Search Results (3,054)

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Human ccRCCs have increased glycolytic metabolism and decreased mitochondrial oxidative metabolism relative to normal kidneys. Our research using human RCC4 ccRCC cells and a murine model of ccRCC, TRACK (TRAnsgenic model/Cancer/Kidney), in which a triple-mutant (P402A, P564A, N803A) human HIF1α is selectively expressed in proximal tubule cells (PTCs), revealed highly induced ATF4, a stress-responsive transcription factor. We then investigated the role of ATF4 in the metabolic changes in ccRCC. Methods: We performed comprehensive analysis of the ccRCC Cancer Genomics Atlas (TCGA) data. We deleted ATF4 in PTCs of TRACK mice and human RCC4 cells. We conducted genome-wide transcriptomic and untargeted metabolomic studies of cortices of WT and CGERA∆T (TRACK mice with PTC-specific ATF4-knockout (KO)) mice and performed glucose isotopologue tracing in parental and ATF4 KO RCC4 cells. Results: Analysis of TCGA data showed increased mRNAs of enzymes in glycolysis and reduced mRNAs of enzymes in the TCA cycle. Transcriptomic and metabolomic studies demonstrated that ATF4 deletion suppressed glycolysis and enhanced TCA cycle metabolism in CGERA∆T versus WT cortices. Glucose isotopologue tracing showed that ATF4 deletion altered glycolysis pathway metabolite levels and shifted glucose metabolism towards the TCA cycle, evidenced by increased intracellular [¹³C₂]citrate in RCC4-ATF4 KO cells. Using the Seahorse XFe96 analyzer we also showed reduced glycolytic capacity and reserve in RCC4-ATF4 KO cells. Conclusions: Collectively, our results demonstrate that ATF4 regulates glycolysis in ccRCC, supporting ATF4 as a therapeutic target. Full article

Background: Heterogeneous data integration remains a major challenge in intelligent information systems, particularly under missing-modality and cross-domain conditions. Existing multimodal fusion approaches often rely on complete datasets and weak alignment mechanisms, limiting their robustness and practical applicability. Objectives: This study aims to develop and evaluate a genomics-guided multimodal representation learning framework that enables robust heterogeneous data fusion, reliable cross-modal correspondence, and accurate prediction under incomplete-data conditions. Methods: We propose a multimodal learning architecture that models genomics as the primary biological anchor and learns conditional projections to imaging modalities, including multiparametric MRI and whole-slide histopathology (WSI). The framework formulates multimodal fusion as a genomics-guided contrastive learning problem, incorporates domain-specific optimization constraints, and learns a latent shared-state representation to support inference without requiring fully paired datasets. Evaluation was conducted using public datasets, including TCGA-PRAD and TCIA, across low-risk versus higher-risk/clinically significant prostate cancer (csPCa) discrimination, Gleason-based risk stratification, and clinically significant outcome prediction tasks under realistic multimodal and missing-modality scenarios. Results: In the adequately powered $\mathrm{G}\mathrm{e}\mathrm{n}\mathrm{o}\mathrm{m}\mathrm{i}\mathrm{c}\mathrm{s}+\mathrm{W}\mathrm{S}\mathrm{I}$ cohort (n = 486), the framework achieved an AUROC of 0.985 ± 0.005 for low-risk versus higher-risk/csPCa discrimination (p < 0.001). Exploratory analysis in a small, matched $\mathrm{G}\mathrm{e}\mathrm{n}\mathrm{o}\mathrm{m}\mathrm{i}\mathrm{c}\mathrm{s}+\mathrm{M}\mathrm{R}\mathrm{I}$ cohort (n = 28) yielded an AUROC of 0.980 ± 0.006 for the same endpoint; these findings are reported descriptively with bootstrap confidence intervals due to limited sample size. Because the negative reference group consisted of low-risk prostate cancer cases rather than cancer-free controls, results are interpreted as within-cancer risk discrimination rather than de novo cancer detection. The framework achieved weighted accuracy up to 92.1%, Cohen’s κ up to 0.86, and reduced critical decision errors by 58%. Calibration remained strong (ECE 0.021–0.024), and decision-curve analysis indicated improved utility with reduced unnecessary invasive workups in retrospective modeling. Robustness analysis demonstrated AUROC degradation below 0.04 under domain shifts. Single-modality inference using genomics alone maintained AUROC > 0.90. Interpretability analysis revealed feature attributions aligned with domain-relevant genomic markers. Conclusions: The proposed framework provides a scalable and generalizable solution for heterogeneous multimodal data fusion, supporting reliable prediction, robustness to missing modalities, and applicability to complex information systems beyond the studied domain. Full article

Background: The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that integrates inputs on nutrient status, energy levels, and growth factor stimulation to accordingly regulate cell growth and metabolism. It does this by activating or repressing target proteins covering a broad array of cellular processes. mTOR nucleates two structurally and functionally distinct protein complexes, mTORC1 and mTORC2. Because of their wide-ranging effects in the cell, both mTOR complexes are presumed to have a large number of targets. However, only a relatively small number have been conclusively identified. Methods: With emphasis on mammalian mTOR, we previously reviewed the extensive mTOR literature (1991–2021) and compiled a list of all reported substrates of mTORC1 and mTORC2. We have updated this list for the period 2022–2025. Results/Conclusions: Many of the targets are involved in autophagy, underscoring the major role of mTOR in the regulation of this process. From the perspective of this Special Issue, targets linked to cancer may be responsible for executing an mTOR-driven pro-oncogenic program and merit future study. Full article

Conventional chondrosarcoma (CS), the second most common primary bone malignancy, presents a significant therapeutic challenge due to high levels of resistance to chemotherapy and radiotherapy. Current treatment is limited to surgical resection, which is often incomplete due to tumor involvement of critical structures. Recent molecular profiling studies have highlighted frequent Isocitrate Dehydrogenase 1 (IDH1) and Isocitrate Dehydrogenase 2 (IDH2) mutations, along with AXL phosphorylation and AXL-associated pathway activity, as candidate molecular features in CS. However, their functional roles may vary by subtype and require context-specific interpretation. IDH1/2 mutations are thought to contribute to CS tumorigenesis through metabolic and epigenetic mechanisms, including D-2-hydroxyglutarate (D-2-HG) accumulation, altered differentiation programs, and epigenetic dysregulation, although direct mechanistic evidence in CS remains less complete than in other IDH-mutant malignancies. Concurrently, AXL, which has been implicated in epithelial-to-mesenchymal transition (EMT), immune evasion, and therapeutic resistance, is emerging as a candidate signaling node in CS biology. Potential convergence between IDH1/2-associated metabolic or epigenetic states and AXL-associated signaling remains hypothesis-generating and requires CS-specific validation. This review synthesizes current evidence on the roles of IDH1/2 mutations and dysregulation of AXL signaling in CS, emphasizing their potential contributions to tumor aggressiveness, immune suppression, and resistance to therapy. Additionally, we explore current developments in targeted therapy exploiting IDH1/2 and AXL dysregulation. Full article

Chronic myeloid leukemia (CML) represents a paradigm of targeted therapy, driven by the BCR::ABL1 fusion kinase. Over the past four decades, therapeutic strategies have evolved from early molecular targeting approaches and interferon-α to tyrosine kinase inhibitors (TKIs), dramatically improving survival and transforming CML into a largely controllable disease. To provide a comprehensive overview of this evolution, we conducted a narrative literature search across the PubMed and Embase databases, selecting peer-reviewed articles, international guidelines, and landmark clinical trials based on their historical and clinical relevance. Through this expert-driven synthesis, focusing on key milestones in CML therapy, including antisense strategies, interferon-based treatment, first-, second-, and third-generation TKIs, and the development of allosteric inhibitors, this paper analyzes current management strategies, treatment-free remission (TFR), and emerging therapies. The introduction of imatinib established proof of principle for oncogene-targeted therapy, leading to sustained survival improvements. Second- and third-generation TKIs further enhanced response depth and addressed resistance, including the T315I mutation. More recently, the development of the allosteric inhibitor asciminib introduced a novel mechanism of action and expanded therapeutic options for pretreated patients. Furthermore, the achievement of deep molecular responses has enabled TFR in approximately 40–60% of selected patients, redefining treatment goals toward functional cure. Emerging agents, including next-generation ATP-competitive and allosteric inhibitors, are showing promising activity in resistant disease and may further improve outcomes. Thus, CML represents a unique model of translational oncology, demonstrating how mechanistic insight can drive therapeutic innovation. Future strategies will focus on increasing TFR rates, overcoming resistance, targeting leukemic stem cells, and improving global access to therapy and monitoring, with the ultimate aim of achieving functional cure in the majority of patients. Full article

Background/Objectives: Chlamydia trachomatis (CT) is a prevalent sexually transmitted pathogen associated with pelvic inflammatory disease, infertility, and has been proposed as a potential contributor to carcinogenesis through chronic inflammation and tissue remodeling. The molecular mechanisms triggered by CT infection in fallopian tube cellular contexts and their relevance to ovarian cancer transcriptomes remain incompletely understood. Methods: We analyzed GSE109428, profiling primary human fallopian tube mesenchymal cells infected with CT, to identify differentially expressed genes and characterize affected pathways using g:Profiler and STRING protein–protein association networks (confidence ≥ 0.7). To provide translational context, we computed ssGSEA scores in TCGA-OV for four signatures capturing IFN/ISG, TNF/NF-κB, NOD/innate immunity, and ECM programs, and evaluated inter-signature correlations and exploratory associations with overall survival (OS) and progression-free interval (PFI). Results: CT infection induced sustained inflammatory and interferon-associated transcriptional programs, with STRING networks highlighting cytokine hubs and a densely connected ISG module. Genes downregulated at 48 h post-infection (48-hpi) showed coherent enrichment for ECM organization and adhesion pathways. In TCGA-OV (n = 307), inflammatory and innate immune signatures co-occurred across tumors, with moderate correlations between TNF/NF-κB and NOD/innate (ρ = 0.591) and IFN/ISG and NOD/innate (ρ = 0.534). Exploratory survival analyses showed no significant associations with OS or PFI in Kaplan–Meier analyses or multivariable Cox models, including clinically adjusted and tumor microenvironment-adjusted specifications. Conclusions: CT infection induces sustained inflammatory and interferon-linked programs and coordinated repression of ECM networks in fallopian tube mesenchymal cells. Analogous immune transcriptional states co-occur in ovarian tumors, though the signatures evaluated did not yield robust prognostic signals in TCGA-OV. As this is an entirely in silico study without experimental validation, these findings should be treated as hypothesis-generating; thus, further mechanistic and experimental studies are warranted to clarify how CT infection-associated pathways may intersect with female tumorigenesis. Full article

Background/Objectives: Uveal melanoma is the most common primary ocular cancer in adults. Patients with metastatic uveal melanoma (mUM) have limited treatment options and poor prognosis. mUM is characterized by high oxidative phosphorylation (OXPHOS), which may be a therapeutic vulnerability for this disease. ONC206 is an imipridone compound that can inhibit OXPHOS indirectly and is currently being evaluated in clinical trials. Thus, we tested the effects of ONC206 on human uveal melanoma cell lines and patient-derived xenografts (PDXs) in vitro and in vivo. Methods: The effects of ONC206 on cell survival, apoptosis, autophagy, oncogenic signaling pathways, and metabolic networks were assessed in vitro using human melanoma cell lines. ONC206 was then tested for safety and anti-tumor activity in vivo using two mUM PDX models. Results: ONC206 treatment produced dose-dependent inhibition of mUM cell growth in vitro, with induction of varying levels of apoptosis and autophagy. ONC206 treatment also downregulated OXPHOS effector proteins and metabolites, thereby impairing mitochondrial OXPHOS. Treatment with ONC206 significantly reduced tumor burden and improved survival in two UM PDX mouse models in vivo. Conclusions: Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM. Full article

Background: Dysregulated G protein-coupled receptor (GPCR) signaling is increasingly implicated as an important driver for oncogenesis. Uveal melanoma (UM) represents a highly metastatic intraocular malignancy primarily driven by activating mutations in G protein family members Gαq/11. Although Tebentafusp, the first FDA-approved bi-specific T-cell engager for UM, improves survival, its activity is restricted to specific human leukocyte antigen (HLA) alleles, highlighting the need to identify broadly expressed targetable proteins for immunotherapeutic strategies. Here we aimed to define surfaceome and phospho-signaling signatures associated with oncogenic Gαq-signaling. Methods: Heterologous and UM in vitro systems were used to interrogate Gαq-driven changes. HEK293T cells were transfected with wild-type Gαq or the oncogenic Gαq (R183Q) mutant, with surface marker profiles quantified by flow cytometry. Complementary immunophenotyping was performed in the Gαq-mutant UM cell line MP46 and Gα11-mutant line MP41. Kinase phosphorylation was assessed in control and Gαq mutant conditions followed by effect size estimation (Hedges’ g), Welch’s t-test, principal component analysis, and Spearman correlation-based network analysis of surface and phosphoprotein readouts. Results: Hyperactive Gαq in HEK293T cells induced graded remodeling of surface protein profiles, including reduced CD56 (NCAM) and CD49c (ITGA3) expression. Similarly, in UM models, MP46 versus MP41 had limited expression of CD56 and CD49c. Moreover, phospho kinase profiling and network analysis identified altered surface-phosphoprotein relationships, including a CD56-p70 S6 kinase association. Conclusions: These data provide new insights into Gαq-driven modulators of UM phenotype of relevance for studies of tumor–microenvironment interaction and metastasis. Full article

Background: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Although the lipid metabolism-associated gene PTGDS has been implicated in tumorigenesis, its functional significance and regulatory mechanisms in LUAD are poorly understood. Methods: We integrated multi-omics data from TCGA and GEO cohorts to evaluate PTGDS expression and its clinicopathological relevance. Functional characterization was performed using gain-of-function models in LUAD cell lines and a xenograft mouse model, assessing proliferation, migration, invasion, and immune microenvironment alterations. Results: PTGDS expression is markedly reduced in LUAD tissues and correlates strongly with advanced disease stage and unfavorable prognosis. Clinically, low PTGDS expression is associated with specific driver mutations and reduced tumor mutation burden. Notably, PTGDS levels correlate with enhanced cytotoxic T-cell infiltration and suppressed M2 macrophage polarization, suggesting immunomodulatory functions. Ectopic expression of PTGDS significantly suppressed malignant behaviors in vitro and tumor growth in vivo. Mechanistically, PTGDS overexpression was associated with reduced expression of CDK1 and PLK1 and increased expression of p21 and p27. Conclusions: Our findings establish PTGDS as a novel tumor suppressor in LUAD that restrains tumor progression through cell cycle modulation and immune microenvironment remodeling, highlighting its potential as both a prognostic biomarker and a therapeutic target. Full article

Background/Objectives: Adoptive transfer of allogeneic natural killer (NK) cells represents a promising off-the-shelf immunotherapy for cancer, offering advantages in safety and availability over autologous T cell therapies. However, generating therapeutically sufficient NK cell numbers remains challenging due to their low frequency in blood sources. Engineered feeder cell co-cultures have enabled substantial expansions of NK cells to clinically relevant doses. Methods: We evaluated the plasma cell leukemia-derived ARH-77 cell line as a feeder for ex vivo NK cell expansion from healthy donor peripheral blood mononuclear cells (PBMCs). Unmodified ARH-77 was compared to K562, followed by engineering both lines to co-express B7-H6 (NKp30 ligand), CD137L (4-1BBL), IL-15, and IL-15Rα via sequential lentiviral transduction. PBMCs were co-cultured with irradiated feeders in cytokine-supplemented (IL-2, IL-21, and later IL-15) RPMI-1640 or DMEM/F-12 medium for up to 28 days. Expansion (fold change in CD3⁻CD56⁺ cells), purity, surface receptor expression, and cytotoxicity (against K562 targets) were quantified. Results: Unmodified ARH-77 supported significantly greater NK cell expansion than K562 (model-estimated 681-fold vs. 155-fold at week 4 in RPMI; p = 0.0018), with higher purity but comparable cytotoxicity and receptor profiles. Engineered ARH-77 cells achieved robust expansion in RPMI, comparable to that of engineered K562 cells. In optimized DMEM/F-12 medium, engineered ARH-77 drove superior expansion (up to model-estimated 101,241-fold; 95% CI 46,771–219,146 at week 4), significantly outperforming engineered K562 (4.4-fold greater; 95% CI 1.01 to 18.54; p = 0.0479) while maintaining high purity and equivalent cytotoxicity. Substantial inter-donor variability influenced expansion magnitude, though relative feeder performance remained consistent across donors. Conclusions: Genetically modified ARH-77 feeder cells provide a potent platform for large-scale ex vivo expansion of functional NK cells. Full article

Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a “versatile player” in oncology. It exerts a dual, context-dependent role in cancer, acting as both a potent tumor suppressor and a facilitator of tumor progression and therapeutic resistance. This review systematically delineates the core molecular regulatory networks of ferroptosis, highlighting the intricate balance between its execution mechanisms—driven by polyunsaturated fatty acid (PUFA) oxidation, iron catalysis, and mitochondrial dysfunction—and the robust endogenous defense systems, including the GSH-GPX4, FSP1/DHODH-CoQ10, and GCH1-BH4 axes. We deeply explore the dichotomous nature of ferroptosis in tumorigenesis: while classical tumor suppressors like p53 and CDKN2A harness ferroptosis to halt tumor growth, cancer cells can hijack lipid metabolic reprogramming and specific enzymes (e.g., iPLA2β) to evade cell death and promote distant metastasis. Furthermore, we dissect the multidimensional crosstalk between ferroptosis and the tumor microenvironment (TME), emphasizing its bidirectional immunoregulatory effects. Although CD8+ T cell-derived IFN-γ can sensitize tumor cells to ferroptosis and amplify anti-tumor immunity, aberrant ferroptotic activation can paradoxically foster an immunosuppressive niche. Finally, we summarize the latest translational strategies using small-molecule inducers and synergistic combination therapies, emphasizing that biomarker-guided patient stratification remains the ultimate paradigm for overcoming resistance and realizing precision ferroptosis-targeted cancer therapy. Full article

Background: Post-remission cytarabine consolidation is a cornerstone of therapy for acute myeloid leukemia (AML), but the optimal dosing strategy in older adults (≥60 years) remains unclear. High-dose cytarabine (HiDAC) is often avoided due to toxicity concerns, and data guiding cumulative dosing are limited. Methods: We conducted a single-center retrospective cohort study of 111 patients aged ≥60 years with AML who achieved complete remission after standard 7 + 3 induction and received at least one cycle of cytarabine consolidation between 2012 and 2024. A 90-day landmark analysis excluded early relapses or deaths. Results: The median age was 65 years; 41% proceeded to allogeneic hematopoietic stem cell transplantation (allo-SCT). Cytarabine consolidation was well tolerated, with no neurotoxicity and only one instance of reversible nephrotoxicity. Patients were stratified by median cumulative cytarabine dose into low-intensity (<18 g/m², LIC) and high-intensity (≥18 g/m², HIC) groups. HIC was associated with improved overall survival compared with LIC (median OS: 31 vs. 13 months, p = 0.02), particularly among non-transplanted patients (25 vs. 7 months, p = 0.01). On multivariable analysis, HIC (HR 0.71, 95% CI 0.51–0.82, p = 0.01) and allo-SCT (HR 0.58, 95% CI 0.44–0.79, p = 0.03) independently predicted superior survival. Conclusions: Higher cumulative cytarabine consolidation is safe, feasible, and associated with improved survival in older AML patients, especially among patients ineligible for transplant. Prospective studies are warranted to define the optimal dosing strategy in this population. Full article

Background: Sphingolipids are essential structural and signaling lipids that support membrane integrity and govern cell fate decisions. While the consequences of chronic sphingolipid inhibition have been extensively explored, the immediate cellular responses to acute suppression of sphingolipid synthesis remain poorly defined. Methods: We analyzed subcellular proteomic changes following an acute reduction in sphingolipid levels induced by myriocin, an inhibitor of de novo sphingolipid synthesis. We then evaluated the cytotoxicity of co-treatment with myriocin and inhibitors of the altered pathways in cancer cells. Results: We found that de novo sphingolipid synthesis is sensitive to myriocin, an inhibitor of serine palmitoyltransferase (SPT), and can be efficiently inhibited within 4 h of treatment. Cells respond to reduced sphingolipid levels by rapidly remodeling their proteome. Mass spectrometry analysis revealed changes in the abundance of hundreds of proteins across the membrane, cytosolic, and nuclear fractions. Gene set enrichment analysis revealed alterations in the proteome across several pathways involved in protein and lipid homeostasis and stress responses, including upregulation of cholesterol homeostasis and lysosome. Co-treatment with myriocin and cholesterol synthesis or lysosomal function inhibitors synergistically reduced cancer cell viability by promoting apoptosis rather than other forms of programmed cell death. Conclusions: Together, our work provides insights into how cells rapidly rewire the abundance of certain protein classes in response to reduced sphingolipid levels and identifies signaling and metabolic pathways that can be exploited for therapeutic intervention. Full article

Background/Objectives: Mammary serine protease inhibitor (maspin) was originally identified as a tumor suppressor gene, as loss of its expression in breast cancer cell lines promotes invasiveness and tumorigenicity. In contrast, normal pancreatic ductal epithelium does not express the maspin protein, and its expression frequency increases as pancreatic intraepithelial neoplasia (PanIN) progresses to pancreatic ductal adenocarcinoma (PDAC). We have previously reported that cytoplasmic-only localization of maspin (cytMaspin) is an independent indicator of poor prognosis in patients with PDAC. However, the functional role of maspin in PDAC remains unclear. Methods: We investigated the subcellular localization and biological function of maspin in PDAC cell lines using Western blotting, immunofluorescence, RNA-seq, wound-healing assays, and invasion assays. Results: Endogenous maspin was detected in most PDAC cell lines, and RNA-seq was performed in S2-007 (panMaspin; nuclear and cytoplasmic localization of maspin) and S2-028 (cytMaspin), which were derived from the same parental cell line (SUIT-2). The invasive capability of S2-028 cells (cytMaspin) was higher than that of S2-007 cells (panMaspin), showing upregulation of the ErbB family and axon-guidance pathways. Furthermore, maspin overexpression in PANC-1 and S2-020 cells resulted in panMaspin and cytMaspin, respectively. PANC-1 cells overexpressing maspin showed decreased invasive capability via suppression of HER2 expression and Akt activation. Conclusions: Although maspin expression has generally been considered an unfavorable prognostic indicator in patients with PDAC, our findings suggest that its biological effects may differ depending on its subcellular localization. Specifically, nuclear localization is linked to less aggressive phenotypes, whereas cytoplasmic localization is associated with more malignant behavior. Full article

Classic Hodgkin lymphoma (cHL) has traditionally been conceptualized as a malignancy confined to lymphoid tissues, with disease extent defined primarily by anatomical staging systems. While this framework has guided clinical management for decades, it incompletely captures the biological complexity of cHL. Emerging evidence from molecular, immunological, and translational studies supports a reinterpretation of cHL as a systemic immunobiological disease rather than a purely nodal malignancy. A defining feature of cHL is the rarity of malignant Hodgkin and Reed–Sternberg (HRS) cells, which orchestrate a highly structured tumor microenvironment through constitutive activation of signaling pathways, including NF-κB and JAK/STAT, and through expression of immune checkpoint ligands. Beyond local effects, HRS cells secrete cytokines, chemokines, and extracellular vesicles that enter the systemic circulation, promoting widespread immune reprogramming. This includes T-cell exhaustion, expansion of regulatory T cells, and activation of immunosuppressive myeloid populations, which collectively shape host immunity beyond the lymph node. Circulating tumor DNA (ctDNA) and soluble mediators such as thymus and activation-regulated chemokine (TARC/CCL17) provide measurable evidence of systemic disease activity and enable dynamic monitoring of tumor burden. These biological insights help explain key clinical features of cHL, including constitutional (“B”) symptoms, extranodal involvement, and heterogeneous patterns of treatment response and resistance. Importantly, integration of ctDNA kinetics, peripheral immune profiling, and functional imaging offers a multidimensional framework for disease assessment that overcomes the limitations of conventional staging systems. Therapeutically, the efficacy of immune checkpoint inhibitors underscores the central role of systemic immune dysregulation, while emerging biomarker-driven strategies support adaptive and personalized approaches to treatment. Collectively, these findings support a paradigm shift toward understanding cHL as a systemic immunobiological disease. This framework has important implications for disease monitoring, therapeutic decision-making, and future research, paving the way for biology-driven, precision medicine approaches in cHL. Full article