Altered expression of specific integrin subunits has been implicated in promoting tumor invasion, resistance to therapy, and interactions with the tumor microenvironment. Given the unique pathogenesis of acral melanoma, integrin-mediated pathways may offer subtype-specific biomarkers and therapeutic targets. Further investigation into integrin signaling could improve understanding of acral melanoma progression and guide the development of precision treatments for this challenging melanoma variant [111,112,113].
Collectively, these findings broaden the concept that the integrins are not isolated adhesion molecules, but central regulators of melanoma cell fate, invasion, immune resistance, and therapeutic responsiveness. Their subtype-specific functions, dynamic regulation, and integration into multiple oncogenic pathways make them compelling yet complex therapeutic targets. Future research should focus on integrin–ECM interactions in well-defined melanoma subtypes to evaluate combinatorial targeting approaches and explore the integration of natural compounds with established and experimental integrin-based therapies to overcome resistance and limit metastatic spread.

5. Conclusions

Six key research axes highlight integrins as multifaceted regulators of melanoma progression, therapeutic resistance, and immune evasion. While each axis demonstrates therapeutic potential, its translational success will depend on addressing specific contradictions, methodological gaps, and biological complexities.
Integrin-targeted therapies are no longer limited to inhibiting adhesion; they now span cytotoxic payload delivery, immune modulation, and therapy sensitization. Their integration into clinical oncology pipelines should follow a biomarker-driven, multi-modal approach, with a strong emphasis on tumor selectivity, immune context, and safety.
In conclusion, integrins have emerged as central regulators in melanoma progression, drug resistance, and immune escape, offering multiple points of therapeutic intervention. Among the current strategies, α6-targeted peptide–toxin conjugates hold clinical promise due to their tumor specificity and ability to synergize with immunotherapy. However, broader clinical success will require moving beyond isolated targets and toward integrin-guided combination therapies that integrate immune modulation, metastasis inhibition, and drug delivery. Future research must prioritize biomarker-driven patient stratification, validation in complex, immunocompetent models, and the development of real-time imaging tools to monitor integrin activity. Clinically, integrins should no longer be viewed as passive adhesion molecules but as actionable hubs for precision oncology.

Author Contributions

Conceptualization, K.A.-N. and I.I.-S.; investigation, K.A.-N. and Z.S.; resources, K.A.-N. and Z.S.; writing—original draft preparation, K.A.-N. and Z.S.; writing—review and editing, I.I.-S. and A.T.S.; visualization, Z.S. and K.A.-N.; supervision, I.I.-S.; A.T.S., project administration, K.A.-N., I.I.-S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding. However, partial support of A.T.S. by DOD grant #W81XWH2210689 and of I.I.-S. by St-54 grant from Medical University of Gdansk is acknowledged.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AKTProtein Kinase B
AMPKAMP-Activated Protein Kinase
BRAFB-type Rapidly Accelerated Fibrosarcoma
CD11cCluster of Differentiation 11c
CD36Cluster of Differentiation 36
CD44Cluster of Differentiation 44
c-RGDCyclic RGD
CRISPRClustered Regularly Interspaced Short Palindromic Repeats technique
CQChloroquine
CYR61Cysteine-Rich Angiogenic Inducer 61
DDRDiscoidin Domain Receptor 1/2
DEAP DOCADiethylaminoethyl-Polymer and Deoxycholic Acid
ECMExtracellular Matrix
EGFEpidermal Growth Factor
EMTEpithelial–Mesenchymal Transition
ERK Extracellular Signal-Regulated Kinase (1/2)
EVsExtracellular Vesicles
FAKFocal Adhesion Kinase
GSDMEGasdermin E
GGPPGeranylgeranyl Pyrophosphate
GTPGuanosine Triphosphate
HDMECsHuman Dermal Microvascular Endothelial Cells
HMGCR3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase
HUVECsHuman Umbilical Vein Endothelial Cells
IGF1Insulin-like Growth Factor 1
ILKIntegrin-Linked Kinase
ITGA1Integrin Alpha-1
ITGAXIntegrin Alpha-X (CD11c)
Itgβ8Integrin Beta-8
JNKC-Jun N-terminal Kinase
KANK2KN motif and Ankyrin Repeat Domain-Containing Protein 2
MAPKMitogen-Activated Protein Kinase
MEKMitogen-Activated Protein Kinase (1/2)
MLCMyosin Light Chain
MYPT1Myosin Phosphatase Target Subunit 1
NECTIN1Nectin Cell Adhesion Molecule 1
RGDArginine-Glycine-Aspartic Acid Peptide
SA-β-GalSenescence-Associated Beta-Galactosidase
SERPINB8Serine Protease Inhibitor B8
siILKSmall Interfering RNA Targeting Integrin-Linked Kinase
siRNASmall Interfering Ribonucleic Acid
STAT3Signal Transducer and Activator of Transcription 3
TGF-βTransforming Growth Factor Beta
mTOR/C1Mechanistic Target of Rapamycin (Complex 1)
MTMicrotubules
PPhosphorylation
p130CasCrk-Associated Substrate
PAC/PTXPaclitaxel
PGC1αPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha
PI3KPhosphoinositide 3-Kinase
PD-1Programmed Cell Death Protein 1
PE24De-immunized Exotoxin A
RAFRapidly Accelerated Fibrosarcoma
RASActive State Ras Protein
RhoA-RasHomolog Family Member A
ROSReactive Oxygen Species
RTKReceptor Tyrosine Kinase
SA β GalSenescence-associated β-Galactosidase
SASPSenescence-associated Secretory Phenotype
SRCProto-Oncogene Tyrosine-Protein Kinase
TAZTranscriptional coactivator
TregRegulatory T Cell
VMVasculogenic Mimicry
YAPYes-Associated Protein,
5-FU5-Fluorouracil

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MDPI and ACS Style

Adamiak-Nikolouzou, K.; Słomiński, A.T.; Skalska, Z.; Inkielewicz-Stępniak, I. Therapeutic Use of Integrin Signaling in Melanoma Cells: Physical Link with the Extracellular Matrix (ECM). Cancers 2025, 17, 3037. https://doi.org/10.3390/cancers17183037

AMA Style

Adamiak-Nikolouzou K, Słomiński AT, Skalska Z, Inkielewicz-Stępniak I. Therapeutic Use of Integrin Signaling in Melanoma Cells: Physical Link with the Extracellular Matrix (ECM). Cancers. 2025; 17(18):3037. https://doi.org/10.3390/cancers17183037

Chicago/Turabian Style

Adamiak-Nikolouzou, Katarzyna, Andrzej T. Słomiński, Zofia Skalska, and Iwona Inkielewicz-Stępniak. 2025. "Therapeutic Use of Integrin Signaling in Melanoma Cells: Physical Link with the Extracellular Matrix (ECM)" Cancers 17, no. 18: 3037. https://doi.org/10.3390/cancers17183037

APA Style

Adamiak-Nikolouzou, K., Słomiński, A. T., Skalska, Z., & Inkielewicz-Stępniak, I. (2025). Therapeutic Use of Integrin Signaling in Melanoma Cells: Physical Link with the Extracellular Matrix (ECM). Cancers, 17(18), 3037. https://doi.org/10.3390/cancers17183037

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