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CCL17

CCL17, also known as thymus and activation-regulated (TARC), is a small belonging to the CC family that functions as a chemoattractant for T lymphocytes, particularly T helper type 2 (Th2) cells and regulatory T cells (Tregs), thereby playing a central role in orchestrating immune cell trafficking and modulating inflammatory responses. This is primarily produced by antigen-presenting cells such as dendritic cells, macrophages, and monocytes, as well as endothelial cells, and is constitutively expressed in the to support T cell development. Encoded by the CCL17 located on 16q21 in humans, CCL17 exhibits a typical featuring a conserved CC motif near the N-, which facilitates its binding to G protein-coupled receptors and, to a lesser extent, CCR8 on target cells. In physiological contexts, CCL17 contributes to homeostatic immune processes by promoting the migration of CCR4-expressing T cells to lymphoid organs and sites of inflammation, influencing Th2-biased immune responses, , and the balance between effector T cells and Tregs. Its expression is upregulated by pro-inflammatory stimuli, including ligands and cytokines like IL-4, amplifying adaptive immunity during infections or allergic conditions. Dysregulated CCL17 production has been implicated in various pathologies; for instance, elevated serum levels serve as a for severity, reflecting Th2-driven inflammation, while in autoimmune diseases such as , it exacerbates inflammation by enhancing and Th17 cell recruitment. Beyond immunity, CCL17's involvement extends to cancer and cardiovascular diseases, where it can promote tumor immune evasion by attracting Tregs or contribute to cardiac through non-immune mechanisms, positioning it as a potential therapeutic target with antagonists like showing promise in CCR4-positive malignancies such as adult T-cell leukemia/lymphoma. Ongoing research highlights its multifaceted roles, from lymphocyte-dependent to broader effects on —as evidenced by clinical trials of anti-CCL17 GSK3858279 for as of 2024—and tissue remodeling in chronic inflammatory settings.

Discovery and Nomenclature

Historical Discovery

CCL17, initially designated as thymus- and activation-regulated chemokine (TARC), was first isolated in 1996 through a signal sequence trap method utilizing an Epstein-Barr virus vector. Researchers constructed a from phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cells (PBMCs) and transfected it into Raji cells expressing , enabling the identification of clones that directed surface expression. This approach led to the of a full-length cDNA (538 bp) encoding a 94-amino-acid protein with a 23-residue signal peptide, homologous to the CC family, and the gene was found to be constitutively expressed in the while transiently induced in activated PBMCs. Early characterizations in the same study demonstrated TARC's production in and its chemotactic activity toward T-cell lines such as Hut78 and Hut102, with maximal migration observed at 100 ng/ml, suggesting a role in T-cell migration within the . The protein specifically bound to T cells (e.g., with Kd = 2.1 nM) and was pertussis toxin-sensitive, indicating involvement of a G-protein-coupled receptor. These findings established TARC as a T-cell-directed . Subsequent key publications from 1997 to 1998 further elucidated its chemotactic properties . In 1997, TARC was identified as a highly specific for the CC 4 (), selectively expressed on Th2-type T cells, confirming its potent chemoattractant effect on CCR4-transfected cells and reinforcing its specificity for T-cell subsets. By 1998, studies showed that TARC, alongside macrophage-derived (MDC/CCL22), functioned as a functional agonist for , eliciting in receptor-expressing cells and highlighting its role in targeted leukocyte recruitment. These early milestones provided the foundational timeline for understanding CCL17's involvement in immune cell trafficking.

Classification and Naming

CCL17, also known as CC motif 17, was designated under the systematic for chemokines and their receptors proposed in 2000 and formally adopted in subsequent updates during the early 2000s to standardize naming across the field. This shift from its initial name, - and activation-regulated (TARC), which was assigned upon its in 1996, facilitated consistent referencing in research and reduced confusion arising from multiple acronyms for the same molecules. The updated system emphasized subfamily classification followed by a unique number, promoting in databases and studies. CCL17 belongs to the CC subfamily of chemokines, characterized by a conserved cysteine motif where the first two cysteines are adjacent (C-C), and typically featuring a small molecular weight of approximately 8-10 kDa. This structural classification distinguishes it from other chemokine subfamilies like CXC, where an amino acid separates the first two cysteines, and underscores its role in leukocyte chemotaxis through this defining motif. Within the CC subfamily, CCL17 shares notable similarities with CCL22 (also known as macrophage-derived chemokine or MDC), particularly in their specific binding to the receptor , which directs Th2 cell migration and immune responses. Both chemokines exhibit high-affinity interactions with , though CCL22 often shows stronger signaling potency in certain contexts, such as receptor internalization. This receptor specificity highlights their functional overlap in attracting regulatory T cells and Th2 lymphocytes, contributing to the standardization benefits of the CCL by grouping related ligands.

Molecular Biology

Gene Structure and Location

The CCL17 gene is situated on the long (q) arm of human at cytogenetic band 16q21, with genomic coordinates spanning 57,396,093 to 57,416,063 on the GRCh38 assembly. This positioning places it within a compact gene cluster on 16q that also encompasses the closely linked genes CCL22 (encoding MDC) and (encoding fractalkine), spanning a region of approximately 200 kb and reflecting shared evolutionary origins among these CC and CX3C subfamily members. The CCL17 gene itself covers about 20 kb of genomic DNA and the primary coding transcript is organized into three exons separated by two introns, a structure typical of many CC chemokine genes that facilitates compact genomic arrangement and efficient transcription. CCL17 exhibits strong evolutionary conservation across mammalian species, with functional orthologs present in mouse (Ccl17 on chromosome 8), rat (Ccl17 on chromosome 19), and chimpanzee (on chromosome 16), underscoring its preserved function in T-cell chemotaxis and thymic development. Sequence identity in the coding regions often exceeds 80% between human and rodent orthologs, highlighting selective pressure on chemokine motifs critical for receptor binding. The promoter region upstream of the CCL17 coding sequence features consensus binding sites for key transcription factors, notably , which mediates inducible expression in response to proinflammatory stimuli such as TNF-α. These regulatory elements, located within approximately 1 kb of the transcription start site, enable context-specific activation in immune cells like dendritic cells and endothelial cells.

Protein Structure and Processing

CCL17 is synthesized as a 94-amino acid precursor protein, featuring a 23-residue N-terminal that directs its and is cleaved during processing to yield the mature 71-amino acid protein. This proteolytic maturation occurs in the and Golgi apparatus, ensuring the is properly folded and exported from producing cells. The precursor sequence, identified through cDNA cloning, highlights the typical architecture of CC chemokines, with the signal peptide rich in hydrophobic residues to facilitate membrane translocation. The mature CCL17 protein exhibits a highly basic character, with an (pI) of approximately 9.5, primarily due to its content of positively charged and residues. This basic nature not only contributes to its at physiological but also enables strong interactions with negatively charged glycosaminoglycans such as , which can modulate its localization and presentation in tissues. Structurally, CCL17 adopts the canonical fold, including a flexible N-terminal , a three-stranded β-sheet , and a C-terminal α-helix, stabilized by the conserved CC motif near the N-terminus. Two intramolecular bonds are critical for maintaining this tertiary structure: one linking residues 11 and 34, and the other connecting cysteines 23 and 47 (numbered relative to the mature protein sequence). These bonds link the N-loop to the β-sheet , enhancing stability and preserving the conformation necessary for . Post-translational modifications of CCL17 are limited but include potential sites for N-linked at residues within consensus sequences (e.g., Asn-X-Ser/Thr motifs), though experimental evidence indicates these are not prominently utilized . Proteolytic processing beyond cleavage may occur under inflammatory conditions, potentially generating truncated forms that alter receptor affinity or stability, as observed in other . Such modifications fine-tune CCL17's bioavailability without fundamentally altering its core structural features.

Expression Patterns

Cellular Sources

CCL17 is constitutively expressed in thymic epithelial cells and dendritic cells, contributing to its role in T-cell development and immune regulation within the . This baseline production is also observed in and bronchial epithelial cells under normal conditions. Under stimulated conditions, CCL17 expression is induced in macrophages, monocytes, and endothelial cells, particularly following activation by proinflammatory cytokines such as or Th2-associated signals like . For instance, signaling, often in combination with , upregulates CCL17 in these immune and vascular cells during inflammatory responses. Tissue-specific expression patterns show elevated CCL17 levels in the skin and lungs even under baseline conditions, alongside high production in secondary lymphoid tissues such as lymph nodes and . According to data from the Human Protein Atlas, CCL17 exhibits low systemic circulating levels overall, with moderate to high expression confined primarily to lymphoid organs and select epithelial-rich sites like and , reflecting its localized immune functions.

Regulation of Expression

The expression of CCL17 is primarily upregulated by Th2 cytokines such as interleukin-4 (IL-4) and interleukin-13 (IL-13), which activate the STAT6 signaling pathway in dendritic cells (DCs) and macrophages. IL-4 binds to its receptor, leading to and nuclear translocation of STAT6, which then binds to specific motifs in the CCL17 promoter, enhancing transcription; this process is essential for CCL17 induction in these immune cells. Similarly, IL-13 signals through a shared receptor complex to activate STAT6, promoting CCL17 production in a cooperative manner with IL-4. Glucocorticoids downregulate CCL17 expression by inhibiting the demethylase JMJD3, which disrupts the epigenetic activation required for transcription. This suppression occurs through glucocorticoid receptor-mediated reduction in JMJD3 expression and activity, thereby preventing the removal of repressive marks and attenuating CCL17 levels in response to proinflammatory stimuli. Transcriptional regulation of CCL17 involves the transcription factors and , activated in response to (GM-CSF) or (TLR) signaling. GM-CSF induces expression, which directly binds to the CCL17 promoter to drive its transcription in monocytes and macrophages. TLR ligands, such as , activate via the TRAF pathway, which binds to sites in the CCL17 promoter, synergizing with other signals to upregulate expression during . Epigenetic modifications, particularly histone acetylation at the CCL17 promoter, facilitate an open state conducive to transcription. IL-4-induced STAT6 signaling promotes histone acetylation by recruiting co-activators, enhancing accessibility at the promoter and enabling and other factors to bind effectively. Additionally, JMJD3-mediated demethylation of repressive marks cooperates with acetylation to sustain CCL17 expression in activated immune cells.

Biological Functions

Receptor Binding and Signaling

CCL17 primarily binds to the G protein-coupled receptor with high affinity, characterized by a dissociation constant (K_d) of 0.5 nM. This interaction is highly specific, as CCL17 does not compete with other CC such as MCP-1, RANTES, MIP-1α, MIP-1β, or LARC for binding. Additionally, CCL17 exhibits a secondary interaction with , another , with an apparent affinity ranging from 1.1 nM (K_d via ) to 9.4 nM (IC_50 in competition assays). Upon binding to , CCL17 activates -mediated signaling pathways, which include the inhibition of adenylate cyclase and subsequent reduction in intracellular levels. This coupling also triggers calcium mobilization in cells expressing , such as 293/EBNA-1 and K562 transfectants, facilitating rapid intracellular calcium flux essential for chemotactic responses. Furthermore, CCL17 stimulation of leads to of the PI3K/Akt pathway, as evidenced by increased of Akt and upregulation of PI3K expression in relevant cellular models. Similar -mediated inhibition of adenylate cyclase occurs through the CCL17-CCR8 interaction, though with distinct downstream effects compared to . The specificity of CCL17 signaling is directed toward CCR4-expressing cells, predominantly subsets of T cells including Th2-polarized memory and effector T cells, while excluding neutrophils, B cells, monocytes, and NK cells, which lack significant CCR4 expression. This selective targeting underpins the chemotactic activity of CCL17 toward CCR4-positive immune cells.

Roles in Immune Homeostasis

CCL17, a that binds to the receptor , plays a key role in maintaining by directing the of specific T subsets to appropriate tissues, thereby supporting balanced immune responses and self-tolerance. In steady-state conditions, CCL17 is constitutively expressed in primary lymphoid organs such as the and secondary lymphoid structures like lymph nodes, as well as in mucosal and barrier sites including the gut and . This expression pattern facilitates the organized trafficking of immune cells without eliciting inflammatory cascades, ensuring the spatial regulation essential for immune surveillance and equilibrium. A primary function of CCL17 in involves the attraction of CCR4-expressing Th2 cells and regulatory T cells (Tregs) to lymphoid organs and mucosal sites, promoting their localization for routine immune monitoring and suppression of aberrant activation. Th2 cells, which are pivotal for type 2 immunity at environmental interfaces, are selectively recruited by CCL17 to sites like cutaneous and mesenteric lymph nodes, aiding in the maintenance of barrier integrity against commensal microbes. Similarly, Tregs, which express high levels of , are drawn to these locations to enforce peripheral suppression, preventing and fostering tolerance to harmless antigens encountered at mucosal surfaces. This targeted recruitment underscores CCL17's role in compartmentalized immune control, distinct from its inducible functions in activated states. CCL17 further contributes to immune by promoting Th2-biased responses in allergy-prone environments, such as mucosal barriers, in a non-inflammatory manner that supports adaptive immunity without tissue damage. At these sites, CCL17 enhances the positioning of Th2 cells to respond to potential threats like helminths or allergens, while Tregs co-recruited by the same chemokine temper excessive activation, preserving equilibrium. In the , CCL17 supports T cell education by aiding the migration of double-positive thymocytes into the medulla via CCR4-mediated interactions with dendritic cells, which is crucial for negative selection and the generation of a self-tolerant T cell repertoire. This process ensures central tolerance, reducing the escape of autoreactive clones into the periphery. Complementing this, CCL17 facilitates through Treg recruitment to non-lymphoid tissues, where these cells suppress misguided responses and maintain long-term immune balance. In and , CCL17 indirectly modulates and activity by orchestrating Th2 and Treg influx, which fine-tunes type 2 effector functions without promoting pathology. In the , CCL17-directed Th2 cell trafficking supports baseline antimicrobial defense and , while Tregs limit accumulation to prevent unnecessary . Likewise, in the lungs, CCL17 helps position regulatory cells to regulate resident , which contribute to remodeling and , and , which aid in IgE-mediated barrier protection; this indirect control via T cell subsets ensures and numbers remain proportional to homeostatic needs. Such mechanisms highlight CCL17's integrative role in tissue-specific immune steady states.

Disease Associations

Cancer

CCL17, also known as thymus and activation-regulated chemokine (TARC), plays a significant role in the of classic (cHL), where it is highly expressed by malignant Reed-Sternberg (RS) cells in over 90% of cases. This expression facilitates the recruitment of CCR4-expressing regulatory T cells (Tregs) and Th2 cells, which suppress anti-tumor immune responses and create an immunosuppressive niche that promotes tumor survival and progression. Elevated serum CCL17 levels in cHL patients serve as a reliable for activity and relapse risk, often preceding clinical symptoms. In solid tumors, CCL17 exhibits context-dependent effects. In , tumor-derived CCL17 promotes by attracting + Tregs to distant sites like the lungs, enhancing immune evasion and supporting tumor dissemination. Similarly, in , elevated CCL17 expression correlates with lymph and poorer , driving Th2 and Treg infiltration that fosters an immunosuppressive . Conversely, in , higher serum CCL17 levels are associated with improved , particularly in response to dendritic cell-based , by promoting the homing of effector T cells to enhance anti-tumor immunity. As a , CCL17 levels in reflect immune infiltrate composition and tumor aggressiveness, with 2025 analyses identifying it as a key prognostic indicator linked to JAK-STAT pathway activation and immune cell recruitment. Mechanistically, CCL17 contributes to tumor progression by promoting in the through CCR4 signaling, which stimulates vascular endothelial growth, and by enabling immune surveillance evasion via preferential Treg accumulation over effector cells. Therapeutic strategies targeting the CCL17/CCR4 axis show promise in preclinical models for disrupting these pro-tumor effects in cancers like cHL.

Inflammatory and Allergic Diseases

CCL17, also known as thymus and activation-regulated chemokine (TARC), plays a pivotal role in the pathogenesis of (AD) by promoting the recruitment of Th2 cells to the skin, which in turn amplifies infiltration and sustains chronic inflammation. Elevated serum levels of CCL17 have been consistently observed in patients with AD, showing a strong positive correlation with disease severity scores such as the SCORAD index, thereby serving as a reliable for monitoring therapeutic responses. In , CCL17 contributes to airway inflammation by facilitating Th2 cell , leading to enhanced recruitment and exacerbation of type 2 immune responses during viral triggers like infections. Beyond AD and , CCL17 drives Th2-mediated responses in contact hypersensitivity, where its expression in following exposure attracts CCR4-expressing Th2 cells, intensifying the inflammatory infiltrate and delaying-type reactions. Similarly, in allograft rejection, CCL17 deficiency impairs T cell-dependent rejection of allogeneic transplants, underscoring its chemotactic role in promoting Th2 to graft sites and contributing to hypersensitivity-mediated graft loss. Recent investigations have highlighted CCL17's involvement in type 2 inflammation within the lungs, particularly in macrophages stimulated by type 2 cytokines, where it emerges as a defining alongside CCL22, supporting sustained Th2 polarization and airway remodeling. Mechanistically, CCL17 amplifies IL-4/IL-13 signaling loops in both and airway epithelia; IL-4 induces CCL17 expression via STAT6-dependent promoter activation, which in turn recruits additional Th2 cells to perpetuate production and inflammatory cascades. This feedback mechanism is central to the chronicity of allergic responses in these tissues.

Autoimmune Diseases

CCL17 contributes to autoimmune pathology by facilitating the aberrant of CCR4-expressing T cells, including pro-inflammatory Th17 cells and regulatory T cells (Tregs), to self-tissues, thereby promoting chronic inflammation and tissue damage. In conditions such as (MS) and its animal model, experimental autoimmune (EAE), CCL17 is expressed by dendritic cells (DCs) in the (CNS), where it drives the migration of Th17 cells and modulates Treg responses, ultimately exacerbating demyelination and . Studies in CCL17-deficient mice demonstrate reduced CNS infiltration of CD4+ T cells and DCs, leading to milder EAE severity and enhanced peripheral Treg expansion, highlighting CCL17's role in sustaining pathogenic immune responses over regulatory ones. Elevated levels of CCL17 in MS patients further support its involvement in human CNS autoimmunity. CCL17 is also associated with (RA), where it facilitates synovial infiltration of inflammatory cells, including Th2 lymphocytes, exacerbating joint inflammation and pain. Elevated CCL17 concentrations in RA and blood promote via , sustaining chronic ; treatment suppresses its production, ameliorating arthritic symptoms in patient samples and mouse models. In systemic (SLE), CCL17 levels are markedly increased in serum and plasma, particularly during active flares and in , serving as a serological marker of disease activity. Produced by conventional DCs type 2 (cDC2s) in renal tissues, CCL17 drives immune cell accumulation and pathology; its blockade reduces kidney damage in experimental models, underscoring its pathogenic contribution. Mechanistically, CCL17 exacerbates through an imbalance that favors pro-inflammatory responses, often by recruiting Th17 cells to target tissues while impairing effective Treg function or migration. In EAE and AD models, this dysregulated homing via leads to preferential expansion or retention of pathogenic effectors over suppressive Tregs, perpetuating self-tissue attack. Such imbalances highlight CCL17's role in shifting immune toward chronic autoimmunity across diverse tissues.

Other Pathological Conditions

CCL17, produced by conventional dendritic cells, promotes vascular inflammation in by a non-canonical pathway signaling through CCR8 on regulatory T (Treg) cells, thereby suppressing Treg migration and function within atherosclerotic plaques via CCL3-dependent mechanisms and signaling. This mechanism exacerbates plaque progression, as demonstrated in studies showing that CCL17-expressing dendritic cells restrain Treg , leading to increased atherogenesis in models. Recent 2024 research has identified a non-canonical chemokine-receptor pathway involving CCL17 that further inhibits Treg attraction via signaling, highlighting its pro-inflammatory role in this cardiovascular . In cardiac hypertrophy and heart failure, CCL17 aggravates pathological remodeling by interfering with protective immune responses, particularly through GM-CSF-mediated signaling in cardiac dendritic cells. Deletion of CCL17 in experimental models reduces left ventricular remodeling, myocardial fibrosis, and cardiomyocyte hypertrophy while improving systolic function, indicating its detrimental impact on heart tissue integrity. Research from 2022 to 2025 has linked GM-CSF-induced CCL17 expression to biased CCR4 signaling that prevents Treg recruitment, thereby promoting fibrosis and dysfunction in angiotensin II-induced hypertrophy. CCL17 levels are elevated in certain infectious diseases, serving as a serum for disease severity. In severe among hemodialysis patients, higher circulating CCL17 predicts progression from mild or moderate to critical illness, reflecting dysregulated responses that amplify . Similarly, in eosinophilic pneumonia, CCL17 acts as a diagnostic , with elevated levels distinguishing acute forms from other causes of acute injury by facilitating and Th2 infiltration into pulmonary tissues. An emerging role for CCL17 in gastrointestinal pathologies involves its contribution to (IBD) progression through recruitment of Th2 and Th17 cells, which sustain chronic mucosal inflammation. A 2025 review on liver immunoregulation underscores CCL17's involvement in hepatic networks that exacerbate IBD-related gut-liver axis dysfunction, potentially via CCR4-mediated T cell trafficking that impairs barrier integrity.

Therapeutic Potential

Targeting CCL17/CCR4 Axis

The targeting of the CCL17/ axis has emerged as a promising therapeutic strategy in , primarily through the development of agents that disrupt ligand-receptor interactions to modulate immune cell trafficking. directed against represent a key advancement in this area. , a defucosylated humanized IgG1 , binds to and enhances (ADCC), leading to the depletion of CCR4-expressing cells, including regulatory T cells (Tregs) that are recruited via CCL17. This mechanism reduces CCL17-mediated Treg infiltration in pathological settings, such as CCR4-positive T-cell lymphomas. received approval from the in 2018 for the treatment of relapsed or refractory or Sézary syndrome, adult T-cell / subtypes characterized by CCR4 overexpression, and has also been approved in and for similar indications. Small-molecule antagonists of offer an alternative approach by competitively inhibiting CCL17 and CCL22 binding to the receptor, thereby blocking of CCR4-positive cells without relying on immune effector functions. Compounds such as AZD2098 and C021 have demonstrated preclinical efficacy in inhibiting CCL17-induced migration of T cells, including in models, where they suppress chemotactic responses and downregulate surface CCR4 expression. These antagonists are under investigation in early-stage development for their potential to limit Treg accumulation in tumor microenvironments and inflammatory sites, with oral enhancing their therapeutic feasibility. Similarly, RPT193, another selective small-molecule CCR4 antagonist, has shown promise in preclinical models of allergic diseases by selectively blocking Th2 cell recruitment. However, development of RPT193 was discontinued in 2024 following FDA feedback on . Neutralizing antibodies against CCL17 itself are also in development to prevent downstream CCR4 activation. Preclinical studies have explored anti-CCL17 monoclonal antibodies, such as those described in patent filings, which block CCL17 binding to and ameliorate inflammatory responses in models of (AD) by reducing Th2 cell infiltration and production. In (MS), animal models of experimental autoimmune have demonstrated that CCL17 blockade inhibits CCR4-dependent T-cell migration into the , suggesting potential for these antibodies in neuroinflammatory conditions. These agents aim to address CCL17-driven pathologies in Th2-dominated diseases like AD and MS. Despite these advances, targeting the CCL17/CCR4 axis presents challenges related to off-target effects, stemming from the broad expression of on various immune cells, including skin-homing T cells and Tregs essential for immune . Inhibition or depletion of CCR4-positive cells can disrupt physiological Treg function and T-cell trafficking, potentially leading to adverse events such as skin toxicities or impaired immune regulation, as observed with . The ubiquitous role of CCR4 in normal immune surveillance necessitates careful selectivity in design to minimize impacts on non-pathological processes.

Clinical Applications and Challenges

Mogamulizumab, a targeting (the primary receptor for CCL17), received FDA approval in 2018 for the treatment of adult patients with relapsed or refractory or Sézary syndrome after at least one prior . In , approval for was granted earlier for relapsed or refractory peripheral (PTCL) and (CTCL), including expansions to adult T-cell /. A phase I trial in (completed in 2025) explored in neoadjuvant combination with nivolumab for solid tumors, demonstrating and antitumor effects, though full approval for these indications remains pending. Preclinical data suggest that targeting the CCL17/CCR4 axis could mitigate in by modulating immune cell migration, warranting further clinical investigation. For , serum CCL17 levels serve as a key in trial designs for anti-inflammatory therapies, though direct CCL17 monoclonal antibodies are not yet in late-stage development; instead, broader Th2-targeted agents are prioritized. Recent 2025 research has highlighted CCL17 as a prognostic in , with high expression correlating with poor , lymph node , and immune escape, serving as a potential tool for risk stratification despite complex associations with immune cell infiltration. Efficacy of CCL17/CCR4-targeted therapies, such as , shows overall response rates of approximately 37% in relapsed CTCL patients, with higher rates (up to 47%) in Sézary syndrome subtypes and median more than doubling compared to standard . These responses are particularly notable in lymphomas with high expression, where serum CCL17 levels aid in patient stratification by predicting better outcomes in those with elevated baseline markers. Despite these advances, clinical applications face significant challenges, including dermatologic toxicities like mogamulizumab-associated , which occurs in up to 25% of patients and can lead to discontinuation in 7% of cases, often requiring vigilant and supportive . Resistance mechanisms involve alternative pathways, such as CCL22-mediated signaling or metabolic reprogramming in tumor cells, which bypass CCR4 blockade and limit long-term efficacy. Furthermore, the scarcity of drugs directly targeting CCL17 itself— with most therapies focusing on the downstream CCR4 receptor—hampers precision approaches and underscores the need for ligand-specific inhibitors to address off-target effects.