Search Results (1,408)

Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment, yet identifying effector proteins and tissue-specific mechanisms underlying genome-wide association study (GWAS) loci remains challenging. This study aimed to systematically prioritize candidate causal circulating proteins and delineate their cellular and transcriptional dynamics in AMD. We integrated plasma protein quantitative trait loci (pQTL) summary statistics from the UK Biobank Pharma Proteomics Project (UKB-PPP; $N=\mathrm{53,022}$) with FinnGen AMD GWAS data using proteome-wide association studies (PWAS), summary-data-based Mendelian randomization (SMR) with the HEIDI test, and Bayesian colocalization analysis. Prioritized candidates were mapped across human and murine retinal single-cell/single-nucleus RNA sequencing atlases. Transcriptional responsiveness was validated in an independent clinical microarray dataset (GSE103060) and in human retinal pigment epithelial cells (ARPE-19) via in vitro inflammatory stimulation and RT-qPCR. Target tractability was assessed using pharmacological databases. Multi-stage genetic screening prioritized five candidate proteins stratified into two confidence tiers: three Tier 1 causal drivers supported by colocalization (PP4 > 0.80)—including risk factors CSF2, IL20RB, and WARS1 (also known as WARS)—alongside two Tier 2 candidates supported by SMR and HEIDI, comprising risk factor PILRA and inversely associated metabolic factor ACADSB. Retinal transcriptomic mapping localized PILRA specifically to microglia, ACADSB to inner retinal neurons, and WARS1 to photoreceptors, RPE, and vascular compartments, while IL20RB and CSF2 exhibited low baseline expression. In independent validation cohorts, IL20RB and WARS1 were significantly up-regulated in choroidal neovascularization (CNV) membrane-derived RPE from patients with AMD ($p<0.01$). Exposure of ARPE-19 cells to TNF-$\alpha$ markedly induced mRNA levels of IL20RB ($P=0.0025$) and WARS1 ($p<0.0001$). Dual normalization against ACTB as a secondary internal reference yielded consistent significant induction. Pathway enrichment highlighted cytokine-driven receptor cascades (JAK-STAT signaling) and mitochondrial substrate catabolism (branched-chain amino acid and fatty acid metabolism). Drug–target profiling identified small molecules and nutraceuticals interacting with ACADSB, CSF2, and WARS1. By combining large-scale plasma proteomic genetics with single-cell mapping and experimental validation, this study identifies a prioritized set of candidate causal proteins linking neuroimmune activation, vascular remodeling, and mitochondrial bioenergetics in AMD, providing candidate entry points for mechanistic and therapeutic exploration. Full article

Both oncolytic virotherapy and immune checkpoint blockade are being actively explored as immunotherapy treatments for glioblastoma, one of the most lethal malignancies. Nevertheless, the antitumor molecular mechanisms of these therapies remain poorly understood, particularly whether they induce overlapping or distinct transcriptional programs. No comprehensive transcriptome-wide characterization and direct comparison of the responses induced by VV-GMCSF-Lact and anti-PD-1 therapy in glioma have been reported. To address this question, we performed whole-transcriptome profiling of GL261 tumors from immunocompetent C57BL/6 mice treated with VV-GMCSF-Lact, anti-PD-1 antibodies, or their combination. We analyzed therapy-associated changes in gene expression, signaling pathways, and tumor composition. Our findings indicate that anti-PD-1 and combination treatment led to distinctive activation of interferon-gamma response, JAK/STAT signaling, and TNF-alpha/NF-kB pathways. In contrast, VV-GMCSF-Lact preferentially activated T, B, and natural killer T cell-associated programs and reduced the relative abundance of malignant cells. Notably, combination therapy was associated with unique molecular patterns, including induction of monocyte and granulocyte chemotaxis-associated genes, downregulation of PP2A-regulated signaling, and suppression of Rap1-related pathways. This suggests that VV-GMCSF-Lact and anti-PD-1 therapy induce transcriptionally distinct, yet complementary, immune reprogramming and support further evaluation of their combination for glioma immunotherapy. Full article

Resistance to BRAF inhibitors (BRAFi), alone or with MEK inhibitors (MEKi), limits durable responses in BRAF-mutant melanoma. To characterize resistance-associated cell-state evolution, we analyzed 674 melanoma cells from six mice bearing tumors from a single patient-derived BRAF V600E-mutant melanoma xenograft (PDX) lineage before treatment, during initial regression, at minimal residual disease, and at resistant regrowth. Unsupervised clustering based on a BRAF-centered network feature set comprising 2506 candidate genes identified six transcriptional states, which were characterized using transcriptomic analyses. Cluster 4 was detected exclusively at resistant regrowth, a phase marked by MAPK pathway reactivation, and exhibited enhanced JAK-STAT/interferon signaling and increased STAT1, STAT2, IRF7, IRF9, and RELB regulon activities. Network inference predicted STAT1-BRAF and IRF7-MET regulatory links, suggesting candidate routes to MAPK reactivation through BRAF overexpression and MET-mediated bypass signaling. External analyses partially recapitulated the resistance-associated transcriptional program in independent melanoma cell-line datasets and yielded limited, inconclusive evidence for the predicted STAT1-BRAF association in public perturbation datasets. Cluster 2 represented a pre-existing proliferative state whose signature was associated with shorter progression-free survival in pretreatment clinical cohorts. Together, these findings distinguish a therapy-associated acquired-resistance state from a pre-existing proliferative resistance-associated state and nominate the predicted STAT1-BRAF and IRF7-MET links for functional validation. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that represents continuous synovial inflammation, oxidative stress, immune dysregulation, and progressive cartilage degradation and bone erosion. Although disease-modifying antirheumatic drugs (DMARDs), including methotrexate (MTX), have improved clinical outcomes, treatment-limiting adverse effects remain a concern. Increasing evidence suggests that natural bioactive compounds may serve as adjunctive approaches by modulating multiple pathogenic pathways. This review summarizes biomarker-based modulation of inflammatory, oxidative, and immune pathways by plant-derived extracts, nutraceuticals, and biologically derived compounds, with particular emphasis on evidence from adjuvant arthritis (AA). AA is a widely used experimental model that reproduces several inflammatory and oxidative features relevant to RA, including cytokine activation, NF-κB/MAPK signaling, Th17/JAK-STAT3 signaling, redox imbalance, and tissue degeneration. Studies in AA indicate that selected natural compounds, alone or in combination with MTX, can reduce inflammatory cytokines (e.g., IL-1β, IL-6, IL-17A), matrix-remodeling markers (e.g., MMP-9), and oxidative-stress markers (e.g., protein carbonyls and lipid peroxidation) while supporting antioxidant defenses (e.g., HO-1 and CAT). Overall, natural bioactive substances may have potential as adjunctive candidates for further investigation in RA, particularly because of their effects on inflammatory and oxidative pathways. Preclinical studies of MTX combinations have reported additional improvements in selected disease-associated outcomes; however, these findings require confirmation in well-designed clinical studies. This review critically evaluates the preclinical evidence for natural bioactive compounds, with a focus on mechanistic studies in AA and the potential for combination strategies with methotrexate. Full article

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen control with the preservation of neural function. This review examines the diverse yet convergent immune evasion strategies employed by major neurotropic RNA and DNA viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), rabies virus (RABV), flaviviruses, alphaviruses, enteroviruses, and JC virus (JCV). We discuss viral interference with innate immune sensing pathways, including RIG-I-like receptors (RLRs) and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling, inhibition of type I interferon induction and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling, modulation of interferon-stimulated effector mechanisms, and disruption of antigen presentation and adaptive immune surveillance. The review further highlights the distinct roles of viral latency, long-term persistence, neuronal–glial interactions, and metabolic reprogramming in facilitating prolonged infection within the CNS. Emerging evidence indicates that successful neurotropic viruses rarely achieve immune evasion through complete suppression of host defenses; instead, they fine-tune antiviral responses to preserve host cell viability while preventing viral clearance. Finally, we discuss current knowledge gaps and emphasize the need for advanced human-relevant models, single-cell and spatial multi-omics, and systems-level approaches to better define virus–host interactions within the CNS. A deeper understanding of these integrated immune evasion networks may reveal novel therapeutic strategies that enhance antiviral immunity while limiting neuroinflammation and preserving neurological function. Full article

Background: Portulaca oleracea L. (POL) has anti-inflammatory and immunomodulatory activities, but its mechanism against atopic dermatitis (AD) remains incompletely understood. Methods: 2,4-dinitrofluorobenzene (DNFB)-induced AD mice were treated orally with POL or dexamethasone for 14 days. We evaluated skin lesions, scratchizng, serum IgE, histopathology, inflammatory cytokines, skin-barrier genes, JAK/STAT phosphorylation, and fecal metabolites. Results: POL alleviated skin lesions and pruritus, reduced serum IgE concentrations, attenuated epidermal hyperplasia and inflammatory-cell and mast-cell infiltration, and restored keratinocyte architecture. It decreased IL-4, IL-13, and IL-31 expression, increased filaggrin and loricrin expression, and inhibited JAK1, STAT1, and STAT3 phosphorylation. Untargeted metabolomics showed that POL mainly regulated unsaturated fatty acid and steroid hormone biosynthesis and restored levels of anti-inflammatory and antiallergic metabolites, including (±)18-HEPE, docosahexaenoyl ethanolamide, and dehydroepiandrosterone. Conclusions: These findings indicate that POL ameliorates AD by suppressing Th2 inflammation through JAK1/STAT3 signaling, correcting lipid-metabolic disturbances, and restoring skin barrier integrity. Full article

Total joint arthroplasty is a surgical procedure with rising global incidence. Although a strong postoperative inflammatory response is necessary for tissue repair following primary arthroplasty, it may prove to be harmful if excessive or prolonged. This could compromise osseointegration, increase pain, and delay the detection of periprosthetic joint infection. This narrative review examines the principal inflammatory pathways activated by primary arthroplasty. Damage-associated molecular patterns produced by injury and cell death, such as High Mobility Group Box 1 Protein, cell-free DNA, extracellular ATP, histones, and heat shock proteins, trigger innate immune activation following surgical trauma. These mediators use inflammasome pathways and pattern recognition receptors to intensify inflammatory signaling. The acute-phase trajectory, characterized by increases in C-reactive protein and erythrocyte sedimentation rate, alongside the role of interleukin-6 as a precursor factor, is examined together with synovial markers to facilitate the differentiation between septic and aseptic inflammation. Cytokine signaling cascades (JAK-STAT, NF-κB, MAPK) and the RANK/RANKL/OPG axis at the bone-immune interface are also considered. This manuscript highlights relevant inflammatory pathways, clinically significant biomarkers, and pathway-guided management strategies to provide an overview of the current research on the biological mechanisms underlying perioperative inflammation in primary arthroplasty. No inflammatory biomarker has yet been validated as a predictor of aseptic loosening. Full article

Background: Effective topical management of sensitive skin remains challenging because inadequate cutaneous delivery limits the therapeutic performance of many anti-inflammatory agents. Glycyrrhetinic acid (GA) possesses well-recognized anti-inflammatory and barrier-protective activities, yet its clinical potential is constrained by poor aqueous solubility and inefficient skin delivery. This study aimed to develop a hyaluronic acid (HA)-engineered ethosomal system to enhance the local delivery and therapeutic efficacy of GA for sensitive skin. Methods: HA-coated GA-loaded ethosomes (HAGA-ETs) were prepared by electrostatic adsorption of HA onto a cationic ethosomal template. The physicochemical properties, release behavior, storage stability, skin retention, cellular uptake, and biological activities of HAGA-ETs were systematically evaluated using TNF-α/IFN-γ-stimulated HaCaT cells and an SLS-induced 3D reconstructed skin model. Results: HAGA-ETs exhibited a mean particle size of 140.1 nm, encapsulation efficiency exceeding 95%, sustained drug release, and good storage stability. Compared with Free-GA and unmodified ethosomes, HAGA-ETs showed improved cytocompatibility, enhanced skin retention, greater keratinocyte uptake, and stronger anti-inflammatory activity. HA pre-saturation attenuated the enhanced cellular uptake of HAGA-ETs, supporting the involvement of HA receptor-mediated cellular interaction. HAGA-ETs also more effectively restored barrier-related markers, suppressed hyper-reactivity- and allergy-associated mediators, and inhibited the activation of MAPK/NF-κB, JAK1/STAT1, and TRPV1-related signaling pathways in both cellular and 3D skin models. Conclusions: HA surface engineering effectively improved the topical delivery and local therapeutic efficacy of GA by enhancing skin retention and keratinocyte interaction. HAGA-ETs represent a promising nanoplatform for the local management of sensitive skin. Full article

Background/Objectives: The background of the research shows that β-thalassemia is a hemoglobinopathy which is characterized by ineffective erythropoiesis and iron overload and this is kept in balance by hepcidin hormone due to BMP/SMAD and JAK/STAT3 pathways. However, it is not known how exactly these signaling pathways are involved in iron metabolism disorders for different forms of β-thalassemia, therefore, the aim of the present research was to analyze circulating levels of hepcidin, STAT3, SMAD1 and SMAD4 in participants with β-thalassemia and evaluate their exploratory discriminatory potential. Methods: The methodology of the research includes a comparative cross-sectional study of 135 patients with β-thalassemia major, intermedia and minor, as well as healthy control individuals based on hemoglobinopathy typing with the high-performance liquid chromatography. The circulating hepcidin levels, SMAD1 and SMAD4 concentrations as well as plasma STAT3 levels were identified and measured by ELISA method. Statistical processing methods include one-way ANOVA, multinomial logistic regression and ROC curve analysis based on ten-fold cross-validation. Results: Hepcidin and SMAD1 levels showed heterogeneity among groups, whereas differences in STAT3 and SMAD4 were not statistically significant. In multinomial logistic regression, lower hepcidin was associated with β-thalassemia major and lower SMAD1 with β-thalassemia intermedia. ROC analysis showed moderate in-sample discrimination for hepcidin and stronger discrimination for SMAD1. Conclusions: Altered circulating hepcidin and SMAD1 patterns may reflect dysregulation of BMP-SMAD/hepcidin signaling across β-thalassemia subtypes. These findings are exploratory and require independent validation before clinical application. Full article

Background/Objectives: Ovarian cancer is one of the most lethal gynecological malignancies worldwide, largely due to late diagnosis and rapid disease progression. Increasing evidence suggests that dysregulation of calcium-binding proteins and microRNA-mediated regulatory networks contributes to ovarian cancer progression. However, the role of S100A6 and its upstream regulatory mechanisms in ovarian cancer remain poorly understood. Methods: S100A6 expression in ovarian cancer cell lines and tissues was assessed by transcriptome sequencing, qPCR, and immunohistochemistry. Functional assays (CCK-8, EdU, Transwell, wound-healing, flow cytometry) and a xenograft model were used to evaluate S100A6 effects. Bioinformatic analysis, dual-luciferase reporter assays, and rescue experiments identified upstream miRNAs. JAK-STAT involvement was examined by Western blot. Survival analysis was performed using Kaplan–Meier Plotter. Results: S100A6 expression was significantly upregulated in ovarian cancer cells and tumor tissues compared with normal controls. Silencing S100A6 inhibited cell proliferation, migration, and invasion while promoting apoptosis in vitro and suppressed tumor growth in vivo. Mechanistically, S100A6 activated the JAK–STAT pathway, and pharmacological inhibition of STAT3 with Stattic reversed S100A6-promoted migration. Further analyses identified Let-7c-3p as a direct upstream regulator of S100A6. Let-7c-3p bound to the 3′-UTR of S100A6 and suppressed its expression, thereby reversing S100A6-mediated oncogenic phenotypes and inhibiting JAK-STAT signaling. Survival analysis revealed that elevated S100A6 expression was associated with shorter progression-free survival in ovarian cancer patients. Conclusions: Our findings identify a novel Let-7c-3p/S100A6/JAK-STAT regulatory axis that promotes ovarian cancer progression. This study provides new insights into the molecular mechanisms underlying ovarian cancer development and suggests that targeting this regulatory network may represent a potential therapeutic strategy. Full article

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that is histologically and clinically heterogeneous. Skeletonization is a computer vision technique used in image description, segmentation, and pattern recognition. Objectives: This retrospective observational study analyzed the 2D-topological heterogeneity of DLBCL. Methods: A series of 153 patients, including 110 patients with DLBCL and 43 patients with reactive lymphoid tissue, were analyzed by skeleton analysis using hematoxylin and eosin (H&E) digitized images. The skeletonization variable was correlated with several clinicopathological characteristics of the patients, including cell of origin Hans’ classifier and Lymph2Cx assay, MYC and BCL2 rearrangement by FISH, immunohistochemistry of BCL2, CASP8, cCASP3, CD163, CDK6, cPARP, CSF1R, E2F1, ISY1, Ki69, LMO2, MDM2, MYC, MYO, TNFAIP8, PD-L1, and p53, and gene expression using a pancancer immune profiling panel. Results: In comparison with reactive tissue, DLBCL was characterized by lower skeletonization: 5665.20 ± 1012.82 vs. 6341.16 ± 548.23, respectively (p < 0.001). Within the DLBCL diagnostic category, high skeletonization correlated with poor overall survival (hazard risk = 2.5, p = 0.003). High skeletonization was also correlated with higher Epstein–Barr virus (EBV) EBER positivity, death within the first two years, high histological entropy, and lower CD5, E2F1, BCL2, ISY1, and TNFAIP8 protein levels (all p values < 0.05). Gene expression was available in a representative subset of 30 cases, including 18 cases with high skeletonization and 12 cases with low skeletonization. High skeletonization was characterized by upregulation of 166 immuno-oncology genes, such as CD274 (PD-L1), NFKB1A, CD68, CSF1R, CCR5, ITGAM, and TGFB1, and enrichment of IL6 JAK STAT3 signaling, inflammatory response, TNF, NFKB, KRAS, apoptosis, and macrophage function pathways by gene set enrichment analysis (GSEA). In multivariate COX regression analysis for overall survival, the prediction value of skeletonization was independent of Hans’ classifier, the International Prognostic Index (IPI), and EBER (p = 0.030, hazard risk = 2.2). Conclusions: DLBCL is characterized by lower skeletonization than reactive lymphoid tissue. In DLBCL, high skeletonization is associated with poor prognosis and enrichment of immuno-oncology markers. Full article

This study examined the effects of the trans-resveratrol (Res) and l-carnitine (l-Car) complex (RC) on mice genetically resistant to obesity. Male DBA/2J mice received low (RCl, 25/300 mg/kg BW) or high (RCh, 50/600 mg/kg BW) doses of the RC for 64 days in a control diet (CD) or a high-fat-high-carbohydrate diet (HFCD). Differential expression (DE) of genes in the liver was analyzed using DNA microarrays. HFCD alone altered 471 genes (1.7%) versus CD. In CD-fed mice, RCl and RCh affected 170 (0.6%) and 321 (1.2%) genes, respectively. In HFCD-fed mice, RCl and RCh affected 109 (0.4%) and 223 (0.8%) genes. Opposite DE changes between HFCD and RC + HFCD occurred in immune recognition and fat-storage genes (Ccl24, Fabp7, Cd74, H2-Ab1, Srebf1, etc.). Uniform responses to HFCD and RC + CD were seen in Ppard, Irs-1, Tsku, Cyp26b1, Il1r1, Onecut1, Per1, Nlrd2, Rgs16, Grem2, Klf9, and Lpin1. RC effects were consistent with liver morphology. Key RC-targeted pathways included retinoid metabolism, PPAR signaling, and antigen presentation. In HFCD-fed mice, additional pathways were steroid biosynthesis, oxylipin metabolism, and Jak-STAT signaling. DBA/2J mice may exhibit an innate compensatory response involving PPAR signaling, Srebf1, and Socs2, and the contribution of polymorphisms in these genes merits separate investigation in future studies of obesity resistance. Full article

Background and Objectives: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and current therapies provide only limited symptomatic relief without effectively slowing its progression. Increasing evidence suggests that aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade contributes to AD-associated neuroinflammation. This study investigated the therapeutic potential and molecular mechanisms of JAK inhibitors in AD using integrated bioinformatics and network pharmacology approaches. Materials and Methods: Potential anti-AD targets of JAK inhibitors were identified using the SwissTargetPrediction and GeneCards databases. Functional enrichment, protein–protein interaction (PPI) analysis, transcriptomic validation using public datasets, regulatory network construction, molecular docking, normal mode analysis (NMA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction were performed to investigate the potential mechanisms of action of these drugs in AD. Results: Our analysis identified 163 shared targets between JAK inhibitors and AD. Enrichment analysis revealed that these genes were primarily involved in protein phosphorylation and were enriched in key signaling pathways, including the neurotrophin, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling pathways. PPI analysis identified AKT1, BCL2, SRC, STAT3, and TNF as five highly ranked hub targets across multiple topological algorithms. Transcriptomic validation confirmed significantly higher expression of these targets in the prefrontal cortex of individuals with AD compared with normal subjects. Molecular docking indicated that pacritinib and momelotinib showed relatively favorable predicted interactions with the hub proteins, while NMA revealed differences in the predicted flexibility of the docked complexes. Furthermore, ADMET prediction showed that pacritinib possesses favorable pharmacokinetic properties for the treatment of AD. Conclusions: Collectively, these findings provide mechanistic insights into the potential effects of JAK inhibitors in AD and identify pacritinib as a computationally prioritized candidate that warrants experimental validation in appropriate AD models. However, as this study is based solely on computational analyses without wet-lab validation, the findings should be considered hypothesis-generating in silico evidence, and the potential safety concerns of pacritinib require further investigation. Full article

Feline intestinal inflammation is a common gastrointestinal disorder in cats and is associated with immune dysregulation, epithelial barrier injury, microbial imbalance, and persistent inflammatory signaling. This entirely in silico study investigated predicted molecular associations between vine tea (Ampelopsis grossedentata) constituents and feline intestinal inflammation using network pharmacology, molecular docking, and molecular dynamics simulation. No feline cells, tissues, animals, or clinical samples were used. Candidate compounds were screened and evaluated with SwissADME as a computational prioritization step, and potential targets were predicted using multiple databases. Human-centric database-derived genes associated with the broad intestinal-inflammation phenotype were subjected to feline ortholog mapping/verification and intersected with predicted vine tea targets. Protein–protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed, followed by construction of a compound-target-pathway-disease network. Ten representative compounds were cross-docked against six core targets, producing 60 docking combinations, and the lowest-energy complex was subjected to a 100 ns molecular dynamics simulation. Seventeen candidate compounds, 966 predicted vine tea targets, and 102 candidate shared targets were retained in the archived workflow. IL6, TNF, IL1B, STAT3, CASP3, and TLR4 were prioritized as core targets. Enrichment analysis linked the shared-target set to inflammatory responses, innate immunity, cytokine activity, Th17 cell differentiation, and the IL-17, Toll-like receptor, NOD-like receptor, NF-kappa B, TNF, JAK-STAT, and PI3K-Akt signaling pathways. Molecular docking predicted favorable interactions between several compounds and the core targets, particularly IL6, and the IL6-cianidanol complex showed the lowest docking energy and relative stability during simulation. Overall, the analyses prioritize candidate compounds, targets, and pathways for subsequent feline-specific validation; they do not demonstrate therapeutic efficacy, target regulation, or biologically relevant exposure in cats. Full article

Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), is defined by malignant CD4+ T-cell clones that evolve within and remodel the skin and systemic immune compartments. For disease biology and immune remodeling, we prioritize evidence from human primary samples; for therapeutic implications, we integrate clinical-trial and translational biomarker studies. We organize evidence by compartment (skin vs. blood) and, within skin, by stage (patch/plaque vs. tumor). Early patch/plaque MF often shows features consistent with constrained inflammation: skin-resident memory T-cell (TRM)-like malignant clones are in a Th1-leaning microenvironment with relatively preserved cytotoxic surveillance. Progression to tumor-stage MF (and/or large-cell transformation) is frequently associated with clonal dominance, Th2 cytokine polarization, upregulation of checkpoint pathways, and remodeling of myeloid/fibroblast populations. SS is typically associated with leukemic clonal dominance, systemic Th2 skewing, and broad impairment of cytotoxic immune control. These trajectories support an interpretive framework that aligns immune-directed therapies with compartment- and stage-associated biology; these include strategies that (i) deplete malignant clones (e.g., CCR4, CD30, KIR3DL2 targeting), (ii) re-engage exhausted effectors (PD-1/PD-L1 axis), (iii) reprogram cytokine balance (IFN-γ, IL-12, extracorporeal photopheresis), or (iv) suppress malignant signaling programs with secondary immune effects (JAK/STAT inhibition). We highlight potential candidate predictive biomarkers at varying levels of maturity, most of which require prospective validation, including antigen density, compartmental tumor burden, tumor cell fraction, effector-cell substrate, and interferon/cytokine signatures. Full article