Search Results (5,709)

Loss of renal function is associated with premature aging of the immune system; however, earlier studies on this topic enrolled patients with reduced GFR and did not distinguish between those with or without proteinuria. Clinical observations suggest that proteinuria alone might also impair immune defense. It is thus an open question whether patients with a urinary albumin-to-creatinine ratio > 300 mg/g (severe albuminuria) independent of their eGFR have an inflammatory risk profile and a disturbed adaptive immune response. This cross-sectional study included 25 patients with severe albuminuria (uACR > 300 mg/g; P-Group), 19 patients with an eGFR < 60 mL/min 1.73 m2 and a uACR < 300 mg/g (G-Group), and 30 patients with adequate kidney function (C-group). All three cohorts have a similar cardiovascular background with arterial hypertension and coronary artery disease. PBMCs from the patients were challenged with the superantigen Staphylococcal enterotoxin B (SEB) as well as with CMV- and SARS-CoV-2-specific antigens. Monocyte subsets and CD86 and HLA-DR expression were determined through flow cytometry. Transcripts of CD28 and IFN-α and -γ were measured by qPCR. Compared to those in the C-group, patients in the G-group showed a higher polyclonal SEB response and had significantly elevated circulating numbers of inflammatory monocytes (subset CD14++CD16+). CD28 transcripts were decreased in the P-group and G-group compared to the C-group, reaching significance for the G-Group. The CMV- and SARS-CoV-2-specific immune response, as measured by the frequency of CD4+69+137+ T and CD8+69+137+ T cells, was comparable in all three groups. Severe albuminuria per se does not alter the antigen-specific immune response; however, patients with reduced GFR, but not those with proteinuria, show inflammatory and polyclonal immune activation. Full article

Microplastics and heavy metals are widely present in the soil, and their combined contamination affects plant growth and physiological characteristics. Currently, research on the growth, physiology, and quality of Panax notoginseng under combined microplastic-heavy metal contamination with biochar amendment is limited. Pine needle biochar was used as the experimental material, and the adsorption mechanism of pine needle biochar for microplastics and cadmium (Cd) was explored through adsorption experiments. Pot experiments were conducted under the combined stress of 0.1% (w/w) microplastics and 6 mg·kg⁻¹ Cd (MP–Cd), with exogenous application of 0.5%, 1%, and 3% biochar. The biomass, Cd content, photosynthetic characteristics, antioxidant system (superoxide anion, O₂⁻; hydrogen peroxide, H₂O₂; malondialdehyde, MDA; superoxide dismutase, SOD; peroxidase, POD; and catalase, CAT), saponin synthase activities (dammarenediol-II synthase, DS; squalene epoxidase, SE; glycosyltransferase, GT; and squalene synthase, SQS), and saponin content (notoginsenoside R₁, ginsenoside Rg₁, and ginsenoside Rb₁) of P. notoginseng were analyzed. The results showed that under the 1% biochar application, the Cd²⁺ adsorption capacity was 1.31 mg·g⁻¹, with a removal rate of 99.91%. Under biochar application, Cd content in all parts of P. notoginseng was significantly decreased, and the magnitude of the decrease increased with increases in the biochar application rate. Under the 3% biochar application, the plant height and biomass were increased by 18.92% and 29.72%, and the net photosynthetic rate (P_n) and stomatal conductance (G_s) were increased by 1.18-fold and 1.5-fold, respectively. Under the 1% biochar application, chlorophyll a and b contents were highest at 0.077 mg·g⁻¹ and 0.052 mg·g⁻¹, respectively, the activity of SE in rhizomes was increased by 20.24%, and the content of notoginsenoside R₁ was significantly increased by 1.01-fold. Under the 3% biochar application, the activity of SQS in rhizomes was significantly increased by 10.38%, and the activities of GT and DS in fibrous roots were increased by 20.29% and 14.82%, respectively. The content of ginsenoside Rb₁ in rhizomes was significantly increased by 69.64%, while the contents of ginsenoside Rg₁ and total saponin in the main root were increased by 1.41-fold and 0.72-fold, respectively. The activities of saponin synthase in various parts of P. notoginseng were GT (717.167 U·L⁻¹) > DS (472.752 IU·L⁻¹) > SE (378.949 U·L⁻¹) > SQS (144.918 U·L⁻¹). In summary, the growth of P. notoginseng and saponin content were increased under combined MP–Cd contamination, with the 3% pine needle biochar application, with Cd content decreased to ensure the safe production of P. notoginseng. Full article

Background/Objectives: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy has been the standard of care for muscle-invasive bladder cancer (MIBC) for two decades, yet a substantial proportion of patients derive no benefit. As antibody–drug conjugates and immune checkpoint inhibitors reshape perioperative treatment, it is unclear which patients retain meaningful benefit from platinum. We describe long-term outcomes and exploratory paired immune and genomic analyses in a single-centre cohort treated with dose-dense MVAC (dd-MVAC). Methods: We retrospectively identified 54 consecutive patients with MIBC treated with neoadjuvant dd-MVAC between November 2013 and November 2019. Forty-two underwent radical cystectomy and are assessable for pathologic response. Immunohistochemistry for CD3, CD8, FOXP3, PD-1, PD-L1, PD-L2, and NY-ESO-1 was evaluable in 31 baseline specimens and 22 paired specimens; paired genomic profiling was evaluable in 12 cases, with paired tumour mutational burden (TMB) in 10 by whole-exome sequencing and 7 by TSO-500. Paired analyses necessarily exclude patients achieving a pathologic complete response (pCR), who have no residual tumour, and most early progressors. Results: pCR was achieved in 11/42 operated patients (26%, 95% CI 15–41). Median follow-up was 87 months (IQR 24–104). Hydronephrosis was the only baseline factor associated with absence of pCR (p = 0.016). Within the operated cohort, pCR was associated with longer recurrence-free survival (log-rank p = 0.017), but the difference in overall survival did not reach significance (p = 0.121). NAC reduced intratumoral FOXP3 (q = 0.001), NY-ESO-1 (q = 0.013), PD-L2 (q = 0.013), and CD3 (q = 0.043) after correction for multiple comparisons, whereas TMB showed no significant change (TSO-500 p = 0.67; WES p = 0.86). No statistically significant association was detected between any baseline immune marker, including PD-L1, and pCR. The mutational landscape was largely concordant before and after NAC. Conclusions: This study was exploratory and was not powered to validate predictive biomarkers. In this long-term cohort, dd-MVAC was associated with measurable depletion of intratumoral immune populations in chemoresistant tumours, while paired genomic profiles remained broadly concordant. No pre-treatment biomarker identified platinum-refractory patients, but the small evaluable subsets mean these are hypothesis-generating rather than negative findings, and prospective studies with pre-specified biomarker endpoints are required. Full article

Mine drainage containing manganese (Mn) and zinc (Zn) poses a major environmental challenge. In Japan, Mn-rich mine drainage frequently exceeds the discharge standards of 10 mg/L for Mn and 2 mg/L for Zn. This study evaluated laboratory-scale continuous-flow constructed wetlands (CWs) for the treatment of both synthetic and actual mine drainage without addition of external organic carbon. The actual mine drainage was collected from an anonymous former Cu–Pb–Zn mine in Japan. Two limestone-filled CWs (2 L), one planted with Phragmites australis and the other unplanted, were operated at hydraulic retention times of 1–2 d. The influent mine drainage contained approximately 66 mg/L Mn and 10–15 mg/L Zn together with Fe, Cu, Cd, and Pb. During 170 days of continuous operation, the planted CW consistently achieved lower effluent Mn and Zn concentrations than the unplanted CW under both synthetic and actual mine drainage conditions. Effluent Mn concentrations in the planted CW ranged from 5.5 to 20.0 mg/L, compared with 46.1–54.2 mg/L in the unplanted CW. Likewise, effluent Zn concentrations ranged from 0.21 to 3.0 mg/L in the planted CW and from 2.4 to 10.1 mg/L in the unplanted CW. The superior performance of the planted CW was associated with enhanced limestone dissolution, elevated pH, and favorable rhizosphere conditions that likely promoted biologically mediated Mn(II) oxidation and the formation of Mn oxides, while Mn carbonate precipitation may also have contributed to Mn removal. These findings demonstrate that limestone-based planted CWs can effectively treat Mn-rich mine drainage without addition of external organic carbon and highlight their potential as sustainable, low-energy passive treatment systems for the long-term management of abandoned mine drainage. Full article

MicroRNAs (miRNAs) are small non-coding RNAs that have emerged as critical regulators of gene expression and key cellular processes in cancer, including tumor cell proliferation, survival, metastasis, and both innate and adaptive immune responses within the tumor microenvironment. Through their ability to modulate immune cell development, differentiation, polarization, antigen presentation, cytokine signaling and immune checkpoint expression, miRNAs play a vital role in shaping immune responses and represent attractive therapeutic candidates for remodeling the tumor immune microenvironment. This review provides a comprehensive overview of the mechanisms through which miRNAs regulate anti-tumor immunity and contribute to immune evasion with particular emphasis on their role in modulating major immune checkpoint pathways, including PD-1/PD-L1, CTLA-4, LAG-3, TIM-3 and CD28-mediated signaling. We further examine the contribution of miRNAs to therapeutic resistance and discuss their potential integration with immune checkpoint blockade, chemotherapy, PARP inhibitors and targeted therapies to enhance antitumor efficacy and overcome treatment resistance. Recent advances in spatial transcriptomics and computational approaches have expanded our understanding of miRNA-mediated regulatory networks at single-cell and tissue levels and provide new insights into tumor–immune interactions. In addition, we evaluate the current progress in the clinical development of miRNA-based therapeutics, including miRNA mimics and inhibitors and discuss the major challenges associated with efficient delivery, off-target effects, immunogenicity and patient heterogeneity. Collectively, the evidence highlights the growing potential of miRNAs as diagnostic biomarkers, therapeutic targets and therapeutic tools in cancer immunotherapy. Continued advances in RNA therapeutics, delivery technologies and multi-omics approaches are expected to accelerate the clinical translation of miRNA-based strategies for personalized cancer therapy. Full article

The unauthorized addition of silver nitrate and excessive heavy metals in hair dye creams poses serious health risks, creating an urgent need for rapid and sensitive detection methods. In this study, a spark discharge-enhanced fiber laser-induced breakdown spectroscopy (SD-LIBS) system was developed for the simultaneous detection of five heavy metal ions (Ag, Pb, Cd, As, Hg) in hair dye creams. The system combines three signal enhancement strategies: high-voltage spark discharge, Au nanoparticle-assisted enhancement, and analyte enrichment on a superhydrophobic–hydrophilic patterned graphite substrate. Hydrophilic micro-pits were fabricated by laser scanning on the superhydrophobic graphite surface to confine and concentrate analyte residues upon droplet drying. Under optimized discharge conditions of 22 nF and 2000 V, the spark discharge achieved a signal-to-noise ratio enhancement of approximately 12 times. Au nanoparticle enhancement further increased the signal intensity by 49.3%. The optimal pit diameter and sample loading volume were 0.1 mm and 30 μL, respectively. The calibration curves for all five elements showed good linearity with R² values close to 0.99, and the lowest detection limits reached 1.9 μg/L for Ag. The average spiked recovery was 82.07%. The method was applied to four commercial hair dye cream samples, and the Ag detection results agreed well with ICP-OES reference values with an average error of 16.41%. This work demonstrates that the proposed SD-LIBS system offers a low-cost, rapid, and sensitive approach for on-site screening of heavy metals in cosmetics and other consumer products. 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

Flax (Linum usitatissimum L.) is a multipurpose crop with considerable potential as a biotechnological platform for producing in vitro seedlings that serve both as sources of pharmacologically valuable phenolic compounds (PCs) and as potential biosorbents/chelators of heavy metals (HMs), including cadmium (Cd). The use of an in vitro culture system under strictly controlled conditions enables the identification of variety-specific responses in flax. The aim of this study was to compare the morphophysiological characteristics, the level of lipid peroxidation (LPO), and phenylpropanoid (PP) and flavonoid (FL) contents in in vitro seedlings of two flax varieties—fiber flax (FF) and oilseed flax (OF)—grown under control conditions and in the presence of Cd (60 and 100 μM). The stem mesostructure was also examined, as the stem is the principal organ responsible for metal transport via its vascular tissues. Our results showed that Cd exposure induced only minor changes in the morphophysiological characteristics of both flax varieties. Using a standardized in vitro system, we demonstrate for the first time that OF accumulated approximately 40% more Cd than FF at both metal concentrations. LPO, assessed by malondialdehyde (MDA) content, remained relatively stable across all treatments, except for a significant increase in OF exposed to 100 μM Cd. Analysis of the phenolic profile revealed that, in FF, the total phenolic content (TPC) and PP content increased relative to the control at 100 μM Cd, indicating the induction of PC-mediated antioxidant defense. In contrast, OF exhibited reduced PP and FL contents under both Cd treatments. Cytochemical analysis revealed a similar localization pattern for Cd and PC, with both accumulating predominantly in the stem epidermis of the in vitro-grown seedlings. However, the two flax types differed markedly in their accumulation profiles: OF accumulated higher levels of Cd, indicating its potential use as a biosorbent for this pollutant, whereas FF exhibited higher PC accumulation, suggesting its suitability as a natural source of PCs. These findings demonstrate that flax responses to Cd exposure are variety-specific. Full article

Platelets express several glycophosphatidylinositol-(GPI-) anchored receptors, mainly involved in protection against lysis by activated complements. Most of these are well-characterised and are expressed on other blood cells. More recently, CD109 with a mass of 175 kDa was also shown to be a GPI-anchored receptor, surface expressed only on activated platelets, with a role as a co-receptor for transforming growth factor-β (TGF-β). CD109 is expressed on a wide range of cells and is a marker for various types of tumors. Activated platelets express an even larger GPI-anchored receptor at about 500 kDa. We have now isolated this and identified it as fibrocystin L, also known as polycystic kidney hepatic disease L1 (PKHD1L1). Fibrocystin L, like other platelet GPI-anchored receptors, is missing or deficient in paroxysmal nocturnal hemoglobinuria. Fibrocystin L is also expressed in activated T-cells and may be involved in immune responses. Recently, there have been additional reports of PKHD1L1 expression and roles as a coat protein of hair-cell stereocilia essential for normal hearing, as well as reports of them in the dentate gyrus in mice involved in susceptibility to seizure. In all these cases, GPI anchors were not reported, but neither were they tested for. During the fluorescence microscopy studies, we used CD109 as a control and observed that it is also a granule protein that had not been previously reported. Full article

Paulownia is one of the most useful and sought-after trees worldwide. Various parts (flowers, fruits, leaves, wood, bark, and seeds) have found practical applications. The present study focuses on the characterization of paulownia fruits, flowers and shells, and their potential non-traditional application for pollutant adsorption. The fruits were found to contain higher amounts of flavonoids (1051.85 ± 10.32 µg mL⁻¹) compared to flowers (401.26 ± 5.48 µg mL⁻¹). This reflects the observed antioxidant activity of the fruits: two times higher than that of the flowers. Salicylic acid was the main phenolic acid (2729.96 ± 16.89 µg mL⁻¹) in the flowers, while quercetin (572.42 ± 10.32 µg mL⁻¹) and rosmarinic acid (352.84 ± 6.97 µg mL⁻¹) were present in higher amounts in the fruits. The lipids from the flowers were rich in linoleic (48.1%) and linolenic (20.0%) acids, while the fruit lipids were rich in linoleic (53.9%) and oleic (19.5%) acids. More than half of the fruits and flowers consisted of insoluble dietary fibers. The shells were rich in cellulose and lignin (42.96 ± 0.61 and 31.23 ± 0.34 g 100 g⁻¹ DW, respectively) and were applied as a natural biosorbent for Cu²⁺, Cd²⁺ and methyl orange removal (99.05%). Paulownia fruits were effective, removing 98.25% of Cu²⁺ (5000 mg L⁻¹). Hence, paulownia shells and flowers could potentially be utilized as non-traditional biosorbents for pollutant removal. Full article

Rhizosphere microbes play a critical role in plant stress adaptation; however, the diversity and functional potential across different tea cultivars remain poorly understood. Here, we employed high-throughput sequencing and fungal isolation across five distinct tea cultivars (cv. A–E). Our results reveal significant divergence among the sampled tea populations: Mucoromycota-dominated communities with higher diversity were observed in cultivars A, B, and C, whereas Ascomycota-dominated communities with lower diversity characterized cultivars D and E. Concomitantly, bacterial heavy MRGs profiles exhibited a parallel dichotomy, with Cd/Zn/Co/As/Mn-related resistance functions enriched in cultivars A, B, and C and Ni/W/Mo-related functions enriched in cultivars D and E. Spearman correlation analysis demonstrated that these divergent MRGs profiles were significantly associated with soil characteristics, such as Ex Al and OM, but not with pH, indicating that edaphic filtering independently shapes bacterial functional potential in the tea rhizosphere. Furthermore, four fungal isolates (L3, L4, L5, and L19) exhibited robust Al tolerance and multiple in vitro plant growth-promoting traits. These findings highlight the tea rhizosphere as a complex environment that drives parallel differentiation in fungal community structure and bacterial resistance gene profiles, providing a foundation for the development of microbial strategies to enhance stress adaptation in acidic tea agroecosystems. Full article

Background: Differences in gene expression between inflammatory-like (iEOS-like) and resident-like (rEOS-like) eosinophil subtypes, and in eosinophil-derived serum mediators, may reflect eosinophil functional activity and their potential role in the pathogenesis of allergic asthma (AA). Methods: Twenty-three patients with non-severe AA and thirteen healthy subjects (HS) were examined. AA patients underwent a bronchial allergen challenge (BAC) with Dermatophagoides pteronyssinus and were re-evaluated 24 h later. Blood eosinophils were isolated by gradient centrifugation and magnetic separation, followed by subtyping based on CD62L expression. Gene expression was assessed by TaqMan-based quantitative PCR. Serum eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), Galectin-10 (Gal10), and NADPH oxidase 2 (NOX2) were measured using ELISA. Results: Blood eosinophil subtypes from AA patients showed significantly higher expression of CLC, ECP, EPX, EDN, MBP, ALOX5, NOX2, and TGF-β1 compared to those from HS (p < 0.05), with no significant changes in LTA4H and LTC4S. iEOS-like cells in AA patients exhibited higher CLC and EPX expression compared to rEOS-like cells, (p < 0.05). Following BAC, CLC, MBP, and TGF-β1 expression increased in both eosinophil subtypes, while EPX and NOX2 increased only in iEOS-like cells (all p < 0.05). Serum ECP, EDN, and Gal10 concentrations were elevated in AA compared to HS and further increased after BAC (all p < 0.05); serum NOX2 remained unchanged. Conclusions: BAC induces a late-phase eosinophilic response in AA characterized by a partially eosinophil subtype-specific increase in gene expression and in circulating eosinophil-derived mediators. An increase in Gal10, observed at the CLC transcript level in eosinophils and in serum—but not in ECP or EDN—suggests the existence of mediator-specific mechanisms that regulate gene expression and extracellular release. Full article

While carbon dots (CDs) are promising green nanomaterials for sustainable agriculture, how they regulate cotton growth via physiological and metabolic reprogramming remains poorly understood. This study evaluated foliar CD application (0–200 mg·L⁻¹) to uncover dose–response patterns and metabolic drivers. CDs exerted a concentration-dependent impact, with 100 mg·L⁻¹ yielding optimal results. This application markedly boosted shoot and root biomass (fresh weight: 103.43% and 44.28%; dry weight: 56.03% and 40.39%) and enhanced specific leaf area by 52.51% over the control. CDs improved photosynthetic efficiency (elevated Pn, Gs, and E values, alongside increased chlorophyll a and carotenoids) and strengthened antioxidant defenses (enhanced leaf POD/SOD and root POD/CAT activities). Despite mild MDA increases indicating oxidative stress, accumulated proline and soluble sugars in roots suggested adaptive osmotic adjustment. These findings suggest that CDs maintain physiological homeostasis by modulating antioxidant defense and osmotic adjustment. Untargeted metabolomics identified 2440 metabolites. Phenylpropanoid biosynthesis and flavonoid biosynthesis were the most prominently enriched pathways based on KEGG enrichment results. K-means and correlation analyses revealed key metabolites linked to cotton biomass. Overall, CDs facilitate cotton development through synergistic physiological and metabolic reprogramming, underscoring their potential as innovative agricultural growth regulators. 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