In keloids, keratinocytes exhibit abnormal patterns of cytokine and chemokine secretion. These factors include interleukins (ILs), tumor necrosis factor (TNF), and transforming growth factor (TGF), among others. The aberrant secretion of these factors not only promotes the proliferation and differentiation of keratinocytes themselves but also attracts and activates immune cells such as macrophages and neutrophils, further exacerbating the inflammatory response and fibrotic process in keloids. As non-professional antigen-presenting cells, keratinocytes also demonstrate significant changes in their antigen presentation function in keloids. By expressing major histocompatibility complex (MHC) molecules and co-stimulatory molecules, they can effectively present antigens to T cells, thereby initiating adaptive immune responses (12, 13). In keloids, keratinocytes can activate T cells by presenting self-antigens or pathogen-derived antigens, leading to the secretion of various cytokines such as IFN-γ and IL-17. These cytokines further promote the formation and development of keloids. This abnormal antigen presentation function may result in an imbalance of the local immune microenvironment in keloids, facilitating their formation and progression.

In the immune microenvironment of keloids, there is a close interaction between keratinocytes and immune cells. On one hand, keratinocytes attract and activate immune cells by secreting chemokines; on the other hand, inflammatory mediators released by immune cells in turn influence the biological behavior of keratinocytes. This interaction forms a complex immune network that collectively regulates the occurrence and development of keloids.

The extracellular matrix (ECM) is a major component of fibrotic tissue in keloids. Keratinocytes participate in the degradation and remodeling of the ECM by secreting various matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (14). In keloids, the imbalance between MMPs and TIMPs secreted by keratinocytes leads to excessive ECM deposition and exacerbated fibrosis.

Keratinocytes play a key role in regulating local immune responses by forming physical barriers and secreting various cytokines, including pro-inflammatory and anti-inflammatory factors. They can express co-stimulatory molecules and participate in antigen presentation, thereby activating T cells. Additionally, keratinocytes induce the migration of immune cells to the site of injury by releasing chemotactic factors, facilitating wound healing. In some cases, they can also achieve local immune tolerance through the expression of immune checkpoint molecules.

Macrophages are a crucial immune component that plays a dual role in tissue repair and fibrosis. Scar is a pathological scar characterized by excessive deposition of collagen and activation of fibroblasts. Macrophages regulate the behavior of fibroblasts and reshape the local microenvironment (17). During early wound healing, they rapidly infiltrate injury sites, clearing debris/pathogens while secreting cytokines to initiate repair processes. These factors include pro-inflammatory cytokines (such as IL-1, IL-6, TNF-α) and growth factors (such as TGF-β, vascular endothelial growth factor (VEGF), etc.). The release of these factors not only attracts more immune cells but also stimulates the proliferation of fibroblasts and collagen synthesis (18). Macrophages also modulate extracellular matrix composition via MMPs, influencing keloid formation (19). Keloid tissue shows increased macrophage infiltration, predominantly M2-polarized cells. These pro-repair, anti-inflammatory M2 macrophages promote fibrosis by secreting growth factors (e.g., TGF-β) that stimulate fibroblast activity and proliferation (20).These findings demonstrate macrophages’ dual role in keloid pathogenesis: participating in initial inflammation while directly modulating fibroblast function through polarization. Importantly, a bidirectional crosstalk exists between macrophages and fibroblasts. Keloid fibroblasts not only respond to macrophage signals but also secrete TGF-β to promote M2 polarization (21), creating a pro-fibrotic feedback loop that exacerbates scarring (22).This macrophage-fibroblast crosstalk critically drives keloid progression through both direct cellular interactions and modulation of the local immune microenvironment (23).Research indicates that macrophages can attract other immune cells (such as lymphocytes and neutrophils) to the site of injury by releasing pro-inflammatory factors. The involvement of these cells can further enhance the local inflammatory response, and sustained inflammation may promote keloid formation (24). Therefore, altering the polarization state of macrophages or inhibiting their pro-inflammatory responses could represent a new strategy for treating keloids.

T cells are a type of lymphocyte produced in the thymus, playing a crucial role in the immune system. Based on their surface markers and functions, T cells can be primarily divided into two major categories: CD4⁺ T cells and CD8⁺ T cells. CD4⁺ T cells can further be subdivided into different subsets, such as Th1 (helper T cells type 1), Th2 (helper T cells type 2), and Th17 (helper T cells type 17). Each subset has unique functions in regulating immune responses and mediating inflammation.

T cells play an important role in modulating immune responses, participating in inflammatory reactions, and contributing to fibrotic mechanisms. Research indicates that T cells influence the occurrence and development of keloids through various mechanisms.

After skin injury, local tissue damage triggers a series of inflammatory responses. The cytokines and chemokines released from the damaged area can induce T cells to migrate from the bloodstream to the site of injury. In this process, the initial immune response primarily relies on the actions of macrophages and dendritic cells (DCs), which effectively capture pathogens and present antigens, thereby activating T cells (25).

Activated T cells begin to proliferate and migrate toward the damaged area, a process regulated by various cytokines, including IL-2, IL-6, and TGF-β. In keloids, the accumulation and activity of CD4⁺ T cells are particularly considered to be closely related to changes in the local microenvironment (26).

Research shows that the number of CD4⁺ T cells significantly increases in keloid tissue, and these cells promote the proliferation of fibroblasts and the synthesis of collagen by secreting cytokines such as IL-6 and IL-13 (27). This finding suggests the importance of Th2-type immune responses in keloid formation, and the release of Th2 cell cytokines may induce fibroblasts to transform into myofibroblasts, thereby exacerbating the fibrotic process.

Additionally, CD8⁺ T cells also play a complex role in the formation of keloids. Although CD8⁺ T cells are generally associated with host defense against infections and tumor surveillance, research has shown that their functions in keloid formation should not be overlooked. Some studies suggest that CD8⁺ T cells can inhibit the proliferation of fibroblasts and collagen synthesis by secreting cytokines such as IFN-γ (28). However, in the keloid environment, this inhibitory effect may be weakened, leading to an abnormal fibrotic response instead.

In addition, the interaction between T cells and other immune cells also has a significant impact on the formation of keloids. For instance, T cells can recruit macrophages and B cells to the damaged area by secreting chemokines, and the activation of these cells can further enhance the inflammatory response (29). Keloid tissue contains a large number of activated macrophages and B cells, which participate in the formation process of keloids through interactions and signal transduction (30).

It is noteworthy that the role of T cells in keloids also involves immune tolerance and autoimmune responses (31). Patients with keloids may exhibit abnormal autoimmune reactions, which could result from T cells incorrectly recognizing or being overly activated by self-antigens. This phenomenon not only leads to a persistent inflammatory state but also further promotes the activation of fibroblasts and collagen production.

Mast cells are immune cells derived from bone marrow, widely distributed in tissues such as the skin, respiratory tract, and gastrointestinal tract. They contain abundant granules that store various bioactive substances, including histamine, proteases (such as trypsin and chymotrypsin), heparin, and various cytokines. When mast cells are stimulated, these substances can be released into the extracellular matrix, participating in various physiological processes such as local inflammatory responses, tissue repair, and immune regulation. In the pathophysiological process of keloid formation, mast cells influence local fibrosis by releasing these inflammatory mediators and cytokines. They are also regarded as important immune cells in the formation of keloids (32).

Mast cells trigger local inflammatory responses by releasing mediators such as histamine (33). The formation of keloids is often accompanied by a chronic inflammatory response, and mast cells are one of the key participants in this reaction. In the early stages of keloid formation, damage to the local tissue leads to the recruitment and activation of mast cells. Once activated, mast cells release a large amount of inflammatory mediators, such as histamine, leukotrienes, and prostaglandins, which promote vasodilation and increase vascular permeability, resulting in localized edema and the accumulation of extracellular matrix (34). These inflammatory responses not only provide a suitable microenvironment for fibroblast proliferation but also further promote keloid formation by regulating the activity of local immune cells.

Mast cells regulate the activity of fibroblasts directly by releasing various growth factors and cytokines (35). In hypertrophic scar tissues, mast cells often exhibit a co-localized distribution with fibroblasts, suggesting an interaction between the two. Studies have found that mast cells can release various growth factors that promote fibrosis, such as TGF-β, PDGF, and fibronectin, etc (36). These factors can stimulate the proliferation and migration of fibroblasts, as well as induce the synthesis of a large amount of extracellular matrix components, especially collagen. Additionally, the cytokines released by mast cells (such as IL-4, IL-13) can also induce the transformation of fibroblasts into myofibroblasts (37). Myofibroblasts are cells with contractile ability that can further tighten and compress local tissues, exacerbating the proliferation of keloids.

Mast cells in keloids not only play a role in promoting the fibrotic process but may also be important in regulating the local immune microenvironment. Studies have shown that the formation of keloids is closely related to the dysregulation of local immune responses, and mast cells, as immune effector cells, can indirectly affect the occurrence and development of keloids by regulating the activity of other immune cells (such as T cells, macrophages, and dendritic cells) (38, 39). For example, the cytokines and chemokines released by mast cells can recruit and activate T cells, thereby modulating the local immune response. In addition, mast cells can interact directly with T cells through the expression of co-stimulatory molecules on their surface, influencing the activation and differentiation of T cells.

The role of mast cells in the formation of keloids is not limited to promoting fibrosis and inflammation. Recent studies have also found that mast cells may have a negative feedback regulatory effect on scar formation by secreting some anti-fibrotic factors or inhibitory molecules (40). For example, heparin released by mast cells has anti-fibrotic properties and can inhibit the proliferation of fibroblasts and collagen synthesis (41). In addition, mast cells may also suppress local inflammatory responses by releasing anti-inflammatory cytokines (such as IL-10), thereby slowing down the proliferation of keloids (42). Therefore, the role of mast cells in the formation of keloids is complex, with both positive effects in promoting fibrosis and potential inhibitory effects through certain pathways.

Mast cells play an important role in immune regulation during the formation of keloids. Mast cells can recognize and bind specific antigens through their surface receptors, triggering a series of immune reactions. These immune responses not only help clear pathogens and harmful substances from the body but also regulate the immune tolerance of the body to its own tissues. However, during the formation of keloids, the immune regulatory function of mast cells may become abnormal, leading to the body’s immune attack on its own tissues, thereby exacerbating the formation and development of keloids.

Tregs are a subset of CD4+ T cells with immune suppressive functions, primarily maintaining immune homeostasis by inhibiting excessive immune responses. The characteristic molecules of Tregs include the transcription factor Foxp3, cell surface molecules CD25, cytotoxic Tlymphocyte-associated antigen 4(CTLA-4), among others. Tregs exert immune suppression through various mechanisms, such as secreting immunosuppressive cytokines (such as IL-10, TGF-β) to inhibit the activity of effector T cells, or directly interacting with antigen-presenting cells to reduce the intensity of immune responses (43).

Tregs play a crucial role in protecting self-immunity in the body, preventing excessive immune responses that could cause tissue damage. However, under certain pathological conditions, the function of Tregs may be erroneously activated or suppressed, leading to inappropriate tissue repair reactions. For example, excessive activation of Tregs may impair the immune system’s monitoring and clearance functions against tumor cells, promoting tumor growth. Similarly, abnormalities in Tregs function may play an important role in the formation of keloids (44).

The main characteristic of keloids is the abnormal proliferation of fibroblasts and excessive deposition of collagen. In normal skin repair processes, fibroblasts secrete an appropriate amount of collagen to repair tissue. However, in the formation of keloids, this process is abnormally activated, leading to the deposition of excessive collagen proteins (especially type I and type III collagens). Stem cells, especially MSCs, inhibit the excessive activation and proliferation of fibroblasts through various pathways. Studies have shown that MSCs can degrade excessive collagen and inhibit the proliferation of fibroblasts in keloids by secreting anti-fibrotic factors such as tumor necrosis factor-α-induced protein 6 (TSG-6) and matrix metalloproteinases (MMPs) (58). Additionally, stem cells can regulate the TGF-β/Smad signaling pathway to suppress key fibrotic signaling processes in the formation of keloids. TGF-β plays a crucial role in the pathological process of keloids, promoting fibroblast proliferation and collagen synthesis. The presence of MSCs can inhibit this fibrotic process by reducing the activation of the TGF-β signaling pathway (59).

Due to their strong immunomodulatory capabilities, MSCs can regulate local and systemic immune environments through various pathways. Firstly, MSCs can inhibit the pro-inflammatory M₁ polarization of macrophages towards an anti-inflammatory M₂ phenotype, thereby reducing the secretion of inflammatory factors and alleviating local inflammation reactions (60, 61). Additionally, MSCs can also secrete various immunomodulatory factors such as IL-10 and prostaglandin E2 (PGE2), which suppress the activation and proliferation of T lymphocytes, regulate Th1/Th2 balance, and restore normal immune system function (62). Therefore, the immunomodulatory effects of stem cells not only alleviate chronic inflammation during the formation of keloids but also inhibit the ongoing development of fibrosis.

Inflammatory response is an important factor in the formation of keloids. After skin tissue injury, the healing process initiates acute and chronic inflammatory responses. Acute inflammation helps clear pathogens and necrotic tissue. However, if the inflammatory response is excessive or prolonged, it can lead to fibrosis. Patients with keloids typically have persistent chronic inflammation, characterized by continuous infiltration of inflammatory cells and high expression of pro-inflammatory factors.

Stem cells, especially MSCs, exert significant anti-inflammatory effects through the secretion of anti-inflammatory factors. Studies have shown that MSCs can inhibit the expression of pro-inflammatory cytokines (such as TNF-a, IL-6, IL-1β, etc.) and reduce the infiltration of inflammatory cells by secreting molecules like PGE2, TSG-6, interleukin-1 receptor antagonist (IL-1RA). This helps alleviate local chronic inflammation (63). Additionally, stem cells can regulate the polarization state of macrophages, converting pro-inflammatory M1-type macrophages into anti-inflammatory M₂-type macrophages, further mitigating the inflammatory response.

The role of stem cells in keloids is not only dependent on their differentiation potential but also closely related to their powerful paracrine effects. Stem cells regulate local cell behavior and tissue microenvironment by secreting a series of bioactive molecules such as growth factors, cytokines, chemokines, etc (64). Particularly in the treatment of keloids, MSCs can promote normal tissue repair and regeneration, reduce abnormal fibrotic reactions by secreting VEGF, fibroblast growth factor (FGF), insulin-like growth factor (IGF), and other factors. Additionally, the exosomes secreted by stem cells, as a type of extracellular vesicle, have shown potential in the treatment of keloids. Exosomes carry various functional molecules such as proteins, mRNA, miRNA, etc., which can be uptaken by surrounding cells to regulate cell growth, differentiation, and matrix synthesis (65). Through these paracrine mechanisms, stem cells can effectively inhibit the formation of keloids and promote the repair of damaged tissues.

In general, stem cells, especially MSC, exhibit immense potential in the treatment of keloids due to their multilineage differentiation potential, anti-fibrotic, anti-inflammatory, and immunomodulatory effects. With the continuous advancement of cell therapy technologies, stem cells are expected to become an effective and safe approach for treating keloids in the future.

TGF-β regulates various immune cells, including macrophages, lymphocytes, and dendritic cells. In keloids, TGF-β inhibits the activation of macrophages, reducing the release of inflammatory mediators such as INF-γ, IL-17, thereby alleviating local inflammation. Additionally, TGF-β promotes the generation and activation of Tregs while inhibiting the proliferation of B lymphocytes and antibody production (67). Tregs play a crucial role in immune regulation by suppressing excessive immune responses. However, in keloids, an excessive number of Tregs may lead to immune dysregulation.

TGF-β can influence the secretion of various cytokines, such as interleukins (IL) and tumor necrosis factor (TNF). In keloids, TGF-β upregulates the expression of anti-inflammatory cytokines like IL-10 while downregulating the levels of pro-inflammatory cytokines such as IL-6 and TNF-α, thus regulating the local immune microenvironment.

TGF-β plays a crucial role in immune response reactions. On one hand, TGF-β can inhibit the proliferation and activation of Th1 cells while promoting the development and differentiation of Th2 cells, thereby regulating the Th1/Th2 immune balance (68). On the other hand, TGF-β can induce the production and activation of regulatory T cells (Tregs), enhancing their immunosuppressive function to inhibit aberrant immune responses in keloids.

The Smad signaling pathway is one of the main downstream signaling pathways of TGF-β. In keloids, TGF-β binds to receptors on the cell membrane, activates receptor-regulated Smad proteins such as Smad2 and Smad3, forming a Smad complex that translocates to the cell nucleus to regulate gene expression (69). In addition to the Smad signaling pathway, TGF-β can also activate various non-Smad signaling pathways such as the MAPK signaling pathway, PI3K/Akt signaling pathway, etc., to exert its biological effects in keloids (70, 71). The activation of these signaling pathways can interact and influence each other, collectively participating in the occurrence and development of keloids.

Therefore, TGF-β in the immune mechanism of keloids plays a role in promoting immune cell infiltration, regulating immune cell function, promoting fibroblast activation and collagen deposition, enhancing mast cell function, and other aspects, affecting the formation and development of keloids.

During the formation of keloids, inflammation occurs, and various immune cells such as macrophages, lymphocytes, etc., are involved. Studies have found that the Wnt signaling pathway plays a regulatory role in the infiltration of immune cells (76, 79, 80). Specifically, Wnt proteins can regulate the expression of chemokines, attracting immune cells to migrate to hypertrophic scar tissues. For example, Wnt3a can upregulate the expression of the chemokine CCL2, promoting the aggregation of macrophages in hypertrophic scar tissues. These immune cells play an important role in the formation of keloids, and the degree of their infiltration is closely related to the severity of keloids.

In addition to regulating the infiltration of immune cells, the Wnt/β-catenin protein signaling pathway can also directly influence the function of immune cells. In hypertrophic scar tissues, Wnt proteins can activate the β-catenin signaling pathway to regulate processes such as proliferation, differentiation, and activation of immune cells (81). For example, Wnt5a can activate the polarization process of macrophages through the non-canonical Wnt pathway, causing them to differentiate into M2-type macrophages. M2-type macrophages play a role in promoting tissue repair and fibrosis during the formation of keloids, and an increase in their number may lead to excessive proliferation of keloids.

During the formation of keloids, the production and release of inflammatory mediators such as TGF-β, PDGF, etc., have a significant impact on the development of keloids. Studies have found that the Wnt signaling pathway can regulate the production of these inflammatory mediators. Specifically, Wnt proteins can upregulate the expression of inflammatory mediators such as TGF-β, PDGF, etc., by activating the β-catenin signaling pathway (82, 83). These inflammatory mediators can further stimulate the proliferation of fibroblasts and collagen synthesis in keloids, leading to the formation and exacerbation of keloids.

The Notch signaling pathway plays an important role in macrophage polarization. Studies have shown that activation of the Notch signaling pathway can promote macrophage polarization towards M1 type (86). The Notch signaling pathway regulates macrophage polarization by inhibiting the expression of signal-regulatory protein α (SIRPα). SIRPα plays a key role in M2-type polarization of macrophages, and its expression is dependent on interaction with CD47 and via SHP-1-mediated intracellular signaling. The Notch signaling pathway inhibits the expression of SIRPα through Hes family co-repressors. In addition, the Notch signaling pathway can also affect the polarization process of macrophages by regulating other molecules such as SOCS3, cylindromatosis, and miR-125a (87). These molecules play an important regulatory role in the macrophage polarization process.

T lymphocytes play a pivotal role in the immune mechanisms underlying keloid formation, with their proliferation and differentiation being tightly regulated by the Notch signaling pathway. Activation of Notch signaling promotes T cell expansion and modulates subset differentiation, exerting dual effects on scar pathogenesis. On one hand, Delta-like ligands engage Notch1 receptors to initiate the RBP-Jκ-dependent transcriptional program, which synergizes with the TGF-β/Smad3 pathway to upregulate Foxp3 expression and drive regulatory T cell differentiation (88). Concurrently, Notch-mediated recruitment of DNMT1 methyltransferase establishes repressive epigenetic marks at the IL2 and IFNG loci through CpG island hypermethylation, effectively suppressing Th1 lineage commitment (89, 90).

Conversely, keratinocyte-derived Jagged1 ligands binding to Notch3 receptors on T cells trigger distinct epigenetic remodeling. The RBP-Jκ/p300 complex facilitates histone acetylation at the GATA3 locus, marked by increased H3K27ac deposition, which opens chromatin accessibility and establishes Th2-polarizing gene expression. As the master transcriptional regulator of Th2 differentiation, GATA3 directly transactivates IL-4, IL-5, and IL-13 genes, creating a profibrotic cytokine milieu that may contribute to keloid pathogenesis. The pathway orchestrates these fate decisions through sophisticated integration of transcriptional networks and epigenetic modifications, ultimately influencing scar tissue homeostasis (91).

Mast cells contribute significantly to keloid pathogenesis through the release of pro-inflammatory mediators including histamine and leukotrienes, which promote extracellular matrix deposition and fibrotic progression. Emerging evidence indicates that the Notch signaling pathway modulates mast cell activation and proliferation, thereby influencing keloid formation (92). In keloid tissue, Notch pathway activation appears to enhance mast cell-mediated inflammatory responses, though the precise molecular mechanisms warrant further investigation.

Notch signaling orchestrates macrophage polarization through dual regulatory mechanisms. At the transcriptional level, the NICD-RBP-Jκ complex directly activates M2 marker genes (Arg1, Mrcl) while suppressing NF-κB-mediated expression of M1-associated genes (TNF-α, iNOS (93). Epigenetically, Notch signaling facilitates HDAC1 recruitment to the IRF8 locus, resulting in H3K9 deacetylation and subsequent silencing of this critical M1 polarization regulato (94). Within keloid microenvironments, fibroblast-derived Jagged1 sustains Notch2 receptor activation in macrophages, promoting a profibrotic M2 phenotype that exacerbates scar formation (95).

The Notch signaling pathway participates in the pathological process of scar tissue by bidirectionally regulating the cytokine network. Research has shown that activation of this pathway in keloid tissue can significantly promote the secretion of key cytokines such as TGF - β and VEGF, which play a central role in abnormal fibrosis and angiogenesis of scar tissue. Of particular note is the positive feedback amplification mechanism between Notch and TGF - β pathway: on the one hand, the intracellular domain NICD of Notch forms a transcription complex with Smad3 protein, directly enhancing the transcriptional activity of TGFB1 gene (96, 97); On the other hand, TGF - β signaling upregulates the expression level of Notch ligand Jagged1 through a Smad4 dependent pathway. This bidirectional molecular loop continuously amplifies pro fibrotic signals, ultimately leading to the sustained progression and difficult to regress pathological features of scar tissue (93). In conclusion, the Notch signaling pathway plays a significant role in the immune mechanisms of keloids. By regulating the polarization of macrophages, proliferation and differentiation of T lymphocytes, activation and proliferation of mast cells, and secretion of cytokines, the Notch signaling pathway may impact the formation and development of keloids. However, many aspects of the specific mechanisms of the Notch signaling pathway in keloids remain unknown. Future research should further explore the detailed mechanisms of the Notch signaling pathway in keloids, particularly its interactions with other signaling pathways and its differential effects in different cell types. Additionally, investigating therapeutic strategies targeting the Notch signaling pathway could lead to the development of new approaches for treating keloids.