Search Results (7,578)

Background/Objectives: Gliomas are among the most aggressive primary brain tumors in adults, characterized by profound molecular heterogeneity and poor response to conventional therapies. Immunotherapy has transformed outcomes in several cancers, yet glioma remains largely refractory, due in part to an immunosuppressive tumor microenvironment. Post-transcriptional regulation of gene expression is increasingly recognized as a key mechanism controlling immune cell function in tumors. Regnase-1, an endoribonuclease regulating the stability of inflammation- and immunity-related mRNAs, is a central modulator of immune responses; however, its role in glioma progression and immune modulation remains poorly understood. This study aimed to evaluate Regnase-1 expression in glioma and investigate its association with tumor grade, prognosis, and immune microenvironment characteristics. Methods: Regnase-1 transcript levels were evaluated by RT-PCR in tumor samples from 40 Moroccan glioma patients and validated using transcriptomic data from The Cancer Genome Atlas (TCGA, n = 672) and the Chinese Glioma Genome Atlas (CGGA, n = 959). Bioinformatic analyses and statistical assessments were performed using established pipelines. Results: Regnase-1 expression was significantly elevated in glioblastoma, IDH-wildtype tumors, and higher tumor grades, correlating with poorer overall survival, and emerging as an independent prognostic factor in the CGGA cohort. High Regnase-1 expression was associated with enrichment of pathways related to angiogenesis, hypoxia, invasion, and immune evasion. Tumors with elevated Regnase-1 showed reduced infiltration of effector immune cells (CD8⁺ T cells, Th1 cells) and increased presence of immunosuppressive populations, including regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages. Single-cell analyses further highlighted exhausted CD8⁺ T cells and regulatory T cells as major populations linked to Regnase-1 expression. Notably, Regnase-1 expression also exhibited strong positive correlations with multiple inhibitory immune checkpoint pathways. Conclusions: Elevated Regnase-1 expression defines an aggressive, immunosuppressive glioma phenotype and is associated with poor prognosis, supporting its potential as a prognostic biomarker and a target for immunomodulatory strategies. Full article

Triple-negative breast cancer is an aggressive and heterogeneous type of invasive breast cancer (BC) in which the cancer cells lack estrogen and progesterone receptors, as well as expression of the human epidermal growth factor 2 protein. This cancer tends to grow and spread faster than other BC subtypes, and is associated with a poor prognosis due to early visceral and neurological recurrences. Multidisciplinary management includes surgery, chemotherapy, radiation therapy, and immunotherapy with targeted immune checkpoint inhibitors (ICIs). The introduction of ICIs has improved outcomes in patients with TNBC, particularly in the metastatic and neoadjuvant settings. Despite these advances, a significant proportion of patients either do not respond to treatment or develop resistance to it. TNBC mortality remains high, underscoring the urgent need to identify novel prognostic and predictive biomarkers to overcome resistance to immunotherapy. Following a brief overview of the clinical features and established biomarkers of TNBC, the current review focuses on immune checkpoint proteins (ICPs) beyond PD-1 and PD-L1, and on the potential use of soluble ICPs rather than the well-established membrane-bound assays. These soluble ICPs are produced through the alternative splicing of messenger (m)RNA or the cleavage/shedding of membrane-bound proteins. This is followed by an overview of current treatment and novel predictive targets in TNBC. Additionally, the involvement of the B- and T-lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/CD160 pathway and its role in the pathogenesis of BC and TNBC are reviewed, highlighting the potential use of BTLA and HVEM as biomarkers. Full article

The interaction between airborne allergens and environmental microplastics is an emerging concern in the context of increasing plastic pollution and allergic disease prevalence. In this study, we investigated the molecular interaction between Cry j 1, the major allergen of Japanese cedar (Cryptomeria japonica) pollen, and polyethylene terephthalate (PET) microplastic surfaces using all-atom molecular dynamics simulations integrated with computational epitope selection analyses. The simulations showed that Cry j 1 adsorbs onto PET primarily through hydrophobic and van der Waals interactions, with residues Pro165, Ala227, Tyr228, and Val163 contributing prominently to surface association. Mapping of selected epitope regions indicated that several linear B-cell epitopes remained solvent exposed following adsorption, whereas two CD4⁺ T-cell epitope regions (T5 and T6) contributed more directly to PET interaction. PET adsorption was accompanied by moderate changes in conformational dynamics, including reduced residue-level flexibility and localized secondary-structure adjustments, while the overall protein fold remained structurally stable throughout the simulation. Small decreases in radius of gyration and solvent-accessible surface area suggested mild adsorption-associated compaction rather than major unfolding. These findings indicate that PET association can influence the structural dynamics and interfacial behavior of Cry j 1 without extensive disruption of its global architecture. Because the study is entirely computational, the immunological implications remain hypothetical and require experimental validation. Nevertheless, this work provides a molecular-level framework for understanding how airborne microplastics may influence allergen behavior and protein-surface interactions in polluted atmospheric environments. Full article

Influenza A virus (IAV) remains a major global health threat despite available vaccines and antiviral agents, while current therapies are limited by drug resistance and safety concerns. Curcuminoids exhibit antiviral and anti-inflammatory activities but are constrained by poor water solubility and low bioavailability. To address these limitations, we investigated the antiviral and immunomodulatory properties of a water-solubilized curcuminoid nanoparticle formulation (C–S/M) in both in vitro and in vivo models of IAV infection. To evaluate the potential antiviral and anti-inflammatory effects of C–S/M, we performed a cytopathic effect (CPE) reduction assay in triplicate at 0.001 MOI and quantitative real-time PCR (qRT-PCR) targeting viral NS1 transcripts in MDCK cells. C–S/M suppressed viral NS1 vRNA levels in MDCK cells at lower curcuminoid-equivalent concentrations than native curcuminoids and attenuated IAV-induced TNF-α, IL-6, and IL-8 production. Furthermore, in vivo antiviral efficacy was evaluated in female C57BL/6 mice intranasally infected with IAV and treated orally with C–S/M. Survival, lung viral loads, pulmonary cytokine levels, and splenic immune cell phenotypes were analyzed. In IAV-infected mice, oral administration of C–S/M modestly improved survival and significantly reduced lung viral burden and pulmonary proinflammatory cytokine levels. In addition, in vivo C–S/M treatment was associated with recovery of virus-suppressed T-cell immune responses, including increased Th1 and activated CD8⁺ T cells, reduced regulatory T-cell expansion, and restoration of multifunctional CD4⁺ and CD8⁺ T cells. These findings suggest that C–S/M exerts antiviral and immunomodulatory effects in experimental IAV infection and may serve as a potential adjunctive candidate for further investigation against influenza-associated inflammation. Full article

Background/Objectives: Gut microbiota dysbiosis is a key driver of inflammatory bowel disease (IBD), and fecal microbiota transplantation (FMT) has emerged as a potential therapeutic strategy. In this study, we investigated the protective effects of toddler-derived FMT against colitis and elucidated the underlying mechanisms. Methods: Firstly, fecal microbiota from healthy toddlers was transplanted into antibiotic-pretreated mice, establishing stable colonization between days 14 and 21 post-transplantation. Results: In a dextran sulfate sodium-induced colitis model, FMT significantly ameliorated colitis symptoms, including reduced disease activity index and restored colon length. Toddler-derived FMT improved the intestinal barrier by preserving goblet cell density and enhancing MUC2 expression. Meanwhile, colonic inflammation was alleviated by FMT, which suppressed pro-inflammatory cytokines, reduced CD4⁺ T cell counts, and associated with downregulation of JAK/STAT-related transcripts. 16S rRNA sequencing revealed that FMT remodeled the gut microbiota by enriching beneficial genera, including Bacteroides, Parabacteroides, Blautia, and Akkermansia, which correlated positively with colon length and negatively with inflammatory markers. Conclusions: These findings provided a theoretical foundation that toddler-derived microbiota represents a potential donor source for FMT in IBD. Full article

Background: Aging profoundly alters host immunity, yet how age-associated immune changes in the liver influence the growth of metastatic tumors remains incompletely understood. Liver metastasis is a major cause of cancer-related mortality, particularly in elderly patients, for whom aggressive treatments are often not feasible. This study aimed to clarify how aging reshapes the hepatic immune microenvironment and to identify age-associated host factors that influence liver metastasis growth. Methods: Tumor-naïve and tumor-bearing young and aged mice were analyzed using a syngeneic MC38 liver metastasis model. Immune cell composition in the liver was assessed by flow cytometry, and gene expression was evaluated by quantitative reverse transcription PCR (RT–qPCR). Public transcriptomic datasets were screened to identify age-associated inflammatory factors. The functional relevance of the S100A8/A9 axis was examined using the small-molecule inhibitor paquinimod. Results: Aging was associated with a distinct baseline immune cell composition in the liver. During liver metastasis, overall growth was comparable between young and aged mice; however, metastatic lesions in aged hosts showed increased expression of multiple inflammation-related genes and prominent accumulation of Ly6G⁺ cells. In silico screening identified S100a9 as one of the most highly upregulated inflammation-related genes in aged livers, which was confirmed in both tumor-naïve and metastatic liver tissues. Pharmacological modulation of the S100A8/A9 axis with paquinimod significantly reduced liver metastasis growth in aged, but not young, mice, and was accompanied by a shift in immune cell composition, including an increased representation of CD8⁺ T cells. Conclusions: These findings indicate that aging is associated with a distinct hepatic immune context that shapes the inflammatory and cellular composition of the tumor microenvironment during liver metastasis. S100A9 emerges as a key age-associated, host-derived factor that is functionally relevant to the growth of liver metastases in aged hosts, supporting the S100A8/A9 axis as a context-specific therapeutic target. Full article

Leishmaniasis caused by Leishmania infantum is a zoonotic disease endemic in many regions worldwide. The antigen-presenting dendritic cells (DCs) bridge the innate and adaptive immune response by activating T lymphocytes. Therefore, the present study examines whether T lymphocyte activation can be directed by autologous DCs primed by extracellular vesicles (EVs) derived from L. infantum. For this, lymphocytes were co-cultured with monocyte-derived DCs (moDCs) that were primed by EVs. moDC signaling and activation were examined by gene expression of toll-like receptors and cytokines. The antigen-presentation ability was analyzed through major histocompatibility complex molecules, and T cell subpopulations were explored by immunophenotyping. In co-cultures, EV-primed moDCs upregulated TLR2, TLR4, and TLR9, along with overexpression of MHC molecules. Co-cultures involving moDCs primed by EVs promoted the upregulation of both pro-inflammatory and regulatory cytokines associated with the expansion of non-conventional regulatory and central memory T cell subsets within the CD8⁺ T cell subpopulation. These findings suggest that activated moDCs can modulate cytotoxic lymphocytes, thereby promoting a balanced inflammatory microenvironment counterbalanced by a concurrent regulatory immune response. Thus, cell-based immune strategies using moDCs loaded with Leishmania-derived EVs represent a potential first step toward the development of innovative and personalized immune prophylactic and therapeutic approaches for leishmaniasis. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long Coronavirus Disease 2019 (long COVID) are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T cell subsets. A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted Analysis of covariance (ANCOVA), correlation network analysis, and principal component analysis (PCA). Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion. In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired C-C chemokine receptor type 7 (CCR7)-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions. These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches. Full article

Background/objective: Approximately 90% of breast cancer-related deaths result from recurrence and metastasis. Emerging evidence indicates that tumor recurrence, invasion, and metastatic spread are strongly influenced by both the tumor microenvironment (TME) and the metastatic niche. M2 macrophages promote immune suppression, inhibit inflammation, and facilitate epithelial-to-mesenchymal transition, invasion, neovascularization, and tumor progression. These phenomena are particularly pronounced in triple-negative breast cancer (TNBC). The objectives of this study were to develop engineered exosomes to selectively deplete CD206+ M2 macrophages from the TME to delay the growth of primary tumors and distal metastasis and enhance overall survival. Methods: Engineered exosomes were developed using our invented platform to selectively target and deplete alternatively activated CD206+ M2 macrophages in primary and metastatic TMEs via antibody-dependent cell-mediated cytotoxicity (ADCC). The engineered exosomes were characterized for size, zeta potential, and successful incorporation of targeting peptides and proteins. Whole-body and tumor-specific biodistribution were assessed. In vitro and in vivo experiments were conducted to evaluate targeting specificity. Toxicity and immunogenicity were examined in immunocompetent animal models. Two treatment paradigms were employed. Results: Engineered exosomes containing M2 macrophage-targeting peptides and Fc-mIgG2b were successfully made, and no significant size difference was observed between the engineered and control exosomes. Both in vitro and in vivo studies confirmed the specificity of the engineered exosomes. Biodistribution studies showed no significant uptake or retention by the resident macrophages in the lung and liver. No significant immune activation, based on cytokine profiling, or organ-specific toxicity was observed in immunocompetent models. Flow cytometry studies using splenocytes showed significant depletion of M2 macrophages following treatments with engineered exosomes; however, no effect on the distribution of T cells was observed. M2-targeting engineered exosomes significantly delayed the post-resection recurrence and metastasis of tumors, and improved animal survival. Conclusions: These findings support the potential of precision exosome-based strategies for enhancing therapeutic outcomes in breast cancer. Full article

Targeted inhibition of the MAPK pathway with BRAF and MEK inhibitors (BRAFi/MEKi) produces rapid tumor regressions in BRAF V600-mutant melanoma, yet most patients ultimately develop acquired resistance. Resistance is not solely a tumor-cell-intrinsic phenomenon; it is accompanied by time-dependent remodeling of the tumor immune microenvironment (TIME) that can shape sensitivity to immune checkpoint inhibitors (ICIs) and inform rational combination or sequencing strategies. Early during MAPK inhibition, melanomas often display increased melanoma antigen expression and enhanced CD8⁺ T-cell infiltration, along with reduced immunosuppressive cytokines, suggesting a transient “immune-permissive” window. However, the same period can show induction of PD-L1 and T-cell exhaustion markers, foreshadowing adaptive immune resistance. At progression, immune-favorable features may diminish and immune evasion mechanisms, such as impaired antigen presentation and MHC-I downregulation, can become prominent and associate with resistance to immunotherapy. Here we review the temporal dynamics of TIME under MAPK inhibition, mechanistic links between resistance programs and immune remodeling, including signaling adaptation, focal adhesion/FAK signaling, dendritic cell dysfunction, antigen-presentation defects, and lymphatic/perilymphatic adipose remodeling, and practical biomarker opportunities across baseline, on-treatment, and progression timepoints. We also summarize emerging therapeutic strategies for post-resistance disease, including optimized ICI combinations, triple therapy concepts, and novel approaches such as combining FAK inhibition with RAF-MEK “clamp” therapy. Finally, we highlight key gaps and propose a framework for longitudinal sampling, standardized multi-omics integration, and TIME-informed trial design. The key distinguishing feature of this review is its time-resolved perspective on TIME remodeling, which links baseline immune contexture, early treatment-induced immune permissiveness, and the immune-evasive state that emerges during acquired resistance. Full article

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that recapitulate tumor architecture, proliferation, angiogenesis, metastasis, and PD-L1 expression. Methods: Tumor specimens from two renal cell carcinoma (RCC) patients were expanded subcutaneously in NOD/SCID mice, transduced with luciferase/red fluorescent protein (Luc/RFP), and orthotopically implanted into mouse kidneys (KiCa-Pt58: sarcomatoid RCC, pT3aN1M1, Fuhrman grade 4; KiCa-Pt118: clear cell RCC with sarcomatoid component, pT3aNxM0, Fuhrman grade 4, respectively). Tumor growth and metastasis were monitored weekly by bioluminescence imaging (BLI). Mice were randomized into vehicle control or four sequential treatment groups (Everolimus→Sunitinib [E→S], Sunitinib→Everolimus [S→E], Pazopanib→Sunitinib [P→S], Pazopanib→Everolimus [P→E]). Drugs were administered orally three times weekly until resistance (>200% BLI increase), with one switch. At necropsy, tumor burden, ex vivo BLI metastasis, weights, H&E histology, and immunohistochemistry (Ki67, CD44, CD31, PD-L1) were assessed. Results: Two independent experiments were performed. In dosing optimization, PDOX tumors recapitulated parental histology and proliferative indices, mirroring patient trajectories. KiCa-Pt58 (metastatic sarcomatoid RCC; deceased 1-month post-nephrectomy) showed aggressive features: rapid engraftment at low doses, early growth (week 2), and lung metastases in 78% of mice (sacrifice day 34), reflecting a fulminant course. KiCa-Pt118 (non-metastatic; patient recurrence-free >8 years post nephrectomy) exhibited indolent behavior: delayed engraftment requiring higher doses plus lymph node stromal (HK) support, slower growth (week 4), no metastases, and later sacrifice (day 78), consistent with remission. In sequential therapy evaluation, for KiCa-Pt58, P→E yielded greatest reductions in tumor weight (p < 0.01), lung metastases (p < 0.01), Ki67+ proliferation, CD31+ angiogenesis, and PD-L1 expression versus control; E→S and S→E were also effective. For KiCa-Pt118, S→E and P→E reduced tumor burden (p < 0.01) and Ki67⁺ proliferation; S→E lowered CD31 and PD-L1. Conclusions: This RCC PDOX platform faithfully preserves patient-specific biology—including metastatic propensity, engraftment efficiency, growth kinetics, and stromal dependency—while enabling real-time evaluation of sequential targeted therapies. Given the limited number of models tested, these findings provide proof-of-concept for individualized treatment exploration in advanced RCC and support future investigation of rational combinations with immune checkpoint blockade in humanized or immunocompetent systems. Full article

Adenosine has emerged as a central metabolic signal linking cellular stress to systemic physiological adaptation. Under conditions such as hypoxia, ischemia, inflammation, and tissue injury, extracellular adenosine triphosphate (eATP) released from stressed cells is sequentially metabolized by the ectonucleotidases CD39 and CD73, generating adenosine that accumulates in the extracellular microenvironment. This stress-responsive nucleoside activates four G-protein-coupled receptors (A1, A2A, A2B, and A3), triggering intracellular signaling networks including the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–protein kinase B (PI3K–Akt), and hypoxia-inducible factor-1 alpha (HIF-1α) pathways. Through these integrated mechanisms, adenosine orchestrates diverse physiological processes such as vascular regulation, metabolic adaptation, immune modulation, and cellular survival. In the cardiovascular system, adenosine promotes coronary vasodilation and ischemic preconditioning, limiting reperfusion injury. In pulmonary tissues, it mediates acute anti-inflammatory responses but may also drive chronic fibrotic remodeling. Within the central nervous system, adenosine functions as a neuromodulator regulating neuronal excitability, sleep–wake homeostasis, and neuroprotection. In the tumor microenvironment, hypoxia-driven adenosine accumulation suppresses cytotoxic T cell and natural killer activity, facilitating immune evasion and tumor progression. Collectively, adenosine signaling represents a central integrative network that links metabolic stress sensing to coordinated cellular adaptation while simultaneously emerging as a clinically actionable therapeutic target across cardiovascular, inflammatory, neurological, and oncological diseases. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease characterized by a multitude of symptoms across various organ systems. Diagnosis has relied heavily on heterogeneous clinical symptom presentation and evolving case definitions, with treatment focused on addressing presenting symptoms due to the paucity of validated biomarkers. Meanwhile, advances have been made in understanding the underlying pathophysiology through strong epidemiologic, clinical, and basic science studies. This narrative review synthesizes recent advances that are likely to drive a shift in understanding from symptom-based classification toward a molecularly defined understanding of the disease. This shift in understanding will likely provide the foundation for future research efforts focused on targeting diagnosis and treatment more effectively. Specifically, we reference the identification of rare genetic risk variants through the HEAL2 deep learning framework, the large-scale DecodeME genome-wide association study, and dynamic epigenetic markers of disease state. In addition, the findings revealed the downstream consequences of this genetic and epigenetic priming: chronic innate immune activation, CD8+ T cell exhaustion characterized by upregulation of the exhaustion-driving transcription factors Thymocyte Selection-Associated HMG Box (TOX) and Eomesodermin (EOMES), and a cellular energy crisis centered on mitochondrial dysfunction. Furthermore, results of recent studies have revealed sex-specific transcriptomic and proteomic signatures of maladaptive recovery. We also highlight the role of machine learning and artificial intelligence integrations in translating high-dimensional multi-omics data into actionable biological insights, including the identification of monocyte subsets via Positive Unlabeled Learning, circulating cell-free RNA diagnostic signatures, and integrated multi-modal disease models such as BioMapAI. The combination of these findings, which highlight multiple identifiable mechanisms of molecular activity, support the feasibility of molecular subtyping, precision diagnostics, and targeted therapeutic strategies for ME/CFS. Full article

Idiopathic pulmonary fibrosis (IPF) and Crohn’s disease (CD) share overlapping immune and fibrotic processes, yet their convergent molecular mechanisms remain poorly defined. Here, we performed an integrative transcriptomic analysis of nine public datasets to identify shared transcriptional signatures across IPF and CD. The main discovery and validation analyses were based on bulk transcriptomic datasets and combined differential expression profiling, weighted gene co-expression network analysis, and machine-learning–based feature prioritization. We identified 28 shared disease-associated module genes, from which three core genes—ZNF395, EEF2K, and BAHD1—were prioritized based on reproducibility and biological consistency. Functional enrichment analysis revealed their involvement in immune regulation, protein homeostasis, and stress-response pathways. Immune deconvolution and supportive single-cell RNA-sequencing further suggested associations between these genes and T-cell and myeloid cell populations, suggesting coordinated immune-fibrotic regulation. Experimental validation in a repetitive bleomycin challenge model and TGF-β1-stimulated fibroblasts showed consistent downregulation of these genes during fibrotic remodeling, supporting their association with fibrosis-related transcriptional states. Collectively, our study identifies conserved immune–fibrotic transcriptional programs shared across intestinal inflammation and pulmonary fibrosis, providing a hypothesis-generating molecular framework for understanding extraintestinal pulmonary involvement in Crohn’s disease and prioritizing candidate genes for future mechanistic investigation. Full article

Esophageal squamous cell carcinoma (ESCC) progression involves dynamic cellular state transitions and tumor microenvironment remodeling, accompanied by extensive transcriptional regulation reprogramming. Here, we systematically mapped the TF-mediated regulatory landscape underlying ESCC progression at single-cell resolution by integrating stage-specific ESCC single-cell transcriptomic datasets comprising over 200,000 cells with TF–target interaction networks. Using a random walk algorithm combined with hypergeometric testing, we identified malignant progression-associated TFs (mpTFs) across multiple cell types and disease stages. Our analysis revealed extensive stage-dependent regulatory remodeling during ESCC progression. TCF4 was identified as an early-stage regulator associated with epithelial–mesenchymal transition activation and malignant invasive phenotypes. In immune lineages, BATF and IRF4 exhibited trajectory-associated activation during CD4⁺ T-cell differentiation and CD8⁺ T-cell exhaustion, suggesting critical roles in immunosuppressive T-cell state transitions. Additionally, mpTF-mediated remodeling of M2 macrophage subpopulations contributed to immunosuppressive tumor microenvironment formation during advanced ESCC progression. We further identified prognosis-associated cell-type-specific and shared mpTFs, including TFAP2C, which was associated with stabilized fibroblast and monocyte functional states and a less aggressive tumor microenvironment phenotype. Collectively, this study provides a comprehensive single-cell atlas of TF-mediated regulatory programs during ESCC progression and offers potential therapeutic targets for precision oncology. Full article