Search Results (1,786)

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Background: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and are associated with substantial molecular and immunological heterogeneity. However, the clinicopathological associations and prognostic relevance of KRAS mutation subtypes and co-occurring genomic alterations in relation to PD-L1 expression and survival outcomes remain incompletely understood, particularly in the immunotherapy era. Methods: This retrospective single-center study included 93 KRAS-mutant NSCLC patients identified among 543 consecutively sequenced cases between March 2024 and March 2025. KRAS mutation subtypes, co-mutations involving TP53, STK11, and KEAP1, PD-L1 expression status, clinicopathological features, and survival outcomes were evaluated. Overall survival was assessed using Kaplan–Meier analysis and Cox proportional hazards regression models. Results: KRAS mutations were detected in 17.1% of NSCLC patients. G12C was the most frequent KRAS subtype (38.7%), followed by G12V (18.3%) and G12D (14.0%). Co-occurring mutations were identified in 73.1% of cases, most commonly involving TP53 (40.9%) and STK11 (33.3%). PD-L1 expression was negative in 48.4% of patients, low in 28.0%, and high in 23.7%. No significant association was identified between KRAS mutation subtype and PD-L1 expression (p = 0.663). STK11-mutated tumors demonstrated a trend toward lower PD-L1 expression levels compared with STK11 wild-type tumors. However, none of the molecular variables retained independent prognostic significance. Immunotherapy was associated with significantly prolonged overall survival (median OS: 24 vs. 7 months, p = 0.013) and remained independently associated with improved survival in multivariate analysis (HR: 0.376, 95% CI: 0.204–0.694, p = 0.002). Advanced-stage disease independently predicted worse survival outcomes (HR: 13.43, 95% CI: 1.81–99.79, p = 0.011). Conclusions: KRAS mutation subtypes and co-occurring genomic alterations demonstrated limited independent prognostic significance in this real-world NSCLC cohort. In contrast, immunotherapy was associated with improved overall survival in this retrospective cohort. These findings should be interpreted as observational and hypothesis-generating rather than evidence of predictive treatment benefit. Larger prospective studies integrating genomic and immune biomarkers are warranted. Full article

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma endemic in children in regions of sub-Saharan Africa, where its incidence geographically overlaps holoendemic Plasmodium falciparum malaria and poorly controlled childhood Epstein–Barr virus (EBV) infection. Despite decades of research, the precise mechanistic synergy between these two pathogens remains incompletely defined. This review synthesizes current epidemiological, immunological, and molecular evidence to propose an integrated model for the etiology of endemic BL. We outline a paradoxical, dual-edged relationship wherein EBV infection during infancy may provide a short-term child survival advantage against severe malaria while simultaneously increasing the long-term oncogenic risk in B-cells infected by EBV. P. falciparum infection triggers polyclonal B-cell activation, increasing the probability of an activation-induced cytidine deaminase (AID)-mediated c-MYC translocation in proportion to the recurrent parasite burden. Concurrently, EBV expands within this B-cell pool and modulates the host immune response, potentially through viral interleukin-10 (vIL-10), to prevent lethal malarial inflammation. At the cellular level, EBV provides a critical “second hit” when it establishes latency I infection that rescues c-MYC-translocated B-cells from apoptosis. This framework explains why BL manifests as a “tumor of malaria survivors,” peaking in incidence years after the highest-risk period for malaria mortality. Ultimately, this model underscores that malaria control is a critical form of cancer control and highlights key future directions for validating these pathways in prospective clinical studies. Full article

Vertigo, dizziness, and oculomotor disturbances may occur as manifestations of immune-mediated disorders affecting the inner ear, central vestibular pathways, or multisystem autoimmune disease. Although uncommon, these conditions are clinically important because delayed recognition may lead to irreversible hearing loss, vestibular dysfunction, or neurological disability. This review summarizes the clinical presentation, diagnostic approach, and treatment of immune-mediated vestibular and oculomotor disorders. We suggest a practical classification into isolated immune-mediated inner ear disease, systemic autoimmune disorders with audio-vestibular involvement, and autoimmune disorders of the central or peripheral nervous system affecting balance and eye movements. Red flags for such conditions include bilateral or progressive symptoms, fluctuating audio-vestibular deficits, associated neurological signs, and accompanied autoimmune disease. Corticosteroids remain the main first-line treatment in many of these disorders, mainly due to missing data from controlled trials. Steroid-sparing immunosuppressants, biologics, and tumor-directed therapies are effective in many cases; however, because of the missing data, they are only used in selected entities without any other choice. A structured neuro-otological and immunological workup is essential to improve diagnostic accuracy and enable timely therapy. Full article

The intratumoral microbiota has emerged as a critical component of the tumor microenvironment (TME), with accumulating evidence indicating that its biological functions are influenced not only by microbial composition but also by their spatial organization within tumor tissues. This review summarizes the historical development and potential origins of intratumoral microbiota, and elaborates on the concept and biological significance of spatial heterogeneity. Based on recurrent spatial distribution patterns reported across different tumor types, we propose a conceptual framework comprising several putative spatial niches, including hypoxic/necrotic, immune-enriched, stromal-associated, invasive/metastatic, and intracellular niches. We further discuss the potential mechanisms contributing to the establishment and maintenance of spatial heterogeneity. The clinical significance of spatial microbial signatures is critically evaluated, alongside a comprehensive overview of spatial analytical methodologies, ranging from in situ hybridization and immunology-based approaches to emerging spatial omics and multi-omics integration strategies. Finally, we address key challenges and limitations, including contamination control, causal inference, barriers to clinical translation, and the underexplored spatial dimensions of the intratumoral mycobiome and virome. By synthesizing current knowledge and identifying critical gaps, this review aims to provide a conceptual and methodological framework for advancing spatially resolved investigations of intratumoral microbiota and facilitating their potential translational applications in precision oncology. Full article

For decades, peritoneal metastases (PM) have been regarded as a terminal manifestation of advanced malignancies and managed primarily with palliative intent because of limited sensitivity to systemic therapies. Accumulating clinical, molecular, and immunological evidence now supports the view that PM is not merely an anatomic pattern of spread but a distinct metastatic niche with characteristic biological, microenvironmental, and therapeutic features. This review summarizes the major routes of PM development—transcoelomic, lymphatic, and hematologic dissemination—and emphasizes how these pathways converge through shared biological programs. Core mechanisms include epithelial–mesenchymal transition (EMT), adhesion signaling, extracellular matrix remodeling, and tumor–immune cell interactions. A central focus is the peritoneal tumor microenvironment: mesothelial-to-mesenchymal transition, cancer-associated fibroblast activity, adipocyte-derived metabolic support, macrophage polarization, and regulatory T-cell enrichment collectively shape an immunotolerant and treatment-resistant niche on the peritoneal surface. In addition, evidence from pre-metastatic niche biology suggests that primary tumor-derived exosomes and epitranscriptomic regulation can prime the peritoneal environment before overt implantation. These features provide a biological rationale for locoregional strategies such as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, as well as emerging intraperitoneal modalities and microenvironment-targeted approaches. Finally, organoid platforms, liquid biopsy-based minimal residual disease monitoring, and theranostic technologies may enable more personalized, biology-driven management of PM. Full article

Cholangiocarcinoma (CCA) is a highly malignant tumor originating from the epithelium of the bile ducts. It has an insidious onset, is difficult to diagnose in its early stages, has a low rate of curative resection, and carries an extremely poor prognosis. Among these, intrahepatic cholangiocarcinoma (iCCA), as the most representative subtype, is a classic “immunologically cold tumor.” The response rate to single-agent immunotherapy is only 5–10%, and the mechanisms of immune resistance are complex and not yet fully elucidated. The tumor microenvironment, serving as the core site of immune resistance, forms a highly immunosuppressive network composed of cancer-associated fibroblasts, hypoxia, metabolic reprogramming, and epigenetic abnormalities; a population of immunosuppressive cells centered on tumor-associated macrophages further amplifies tolerance signals; and the gut–biliary microbiome exerts systemic immune regulation via the gut–liver axis. Based on mutant mouse models generated via tail vein injection and in-depth studies of mutations in key signaling pathways, our understanding of the mechanisms underlying iCCA’s immune resistance is deepening at both the molecular and systems levels. This article reviews the local and systemic regulatory mechanisms of immune resistance in primary iCCA, summarizes the research value of experimental and preclinical models, and reviews novel strategies such as tumor microenvironment remodeling, activation of immune cell networks, microbiome interventions, and multidimensional combination therapies. It analyzes current research bottlenecks and clinical challenges and outlines the future direction of precision immunotherapy, aiming to provide a theoretical basis and new insights for overcoming iCCA immunotherapy resistance and advancing clinical translation. Full article

The tumor microbiome has been implicated in pancreatic ductal adenocarcinoma (PDAC)’s poor response to treatment, demanding new methods for understanding host-microbe interactions in therapy. Traditional 2D systems, while widely used, fail to adequately recapitulate human PDAC due to insufficient representation of structural, immunological and stromal components. Differences in cancer-specific microbiomes, microbe-immune interactions, and the unique physiological and immunosuppressive features unique to PDAC have hindered the clinical translation of immune therapies. Reproducible 3D culture systems that integrate the human microbe-tumor-immune (MTI) axis represent a promising avenue for treatment research, yet they remain underexplored in PDAC. In this narrative review, we discuss the key microbial determinants of therapy resistance, explore the current 3D multicellular modeling approaches in other cancer types, and provide a path forward for similar integrative translational models in PDAC. Full article

Radiotherapy (RT) has traditionally been considered a local treatment modality; however, accumulating evidence suggests that it can induce systemic antitumor responses outside the irradiated field. The classical abscopal effect, defined as the regression of non-irradiated tumor lesions following localized RT, has gained renewed attention in the era of immune checkpoint inhibitors (ICIs). Preclinical and clinical studies have demonstrated that RT can promote immunogenic cell death, antigen presentation, cytokine release, and adaptive immune activation, processes that may contribute to systemic antitumor immunity, particularly when combined with ICIs. Clinically apparent abscopal responses remain rare and heterogeneous, and the biological mechanisms underlying these phenomena are not completely understood. Systemic tumor regression has occasionally been observed in clinical settings that do not involve checkpoint blockade, including RT alone, chemotherapy-containing regimens, and central nervous system-directed therapies. These findings suggest that radiation-associated systemic antitumor responses may arise through overlapping immunologic mechanisms involving both innate and adaptive immunity, tumor microenvironment remodeling, and treatment-associated cellular stress. This review summarizes the current clinical evidence and biological mechanisms underlying radiation-associated systemic antitumor responses and discusses emerging concepts extending beyond the conventional RT–immunotherapy paradigm. We further examined unresolved challenges, including treatment heterogeneity, biomarker limitations, pseudoprogression, and difficulties in mechanistic confirmation. Finally, we propose that the broader “beyond-abscopal” framework may serve as a hypothesis-generating conceptual model for investigating systemic tumor responses across diverse treatment contexts while emphasizing the need for cautious interpretation and prospective translational validation. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains among the most therapeutically intractable malignancies, with a 5-year survival rate of approximately 10% and near-universal resistance to immune checkpoint inhibitor (ICI) therapy. This refractoriness arises from the convergence of pronounced intratumoral heterogeneity (ITH) and a profoundly immunosuppressive tumor microenvironment (TME), which together configure PDAC as a prototypical immune-excluded tumor. Beyond low tumor mutational burden, PDAC exhibits layered genetic, epigenetic, transcriptional, and metabolic heterogeneity that enables rapid adaptation and immune evasion under selective pressure, while dense desmoplastic stroma, cancer-associated fibroblasts (CAFs), and immunosuppressive immune populations collectively impose formidable physical and immunologic barriers to antitumor immunity. In this review, we synthesize multi-omics, spatial transcriptomic, and immunologic evidence to elucidate how ITH and the TME dynamically interact to reinforce immune resistance. We examine reciprocal crosstalk mechanisms—including immune-driven clonal selection, interclonal cooperation, metabolic niche specialization, and metabolic–epigenetic coupling—and discuss emerging platforms such as single-cell spatial omics, patient-derived organoid immune co-culture systems, and longitudinal circulating tumor DNA monitoring that enable high-resolution mapping of ITH–TME dynamics. Finally, we evaluate ITH–TME-guided combination therapeutic strategies targeting oncogenic drivers, stromal architecture, myeloid suppression, and metabolic checkpoints, and propose a prioritized framework for near-term and speculative clinical translation in PDAC. Full article

Theranostics is a novel approach that integrates diagnostic and therapeutic efficacy on a single platform, holding great promise for precision medicine by enabling real-time monitoring of disease progression and therapeutic response. Despite significant advances, the successful development and delivery of theranostic systems are critically limited by multiple biological barriers present at systemic, tissue, cellular, anatomical, and immunological levels. These barriers restrict bioavailability, target accessibility, and therapeutic efficacy, while often increasing off-target accumulation and adverse effects. This review provides a comprehensive overview of the major biological barriers encountered in theranostic development, including physiological barriers such as plasma protein binding, renal clearance, and hepatic metabolism; anatomical barriers like endothelial linings, the blood–brain barrier (BBB), and the tumor microenvironment; cellular barriers involving membrane permeability, intracellular trafficking, and endo-lysosomal entrapment; and immunological barriers such as immune recognition, inflammatory responses, and complement activation. Special emphasis is placed on the BBB, highlighting its structural complexity, transport mechanisms, and strategies such as molecular Trojan-horse technology, receptor-mediated and adsorptive-mediated transcytosis, and nanocarrier-based approaches to enhance central nervous system delivery. The review further discusses targeted delivery challenges, including receptor heterogeneity and multidrug resistance, and critically evaluates current strategies to overcome these barriers through surface functionalization, stimuli-responsive systems, biomimetic carriers, and controlled-release mechanisms. Finally, recent advances, clinical challenges, and future perspectives—including personalized theranostics, artificial intelligence—assisted design, and next-generation barrier-penetrating systems—are explored. Overall, this review aims to provide a structured understanding of biological barriers in theranostics and highlight innovative approaches to improve their translational potential. Full article

Immunotherapy has transformed cancer treatment; however, clinical benefit remains limited to a subset of patients, underscoring the need for robust biomarkers that capture tumor-immune interactions across cancer types. In this study, we performed a comprehensive pan-cancer, multi-omics characterization of the immune checkpoint–related molecules CD70, CD80, and TIGIT to evaluate their diagnostic, prognostic, and immunological relevance. Using integrative analyses of transcriptomic, epigenomic, genomic, pharmacogenomic, and single-cell RNA-sequencing data from The Cancer Genome Atlas and complementary resources, we assessed expression patterns, DNA methylation, somatic mutations, copy number alterations, immune infiltration, tumor stemness, and drug sensitivity. CD70, CD80, and TIGIT were broadly dysregulated across multiple malignancies, with coordinated overexpression particularly evident in kidney renal clear-cell carcinoma. Elevated expression of these immune checkpoints was associated with advanced tumor stage, aggressive molecular subtypes, and unfavorable survival outcomes in selected cancers, including uveal melanoma and renal malignancies. Functional analyses revealed significant associations between checkpoint expression and key oncogenic pathways, including epithelial–mesenchymal transition, apoptosis, and hormone receptor signaling, suggesting links with tumor progression and immune activation states. Immune deconvolution analyses indicated that TIGIT expression is associated with a T-cell–inflamed microenvironment and reduced neutrophil infiltration, while CD80 exhibited methylation-dependent associations with immune cell composition. Genomic and epigenetic alterations were found to correlate with checkpoint expression patterns and immune phenotypes across tumor types. Pharmacogenomic profiling identified associations between checkpoint expression and sensitivity to multiple anticancer agents; however, these findings are based on cell line datasets and should be considered predictive. Single-cell transcriptomic analyses further resolved cell-type–specific expression patterns, distinguishing tumor-intrinsic from immune-restricted expression profiles. Collectively, our findings establish CD70, CD80, and TIGIT as integrative biomarkers of tumor progression, immune contexture, and therapeutic response, providing a rationale for their clinical exploitation in precision immuno-oncology. Full article

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article

Background: The tumor immune microenvironment, particularly the role of cytotoxic CD8+ T lymphocytes, is crucial in cancer progression but remains poorly understood in pituitary neuroendocrine tumors (PitNETs). The significance of CD8+ cell infiltration varies across PitNET subtypes, suggesting a complex interplay with tumor cell lineage. This study aimed to characterize the distribution of CD8+ tumor-infiltrating lymphocytes across different PitNET subtypes defined by the current WHO classification and to explore their association with clinicopathological features. Methods: We conducted a retrospective study on 40 surgically resected PitNETs. All cases were classified based on immunohistochemical expression of pituitary hormones and lineage-specific transcription factors (PIT-1, TPIT, SF-1). CD8+ lymphocyte density was quantified using immunohistochemistry and calculated as cells/mm². Exploratory statistical analysis was performed based on non-parametric tests to compare CD8+ cell density across tumor subtypes and with parameters like tumor size, invasiveness (Knosp grade), and proliferation index (Ki-67). Findings are to be treated as observational trends. Results: The highest density of CD8+ lymphocytes was observed in plurihormonal PIT-1-positive tumors [17.61 cells/mm² (IQR: 17.61–60.36)], followed by somatotroph [13.2 (6.6–15.72)] and mammosomatotroph [13.83 (0–21.38)] tumors. A difference in CD8+ density was found between PIT-1-positive and PIT-1-negative tumors (n1 = 34, n2 = 6, U = 49.5, p_exact = 0.050, r = 0.33); the medium effect size indicates a possible lineage-related trend. Another difference was observed between SF-1-positive and SF-1-negative tumors (p = 0.025), with SF-1 lineage tumors showing the lowest infiltration. No correlations were found between CD8+ density and tumor size, Knosp grade, or Ki-67 index. Conclusions: The distribution of intratumoral CD8+ T lymphocytes in PitNETs is highly heterogeneous and appears to be strongly dictated by the transcription factor-defined tumor lineage rather than by traditional clinicopathological markers of aggressiveness. PIT-1 lineage tumors harbor a more active immune microenvironment, while SF-1 lineage tumors are relatively ‘immune-poor’. These findings highlight the immunological diversity of PitNETs and support further investigation of the tumor immune landscape. Collaborative multi-institutional studies are required to validate these trends. Full article

Background: Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 mutations, leading to elastic fiber disarray and early thoracic aortic aneurysm (TAA) formation. Currently, pharmacological treatments lack specificity and only delay progression. We previously reported a specific TGFβ-driven miR-632 upregulation in MFS TAA tissues and blood causing smooth muscle cell dedifferentiation and aortic wall degeneration. This study evaluated the effects of three conventional antihypertensive drugs (β-blocker, ACE inhibitor, and sartan) on parietal remodeling, comparing them with a miR-632 inhibitor in an ex vivo TGFβ1-induced model of MFS TAA. Methods and Results: Using an ex vivo paired experimental framework based on independent biological pools of human TAA tissue, gene expression and Western blot analyses demonstrated that only losartan significantly reduced miR-632 and vascular degeneration markers. Notably, combined treatment with ramipril and carvedilol compromised losartan’s efficacy, highlighting the need for careful therapeutic selection. In this ex vivo setting, miR-632 inhibition demonstrated a promising capacity to counteract aortic remodeling, serving as a mechanistic proof-of-concept that warrants further preclinical in vivo validation. Conclusions: Our data emphasize that choosing the right treatment in MFS aortopathy requires understanding its specific impact on cellular pathways. Our findings identify losartan as the most effective standard drug in this model, while suggesting miR-632 as a potential future target to stabilize the aortic wall and, prospectively, delay surgery. Full article