Clinical Implications of the Skin Microbiota in the Therapy of Cutaneous T Cell Lymphoma: A Scoping Review

Abstract

Cutaneous T cell lymphomas (CTCL) are non-Hodgkin T cell malignancies defined by malignant T cell transformation and accumulation in the skin. Limited understanding of CTCL pathogenesis, including the role of the tumor microenvironment, hinders effective treatment. Emerging evidence implicates the skin microbiota as a key modulator of disease, with microbial dysbiosis contributing to progression and representing a novel therapeutic target. This review synthesizes findings from 37 rigorously selected studies, outlining current knowledge of the CTCL-associated microbiome, mycobiome, and virome. It evaluates therapeutic strategies aimed at microbial colonization, emphasizing the potential of modulating host–microbe interactions. Additionally, we provide comprehensive clinical insight into the indications for microbial-modulating strategies of the microbiota in CTCL.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-025-01619-4.

Key Summary Points

Malignant T cells accumulate in the skin of patients with cutaneous T cell lymphoma (CTCL), making the investigation of immunogenic microbes within the tumor microenvironment critical to understanding pathogenesis and therapy.

Beyond bacterial inhabitants, this review covers the fungal and viral critical colonizers of the skin in CTCL, an area that remains underinvestigated.

We theorize that microbial dysbiosis can contribute to CTCL flares and disease progression; therefore, the prudent use of microbial-modulating interventions may impact patient outcomes.

Our findings demonstrated that in specific clinical scenarios, the use of microbial-targeted therapies against critical colonizers or infections in adjunct to conventional CTCL therapies may improve patient outcomes.

Given the burden of refractory disease among patients with dysbiosis, further investigation into host–microbe interactions in CTCL are warranted.

Introduction

Cutaneous T cell lymphomas (CTCL) are rare and complex non-Hodgkin lymphomas that are characterized by the accumulation of malignant T cells in the skin [1]. Mycosis fungoides (MF) accounts for the majority of cases (37.5–72.0%), followed by Sézary syndrome (SS), which is an aggressive leukemic variant (1.6–5.0%) [2–4]. Achieving remission can remain a challenge due to frequent relapse, absence of consistently effective treatments, and elevated infection risk [5–8]. The underlying mechanisms driving pathogenesis remain incompletely understood, as no single factor or set of factors are known to cause CTCL. While dysregulation of certain signalling pathways including MAPK, NF-κB, and NFAT can promote malignant transformation [9], these factors do not fully account for disease development. Therefore, it is essential to investigate beyond malignant T cells and examine the tumor microenvironment, which may hold key insights into the etiology of CTCL.

The cutaneous microbiota is an active component within the neoplastic microenvironment in CTCL [10]. Skin microorganisms influence expression of innate immune factors and the function of local adaptive immune milieu, including cutaneous T cells [11]. Emerging evidence reveals immunologic dysregulation in CTCL, such as a shift towards type 2 immunity, immune tolerance, and influence from host–microbe interactions (Fig. 1) [12–14]. Indeed, CTCL has been theorized to derive from chronic antigenic stimulation of T cells [15]. Among microbial taxa investigated in humans, Staphylococcus aureus has garnered significant attention for producing toxins that act as “superantigens” and promote malignant T cell expansion [16–20]. A question remains as to whether microbial-targeted therapies can be used to restore homeostatic skin colonization and influence disease progression in CTCL.

Fig. 1.

Schematic of the skin immunopathogenesis and microbiota remodeling in CTCL. In healthy human skin, resident T cells are predominantly Th1-skewed effector memory cells, with fewer Th2 and Treg cells. The lymphocytes accumulate near vessels and skin appendages. The skin microbiota comprises of a diverse variety of microorganisms, including bacteria, fungi, and viruses, which inhabit the skin surface and appendageal structures. In early-stage CTCL, malignant CD4⁺ T cells localize predominantly within the epidermis, forming patches and plaques. In advanced stages, malignant T cells infiltrate the dermis, forming nodular aggregates characteristic of tumor-stage CTCL. At first, the surrounding immune milieu is Th1-skewed, characterized by IFNγ and IL-2 production from Th1 cells, supporting anti-tumor immunity by activating cytotoxic CD8⁺ T cells and NK cells. As disease progresses, malignant T cells shift to a Th2 cytokine profile, secreting IL-4, IL-5, and IL-13, which suppress Th1 differentiation and cytotoxic T cell responses. Additionally, regulatory cytokines such as IL-10 and TGFβ are produced, further inhibiting host cell-mediated immunity and increasing susceptibility to infections and secondary malignancies. Bacterial superantigens, notably Staphylococcal enterotoxins, can exacerbate disease by interacting with MHC class II molecules on malignant T cells, leading to indirect activation and proliferation. CD4 cluster of differentiation 4, GM-CSF granulocyte–macrophage colony-stimulating factor, IFNγ interferon gamma, IL interleukin, MHC major histocompatibility complex, NK natural killer, SE staphylococcal enterotoxins, Th1 type 1 hyper cell, Th2 type 2 helper cell, TGF transforming growth factor, Treg regulatory T cell. Created in BioRender. Czyz, S. (2025) https://BioRender.com/0fqi15h

Clinical applications of this concept have been shown. Notably, Lindahl et al. demonstrated that systemic antibiotic therapy attenuates disease activity in advanced CTCL [21]. Increased nasal and skin colonization with S. aureus has been noted in patients with CTCL, which is thought to trigger and contribute to lesional flares [22, 23]. Regulatory agencies currently consider the available evidence promising but insufficient to recommend routine microbial-targeted therapy in patients without overt infections [24, 25]. However, there remains compelling therapeutic potential within strategies aimed at restoring a physiologic skin microbiota and promoting a balanced cutaneous immune milieu in patients with CTCL.

In this scoping review, we synthesize the available evidence on skin microbiota alterations in CTCL and evaluate the therapeutic effects of microbial-targeted interventions in CTCL treatment. We aim to identify knowledge gaps and propose future directions including the modulation of skin microbiota as a proactive strategy in improving clinical outcomes for patients with CTCL.

Materials and Methods

Data Source

The current scoping review was conducted according to the JBI Manual for Evidence Synthesis: Scoping Reviews Chapter and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews [26, 27]. We performed a systematic literature search of PubMed (MEDLINE) and Embase databases from January 1, 2000 to June 15, 2025. Our search strategy was designed to capture research articles assessing the skin microbiome of patients with CTCL or disease outcomes following antimicrobial treatment in patients with CTCL and is outlined in Table 1.

Table 1.

Example search strategy for OVID (Medline)

#	Searches	Results
1	exp Lymphoma, T-Cell, Cutaneous/ or CTCL*.mp	11,886
2	exp Mycosis Fungoides/ or mycosis fungoid*.mp	8469
3	exp Sezary Syndrome/ or sezary*.mp	3281
4	cutaneous t-cell lymph*.mp	6012
5	1 or 2 or 3 or 4	14,807
6	exp Microbiota/ or microbio*.mp	1,097,501
7	exp Mycobiome/ or mycobio*.mp	3467
8	exp Virome/ or virome*.mp	2727
9	exp Staphylococcal Infections/ or exp Staphylococcus aureus/ or staph*.mp. or exp Staphylococcus/	233,762
10	skin colon*.mp	668
11	antibiotic*.mp. or exp Anti-Bacterial Agents/	1,058,758
12	exp Anti-Infective Agents, Local/ or antiseptic*.mp. or exp Anti-Infective Agents/	1,856,904
13	exp Antiviral Agents/ or antiviral*.mp	465,549
14	exp Antifungal Agents/ or antifung*.mp	219,075
15	6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14	3,029,772
16	5 and 15	1213
17	limit 16 to yr = “2000 − Current”	706

Search date. Databases were searched from January 1, 2000 to June 15, 2025

CTCL cutaneous T cell lymphoma

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Study Selection

Two reviewers (SC, JQ) independently screened titles and abstracts of all identified citations for potentially relevant articles. Discrepancies were resolved through discussion and consensus with a third reviewer (JH). Full-text articles were independently assessed by both reviewers (SC, JQ) on the basis of the following exclusion criteria:

1. Non-original article (e.g., review), conference abstract, or editorial.

2. Does not pertain to CTCL (specifically SS and MF subtypes).

3. Does not assess adult humans with CTCL (e.g., pediatric population, ex vivo studies).

4. Does not investigate bacterial, viral, and/or fungal skin colonization in CTCL and does not report outcomes of microbial-targeted therapy in patients with CTCL.

To capture the full spectrum of literature on skin colonization in CTCL, we included both studies that identified colonization status using high-throughput genetic sequencing techniques (microbial composition referred to as the microbiome) and more targeted methods, like hospital-based culture techniques (microbial composition referred to as microbiota). No exceptions were made on the basis of language; non-English studies were translated using Google Translate (https://translate.google.com). Finally, reference lists of included studies were screened to identify any additional articles missed by the primary search strategy.

Data Extraction and Synthesis

The following data were extracted from all included studies: publication information; study design; participant demographics; CTCL subtype and disease staging. For studies assessing skin microbiome composition, additional information on collection techniques, analysis methods, and microbiota characteristics were extracted. For studies assessing antimicrobial treatment, additional information on prescribed antimicrobial, antimicrobial treatment outcomes (e.g., Modified severity-weighted assessment tool (mSWAT), body surface area (BSA), observational improvement), and other non-microbial therapeutic treatment courses were extracted. Data were extracted in duplicate (SC and KY) with conflicts resolved by discussion. Data were synthesized descriptively (see Supplementary Material Tables 1 and 2), then tabulated and visualized to highlight key patterns, knowledge gaps, and heterogeneity in study design or reporting.

Results

Literature Search

Our search strategy identified 2532 unique citations (Fig. 2). Following title and abstract screening, 187 full text records were assessed for eligibility, and 37 studies were included; 17 of the studies assessed skin microbiota, while 21 of the studies assessed microbial-targeted therapies.

Fig. 2.

Flow diagram of study selection

Skin Microbiome Composition

Patient Demographics

We identified 17 references out of the total 37 studies included that assessed skin microbiota comprising data from 642 patients with CTCL. There was a higher proportion of male sex (57.6%, n = 370) compared to female sex (42.4%, n = 272) represented, although the degree of male sex predominance was lower than previously reported rates [3]. Six studies reported race or ethnicity, with the majority of participants identified as Caucasian/White (n = 193), followed by Black/African American (n = 47), and patients characterized as “Other” (n = 4). Representation from certain global regions such as Asia and South America remains limited in the literature, yet an increased frequency of CTCL was reported within these groups when compared to other parts of the world [28]. Of the studies that reported disease staging, microbiome composition was more frequently assessed in early-stage disease (IA–IIA, n = 391) than in advanced-stage cases (IIB–IVB, n = 169).

Microbe Analysis Methods

Among microbial domains, bacteria were the most frequently studied (15 of 17 studies), followed by viruses (6 of 17 studies) and fungi (3 of 17 studies) (Fig. 3a), reflecting the predominance of bacterial species in skin colonization [10]. Broad sequencing approaches including whole-genome/metagenomic sequencing were used in four studies, while targeted methodologies including standard culture, PCR or RT-PCR, 16S rRNA sequencing, and molecular histopathology were employed in 13 studies (Fig. 3b). Furthermore, usage of greater resolution and comprehensive methods tended to increase in studies published from 2020 onwards.

Fig. 3.

An overview of the characteristics of studies assessing the skin microbiome in CTCL and antimicrobial therapeutic outcomes. a Pie chart demonstrating the proportion of studies included that analyze bacterial, viral and fungal compositions in patients with CTCL. b Figure depicting the change in skin microbiome assessment techniques in the field of CTCL. The number of studies using the assessment techniques is graphed to the year the study was published. c An overview of the prominent bacteria, virus, and fungi that were studied across the studies included. Bar charts indicate the number of studies that analyze each microbial taxa and whether they reported a significant increase, decrease, or no change when comparing lesional skin of patients with CTCL to non-lesional skin or healthy controls. d Pie chart demonstrating the proportion of studies included that assess the use of antibiotics, antivirals, antifungals, and direct decolonization techniques of the skin in patients with CTCL. CTCL cutaneous T cell lymphoma

Sites of skin sampling were inconsistent both within and between studies; swabs were obtained from various anatomical locations including head and neck, arm, axillary, trunk, back, buttock, thigh, leg, and foot. Given the well-characterized site-specificity of the skin microbiome, this variability could contribute to interstudy heterogeneity [29].

Skin Microbiota Composition

A culture-based assessment of the skin microbiota by Allen et al. found that 75.4% of patients with CTCL were colonized by S. aureus, with coagulase-negative Staphylococcus (CoNS) and Corynebacterium spp. representing the next most frequent taxa [30]. This is quite striking as S. aureus only colonizes 20–30% of nares in the general population and its presence on healthy skin is typically minimal or transient [31, 32]. Other detected genera included Pseudomonas and Klebsiella, although at a lower prevalence [30]. The predominance of potential pathogens may reflect microbial dysbiosis observed in the patients with advanced-stage CTCL within their study.

S. aureus was the most frequently examined species across all studies, likely due to its proposed role in CTCL pathogenesis. However, findings were inconsistent. Some studies reported increased S. aureus abundance in CTCL lesional skin, while others determined no difference compared to healthy controls or non-lesional skin (Fig. 3c). When analyzing intra-patient comparisons of lesional and non-lesional skin, three out of six studies suggested S. aureus enrichment at lesional sites [33–38]. One study by Olesen et al. did not report significant differences in microbiome composition between lesional and non-lesional skin; however, when data were stratified by MF, folliculotropic mycosis fungoides (FMF), and SS subtypes, variations in S. aureus abundance were shown [37]. In contrast, when the skin microbiome of patients with CTCL was compared to healthy, age- and sex-matched controls, no significant differences in S. aureus were observed [32, 39, 40]. Although Nguyen et al. reported a trend towards greater S. aureus abundance in CTCL lesions (P = 0.07), the association did not reach statistical significance as a result of a limited sample size [40]. A possible increase in lesional S. aureus burden with advancing disease stage was noted, though few studies formally evaluated this [34, 40]. As more than two-thirds of patients studied had early-stage disease, and dysbiosis is likely more pronounced in advanced stages, larger cohorts of late-stage patients are warranted in future studies.

Other bacterial genera noted by the literature include Corynebacterium and Cutibacterium spp. Corynebacterium was more prevalent in lesional skin, while Staphylococcus epidermidis and Cutibacterium acnes were less prevalent in lesional skin. Harkins et al., in contrast, observed no significant changes in S. aureus but did report increased CoNS colonization in patients with CTCL [32]. Intriguingly, Borrelia burgdorferi DNA was detected in lesions and hypothesized to serve as a potential antigenic driver of lymphomagenesis in two Italian studies [41, 42]. One study evaluated Chlamydia pneumoniae but found no evidence supporting an etiopathogenetic role in MF [43].

Bacterial signatures associated with narrowband ultraviolet B (nbUVB) treatment response was also explored [44]. Phototherapy responders exhibited elevated baseline Staphylococcus across lesional and non-lesional skin, with Staphylococcus capitis and Staphylococcus warneri enriched in lesions. Following nbUVB, responders showed increased Streptococcus and Acinetobacter in lesional skin, accompanied by a decreased abundance of S. aureus. These findings suggest that distinct microbial profiles may be associated with phototherapy responsiveness.

From a viral perspective, Epstein–Barr virus (EBV) was identified in some reports to be a possible risk factor, with studies indicating increased viral load in MF lesions [45, 46]. Another German study reported high human T cell leukemia virus type 1 (HTLV-1) prevalence in lesional skin [41]. Fungal data were sparse, and no consistent trends in fungal colonization were reported across studies when comparing lesional, non-lesional, and healthy skin.

Microbial-Targeted Therapeutics

Patient Demographics

We identified 21 studies out of the 37 studies included that evaluated the outcomes of microbial-based therapy in patients with CTCL, comprising a total of 231 individuals. Among these, 46.8% (n = 108) identified as female and 53.2% (n = 123) as male. Eight studies reported patient race or ethnicity, with most individuals identified as White (n = 90), followed by Black (n = 51), Hispanic (n = 8), and Asian (n = 1). There was a predominance of advanced-stage disease with 136 patients with stage IIB–IVB disease compared to 88 patients with early-stage IA–IIA disease. This predominance likely reflects antimicrobial use in refractory CTCL, where barrier disruption and immune dysregulation heighten microbial dysbiosis and infection susceptibility.

Antimicrobials Used

Patients were treated with a wide range of antiseptic treatments, antibiotics, antifungals, and antivirals (Fig. 3d). Antiseptics included baths containing 0.4% chlorhexidine gluconate [47]. Mupirocin 2% was frequently employed for skin decolonization. Commonly reported systemic antibiotics included clindamycin, ampicillin, dicloxacillin, ciprofloxacin, and doxycycline; doxycycline was commonly selected for both its antimicrobial and anti-inflammatory properties. Vancomycin was reserved for severe infections and/or very ill patients, particularly in hospitalized cases or those with ulcerated tumors [47–50]. The various antimicrobial regimens were mainly driven by conventional culture-based sensitivities, unless the study was interventional in nature. Itraconazole was frequently administered for suspected opportunistic fungal infections, which were prevalent in patients with CTCL [51–53]. Antifungal and antiviral agents were typically introduced in the setting of documented co-infections. Most patients were already receiving CTCL-directed therapies at the time of antimicrobial administration, such as phototherapy, radiation therapy, methotrexate, interferon, brentuximab, oral retinoids, chemotherapy, topical corticosteroids, or immunomodulators (e.g., topical imiquimod).

Patient Outcomes

Several cases illustrated the therapeutic synergy between antimicrobials and CTCL-directed treatments, particularly for fungal involvement. In one report, orally administered itraconazole alone failed to clear tinea corporis in a patient with recurrent infections [52]. However, once a biopsy confirmed patch-stage MF, concurrent treatment with orally administered itraconazole, methoxsalen, and ultraviolet A phototherapy resulted in fungal clearance and sustained MF remission [52]. Similarly, in a patient with CTCL and refractory fungal infection, resolution occurred only after switching from leukocyte to lymphoblastoid interferon alongside itraconazole, resulting in improvement of both fungal burden and CTCL lesions [51]. Such findings suggest a complex interplay between fungal colonization, CTCL therapeutics, and disease activity.

This pattern of CTCL regression coinciding with resolution of microbial colonization or infection also extends to bacteria. The aggressive and transient treatment with antibiotics decreased clinical symptoms in advanced-stage CTCL [21, 54]. Chi et al. described a patient with stage IVA pustular MF who received vancomycin in the context of S. aureus-driven sepsis, leading to improvement of their MF lesions [48]. A similar phenomenon was reported in a patient with neoplastic lesions infected with Corynebacterium striatum, where penicillin therapy reduced erythema and purulence, and complete regression of MF occurred following subsequent chemotherapy [55]. Additionally, one study showed that mupirocin 2% ointment and systemic antibiotics targeting S. aureus colonization led to objective improvement on cutaneous examination in 58% of patients with all stages of MF/SS [23]. Collectively, these observations suggest that microbial pathogens may exacerbate disease activity, even if they are not direct oncogenic drivers.

Antimicrobial therapy alone conferred benefit in select cases. 1% Gentian violet resulted in a sustained partial response in a patient with early-stage MF that failed nbUVB, topical corticosteroid, and retinoid treatments [56]. A patient with rare zosteriform MF was treated empirically with valacyclovir in the absence of virologic confirmation, leading to resolution of her lesions [57]. Interestingly, she experienced a recurrence of MF upon cessation of antivirals, and prior treatments, including triamcinolone acetonide 0.1% and bexarotene gel, were ineffective [57]. In another case series, antibiotic therapy directed against Enterococcus species without concurrent CTCL treatment led to healing of ulcerated tumors with eschars in some reports [58].

Notably, four studies highlighted positive outcomes for antimicrobial therapy in erythrodermic CTCL [23, 47, 49, 59]. Talpur et al. demonstrated that 50% of patients with erythrodermic CTCL and S. aureus colonization had dramatic reduction in their BSA with oral antibiotic treatment [23]. One patient with SS and an erythrodermic flare showed pronounced mSWAT improvement following IV vancomycin and cefepime, in combination with bleach baths of 15 mL chlorhexidine gluconate 0.4% and topical corticosteroid wraps [47]. Another analysis of 26 patients with erythrodermic CTCL demonstrated BSA and mSWAT improvement following antibiotic regimens targeting S. aureus in approximately 50% of the cases [49]. In Purnak et al., most patients with advanced-stage CTCL received long-term antibiotic therapy and antibiotics were suggested to improve or clear erythroderma [59].

However, antimicrobial therapy did not universally yield clinical benefit [60–62]. Panasiti et al. described a case of progressive MF with ulcerated tumors that grew CoNS but did not respond positively to antibiotics [60]. However, this may align with the hypothesis that critical colonization with specific bacteria like S. aureus modulates CTCL disease, rather than mere bacterial colonization itself. Another case described stage IB MF lesion progression despite clearance of Trichophyton rubrum dermatophytosis [61]. In a comparative study, doxycycline was found to be significantly less effective at reducing mSWAT, Composite Assessment of Index Lesion Severity, and histopathological scores relative to psoralen + ultraviolet A light in early-stage disease after 12 weeks [63]. Doxycycline only mildly attenuated disease when used alone [63, 64].

Lastly, prophylactic antibiotic use was variably effective and was associated with complications. Secondary infections were common, with some cases progressing to bacteremia or death from resistant pathogens [30, 58]. For example, Tsambiras et al. reported an initial tumor response to antibiotics, but recurrent infections and hospitalizations prevented further chemotherapy, ultimately contributing to patient mortality [50]. No clear protective effect of antimicrobial prophylaxis could be determined from the literature, underscoring the need for judicious antibiotic use in the context of rising antimicrobial resistance.

Discussion

CTCL is characterized by the aberrant accumulation of skin-homing lymphocytes, accompanied by immune dysregulation, epidermal barrier compromise, and chronic inflammation [1]. Emerging evidence suggests the skin microbiome may contribute to disease pathogenesis, with potential implications for therapeutic approaches. Despite advances in microbiome sequencing technologies, our review suggests that the current understanding of the skin microbiome in CTCL remains inconclusive. This is likely due to limited sample sizes and a lack of standardized methodological approaches, including microbial extraction methods and patient-related factors.

Case–control and intra-patient comparisons of lesional versus non-lesional skin revealed variable microbiome compositions. Notably, only a subset of intra-patient studies reported S. aureus enrichment in lesional skin, whereas no inter-patient studies observed this pattern. This may reflect broader trends in skin microbiome research where intra-individual variation tends to be less than inter-individual differences, partially due to environmental influences such as household and diet [65–67]. It is possible that intra-individual changes between lesional and non-lesional skin may capture more biologically meaningful changes by reducing confounding factors. Longitudinal studies would be ideal to determine causal relationships by tracking skin microbiome changes over time, although feasibility is limited as a result of difficulties in predicting CTCL onset.

Moreover, our literature search highlights a lack of demographic diversity as few studies included patients from disproportionately affected populations such as Asia or South America. Greater ethnic and racial representation is important to understand how host–microbiota interactions affect those from various backgrounds. A more comprehensive understanding of individualized microbiome characteristics can help identify patients with CTCL who would benefit from microbial-modifying approaches. This was uniquely illustrated by Hooper’s group, providing insight into the association between skin microbial signatures and positive responses to nbUVB [44]. Such developments can increase efficacy of existing therapeutic approaches by combining CTCL treatment modalities with microbial-modulating strategies.

The chronic antigenic stimulation of T cells in CTCL is a theory with accumulating evidence. Studies show that S. aureus microbial-derived products can activate malignant and non-malignant T cells, promoting oncogenic signalling pathways supporting tumor survival and evasion [18, 20, 68–70]. This upregulation may lead to the Th2-dominated response in CTCL. However, these findings are mainly supported by experimental models and ex vivo studies and have yet to be translated to clinical investigation. Quite interestingly, hypereosinophilia was found to be associated with a positive response to antibiotics against S. aureus in one study [49]. It is arguable that in a Th2-skewed milieu, you would theoretically see an increase in eosinophils due to IL-5 production. Therefore, patients with pronounced bacterial dysbiosis leading to Th2-dominance, as reflected by hypereosinophilia, may have a higher likelihood of CTCL improvement with bacterial-targeted therapies.

Furthermore, IL-13 is a central cytokine to type 2 immunity that is upregulated by malignant T cells. This leads to the activation of JAK/STAT signaling in keratinocytes and repression of filaggrin expression [71]. As a result, the epithelial barrier becomes compromised, allowing further colonization with S. aureus, contributing to the continuous antigenic stimulation of malignant T cells in CTCL [71]. S. aureus has also been implicated to have direct effects on epithelial cells, degrading desmoglein-1 and filaggrin through increased keratinocyte protease activity [72]. Interestingly, emerging studies are evaluating the potential therapeutic utility of JAK inhibitors in CTCL now [73]. However, dupilumab, a targeted monoclonal antibody that inhibits both IL-4 and IL-13, has been shown to unmask CTCL [74]. The mechanisms behind this are not understood but indicate the complexity of this disease. While some studies included in our review implicate viral signatures in the cutaneous microenvironment of MF, the evidence remains correlative. Unlike bacterial drivers, mechanistic links to oncogenic signaling in CTCL are still being established for the virome and mycobiome.

A nuanced interplay may exist between antimicrobial treatment and clinical improvement in CTCL, suggesting that infection or critical colonization may modulate pathogenesis. Antimicrobial interventions frequently potentiated the efficacy of CTCL-directed therapies as infection resolution often concurred with disease remission, implicating a role for microbes in disease persistence and flares. These effects extended across taxa, with fungal infections responding more favorably to antifungals when combined with phototherapy or immunomodulation, and bacterial infections or colonization, including S. aureus or Corynebacterium, showing improvement with targeted antibiotics. This was especially highlighted in erythrodermic patients. However, the literature was dominated by individual case reports and few interventional studies, signifying the rarity of CTCL. Given case studies are hypothesis-generating, robust studies are warranted to guide the integration of microbial-targeted therapies with other CTCL treatment modalities.

While routine antimicrobial therapy is not recommended, clinicians should be aware that infection and critical colonization can exacerbate disease symptoms, and treatment may benefit both the infection and lymphoma lesions. Antimicrobial therapy may be most relevant in clinical contexts characterized by known S. aureus skin colonization, concomitant fungal infection, erythrodermic flares, hypereosinophilia, or lesions exhibiting ulceration and pustular inflammation.

Innovative microbial-modulating strategies are a critical direction for the field. Currently, limited evidence supports the use of probiotics in dermatologic diseases. Some data suggest that short-chain fructo-oligosaccharides can selectively inhibit S. aureus while promoting commensals like S. epidermidis [75]. Postbiotic metabolites, such as butyrate, can dampen inflammation and enhance antimicrobial peptide expression against S. aureus [76, 77]. In CTCL, however, no clinical or preclinical studies have examined prebiotic, probiotic, or postbiotic interventions. Nonetheless, the mechanistic rationale and demonstrated efficacy in related models suggest that these interventions could be beneficial adjuncts. Our review suggested that a reduction in commensal bacteria, such as S. epidermidis and C. acnes, was seen in lesional skin. Enrichment of these commensals could counterbalance and protect against S. aureus dominance.

Finally, antimicrobial stewardship is paramount, as overuse of antimicrobials promotes resistance and increases the risk of adverse drug events, leading to higher healthcare costs and worse patient outcomes [30, 78]. Our data demonstrated this as therapeutic gains were not universal [49]. Therefore, another area of future development includes treatments that preserve benefit while minimizing risk of antimicrobial resistance. More studies are coming out regarding the use of bacteriophages, specifically endolysins, that can target S. aureus colonization [79, 80]. This is significant given the enhanced efficacy against multidrug-resistant strains. However, bacteriophage use in CTCL treatment has not been studied in humans yet, and standardization of protocols is underway. In the interim, careful use of antibiotic treatment and prophylaxis is indicated.

Collectively, the findings of this scoping review suggest that microbial dysbiosis and critical colonization may fuel cutaneous inflammation and tumor progression in susceptible hosts, and that targeted antimicrobial therapy may serve as a valuable adjunct in CTCL management when applied prudently.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Conceptualization: Sonia Czyz, Jori Hardin; Methodology: Sonia Czyz, Joshua Quan, Jori Hardin; Data Collection: Sonia Czyz, Joshua Quan, Kerry Yang; Writing—Original Draft: Sonia Czyz, Joshua Quan; Writing—Review and Editing: Sonia Czyz, Joshua Quan, Jori Hardin, Raed Alhusayen; Supervision: Jori Hardin, Raed Alhusayen.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflicts of Interest

Sonia Czyz, Joshua Quan, Kerry Yang, Raed Alhusayen and Jori Hardin have no conflicts to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.