Search Results (584)

Non-coding RNA (ncRNA) encompasses a large family of molecules that are crucial regulators of gene expression. This family includes microRNA, piwi-interacting RNA, and long non-coding RNA (lncRNA); each class is associated with different mechanisms of action that influence gene expression. Based on the available evidence, these molecules have important roles in physiological and pathological processes. For example, ncRNAs are strongly implicated in oncogenesis by mediating the expression of tumour suppressors and oncogenes. This review comprehensively describes the latest findings regarding the roles of lncRNAs in the pathophysiology of melanoma. Key aspects of melanoma biology and various mechanisms regulated by lncRNAs are discussed. Furthermore, future areas exploring potential biomarkers and therapeutic targets are presented. Full article

Background/Objectives: The delta neutrophil index (DNI)—a hematology analyzer-derived measure of circulating immature granulocytes—may assist pre-biopsy decision-making, yet its behavior across tumor types is incompletely defined. We examined whether pre-biopsy DNI differs by pathology category, tumor class, and definitive histology, and evaluated diagnostic performance. Methods: In this retrospective, single-center cohort, consecutive inpatients with malignancy were screened (n = 2009). Exclusions included positive blood cultures, prior chemotherapy/radiotherapy before index labs, and lack of definitive pathology, yielding 1313 analyzable cases. All laboratories, including DNI, were obtained before diagnostic biopsy. DNI was assessed as a continuous variable and categorized (Zero = 0; High > 0.6). Groupwise differences used Kruskal–Wallis and χ² tests with FDR control; discrimination used ROC analyses (one-versus-rest/pairwise). Results: DNI distributions differed across pathology, tumor class, and definitive diagnoses (all p < 0.001). High DNI (>0.6) and Zero DNI (=0) proportions also varied significantly by grouping. Hematologic malignancies showed the highest DNI (median ~1.0) compared with sarcoma and carcinoma (medians ~0.4). Using DNI alone, one-versus-rest AUCs were 0.735 (hematologic), 0.692 (melanoma), 0.672 (sarcoma), and 0.652 (carcinoma); the strongest pairwise separation was hematologic versus sarcoma (AUC 0.780). For specific solid tumors, including breast and renal cell carcinoma, single-marker discrimination was modest; no clinically actionable RCC cutoff emerged. Sensitivity analyses restricted to culture-negative cases yielded consistent findings. Conclusions: Pre-biopsy DNI exhibits tumor-type-dependent variation and provides adjunct diagnostic signal—the strongest for hematologic malignancy—yet is insufficient alone for solid tumor subtyping. Integration with clinical assessment and routine biomarkers, and multi-center validation with device harmonization are warranted. Full article

High-grade gliomas—particularly glioblastoma (GBM)—remain refractory to standard-of-care surgery followed by chemoradiation, with a median overall survival of ~15 months. Oncolytic viruses (OVs), which selectively infect and lyse tumor cells while engaging antitumor immunity, offer a mechanistically distinct therapeutic modality. This review synthesizes clinical progress of OVs in GBM, with emphasis on oncolytic herpes simplex virus (oHSV) and coverage of other vectors (adenovirus, reovirus, Newcastle disease virus, vaccinia virus) across phase I–III trials, focusing on efficacy and safety. Key observations include the encouraging clinical trajectory of oHSV exemplars—T-VEC (approved for melanoma) and G47Δ (approved in Japan for recurrent GBM)—the multi-center exploration of the adenovirus DNX-2401 combined with programmed death-1 (PD-1) blockade, and the early-stage status of reovirus (pelareorep) and Newcastle disease virus programs. Emerging evidence indicates that oHSV therapy augments immune infiltration within the tumor microenvironment and alleviates immunosuppression, with synergy when combined with chemotherapy or immune checkpoint inhibitors. Persistent challenges include GBM’s inherently immunosuppressive milieu, limitations imposed by the blood–brain barrier, intrapatient viral delivery and biodistribution, and concerns about viral shedding. Future directions encompass programmable vector design, optimization of systemic delivery, biomarker-guided patient selection, and rational combination immunotherapy. Collectively, OVs represent a promising immunotherapeutic strategy in GBM; further gains will hinge on vector engineering and precision combinations to translate mechanistic promise into durable clinical benefit. Full article

Cancer cell plasticity drives metastasis and therapy resistance through dynamic transitions between epithelial, mesenchymal, and neural crest stem-like (NCSC) states; however, a unifying mechanism that stabilizes these transitions remains undefined. To address this gap, we introduce a N-cadherin (CDH2)-centered redox–adhesion–exosome (RAX) hub that links oxidative signaling, adhesion dynamics, and exosome-mediated immune communication into a closed-loop framework. Within this network, reactive oxygen species (ROS) pulses license epithelial–mesenchymal transition (EMT), AXL–FAK/Src signaling consolidates mesenchymal adhesion, and selective exosomal cargoes—including miR-21, miR-200, miR-210, and PD-L1—propagate plasticity and immune evasion. Lipid peroxidation acts as a central checkpoint connecting ROS metabolism to PUFA membrane remodeling and ferroptosis vulnerability, buffered by NRF2–GPX4 and FSP1/DHODH axes, thereby converting transient oxidative pulses into persistent malignant states. Mechanistically, the RAX hub synthesizes findings from EMT/CSC biology, ferroptosis defenses, and exosome research into a self-reinforcing system that sustains tumor heterogeneity and stress resilience. Evidence from single-cell and spatial transcriptomics, intravital ROS imaging, and exosome cargo-selector studies supports the feasibility of this model. We further outline validation strategies employing HyPer–EMT–CDH2 tri-reporters, CRISPR perturbation of YBX1/ALIX cargo selectors, and spatial multi-omics in EMT-high tumors. Clinically, tumors enriched in EMT/NCSC programs—such as melanoma, neuroblastoma, small-cell lung cancer, pancreatic ductal adenocarcinoma, and triple-negative breast cancer (TNBC)—represent RAX-dependent contexts. These insights highlight biomarker-guided opportunities to target adhesion switches, ferroptosis defenses, and exosome biogenesis through lipid peroxidation-centered strategies using liquid-biopsy panels (exosomal CDH2, miR-200, miR-210) combined with organoid and xenograft models. By linking lipid peroxidation to ferroptosis defense and oxidative stress adaptation, the RAX hub aligns with the thematic focus of lipid metabolism and redox control in cancer progression. Collectively, the RAX framework may provide a conceptual basis for precision oncology by reframing metastasis and therapy resistance as emergent network properties. Full article

Background/Objectives: Immunotherapy and targeted therapy have revolutionized the treatment of advanced cutaneous melanoma. However, predicting individual response and managing resistance remain major challenges. This narrative review aims to evaluate the prognostic and predictive value of treatment-related adverse events (TRAEs) and circulating biomarkers—including lactate dehydrogenase (LDH), circulating tumor DNA (ctDNA), and microRNAs (miRNAs)—in anticipating therapeutic outcomes and personalizing treatment strategies. Methods: A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science for studies published between January 2010 and September 2025. Eligible studies included clinical trials, observational cohorts, and translational research evaluating biomarkers or toxicity profiles in melanoma patients receiving immune checkpoint inhibitors or BRAF/MEK inhibitors. Emphasis was placed on dynamic indicators of treatment efficacy and integrative modeling approaches. Results: Evidence indicates that the emergence of low-to-moderate grade TRAEs—especially immune-related events like vitiligo, thyroiditis, and rash—is positively associated with response to immunotherapy. Similarly, pyrexia and dermatologic toxicities may correlate with outcomes under BRAF/MEK inhibition. ctDNA clearance within 6–12 weeks of therapy strongly predicts durable response and precedes radiologic changes. Specific miRNAs (e.g., miR-21-5p, miR-146a-5p) demonstrate dynamic modulation during treatment and may signal response or resistance. Interferon-driven gene expression profiles further stratify tumors into “hot” or “cold” immune phenotypes, refining predictive accuracy. Conclusions: Integrative models combining TRAEs, ctDNA, miRNA signatures, and interferon-related gene expression offer a multi-dimensional framework for early, individualized response monitoring. Prospective validation, harmonization of assays, and incorporation into adaptive clinical workflows are key to translating these insights into personalized melanoma care. Full article

Background: Tumor immunogenicity is a concept for modeling the susceptibility of tumors to immune checkpoint inhibitors (ICIs) and other immunotherapies. Single biomarkers, such as tumor mutation burden (TMB) or PDL1 expression, have been shown to correlate with ICI outcomes but are poor predictors of overall and progression-free survival (OS, PFS). Complex machine learning models that integrate multiple biomarkers have shown improved predictions but often lack clear a priori interpretability. In this study, we developed a coherent Multi-Omics Tumor Immunogenicity score (MOTIscore) that combines immunogenicity biomarkers derived from genomic and transcriptomic data and demonstrated its generalizability across multiple cancer types. Methods: Several immunogenicity biomarkers, including TMB, neoantigen burden, T-cell receptor repertoire, PDL1 expression, B2M expression, and variants in pathways of ICI response and resistance, were integrated using a weighted sum scoring scheme. The weights were determined using statistical tests in a large melanoma ICI cohort. We compared the MOTIscore with a machine learning (ML) model trained using the same biomarkers and evaluated the model using melanoma, gastric cancer, and pan-cancer datasets. Results: MOTIscore achieved results similar to those of the ML model in predicting ICI in melanoma and gastric cancer, with both outperforming TMB. Gastric cancer and melanoma patients with high MOTIscores had a significantly extended overall and progression-free survival. Gene set enrichment analysis revealed the enrichment of immune-related pathways in patients with high MOTIscores. Differential expression analysis between patients with high and low immunogenicity identified highly expressed C-X-C motif chemokine ligands as important characteristics associated with successful ICI therapy and significantly improved PFS. MOTIscores varied widely across cancers treated in the molecular tumor board at our hospital and showed distinct distributions between non-immunogenic and immunogenic cancer types. Conclusions: MOTIscore demonstrated improved ICI outcome predictions compared to single-omics biomarkers. Patients with higher tumor immunogenicity also show significantly improved OS and PFS in melanoma and gastric cancer. The results demonstrate the potential use of the MOTIscore to prioritize ICI in personalized cancer treatment. However, ICI outcomes and survival should be investigated in prospective studies, and additional cancer types and larger patient cohorts are needed. Full article

Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 have significantly improved outcomes in patients with advanced melanoma. However, the optimal treatment duration remains undefined. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for treatment response monitoring and surveillance and can predict long-term clinical outcomes. Methods: Clinical and ctDNA data from prospectively enrolled patients with stage IV melanoma treated with anti–PD-1-based therapy at a single academic center were retrospectively analyzed. Of the 56 patients eligible, 28 underwent serial ctDNA testing during ICI treatment and follow-up (median 31 months) using a personalized, tumor-informed assay. Landmark analysis at 6 and 9 months was performed to assess progression-free survival (PFS) based on ctDNA status. Multivariable Cox regression was used to identify independent predictors of long-term outcomes. Results: Pre-ICI treatment, 91.7% (11/12) of evaluable patients were ctDNA-positive. At 6 months, ctDNA negativity or clearance was observed in 47.4% (9/19), and was strongly associated with improved PFS in the landmark analysis (HR: 10.0, p = 0.03; 2-year PFS: 89% in ctDNA-negative versus 30% in ctDNA-positive groups). At 9 months, persistent ctDNA positivity trended toward worse PFS. Multivariate analysis confirmed ctDNA status at the 6-month landmark timepoint to be an independent predictor of long-term benefit. Conclusions: Tumor-informed ctDNA testing is a robust, non-invasive tool to predict long-term benefit from anti–PD-1-based therapy in advanced melanoma. ctDNA clearance or sustained negativity at 6 months may serve as a surrogate for durable response and could inform individualized treatment discontinuation strategies, and minimize toxicity and cost while maintaining efficacy. These findings, derived from a limited single-center cohort, warrant further exploration and validation in larger studies. Full article

Background/Objectives: Retinoblastoma (RB) and uveal melanoma (UM) remain vision-threatening and lethal ocular malignancies with limited molecular markers of differentiation state and prognosis. We investigated whether proteins governing endocytosis and signaling, including Megalin (LRP2), Cubilin (CUBN), Caveolin-1, GAIP-interacting protein C-terminus 1 (GIPC1), and Disabled homolog 2-interacting protein (DAB2IP), exhibit subtype-specific expression patterns in ocular tumors and whether these patterns are related to transcriptomic profiles and survival. Methods: Formalin-fixed, paraffin-embedded human ocular tissues included controls (n = 10), retinoblastoma (n = 10), and UM subtypes (epithelioid, spindle, mixoid; total n = 30). Immunofluorescence for LRP2, CUBN, CAV1, GIPC1, and DAB2IP was quantified using ImageJ (version 1.54g) across standardized high-power fields; per-specimen means were used for statistical analysis (Shapiro–Wilk test; one-way ANOVA with Tukey’s post hoc test). Public data analyses comprised: (i) overall survival in TCGA-UVM using GEPIA2; (ii) differential expression in GEO datasets (GSE62075: melanocytes vs. UM cell lines; GSE208143: retinoblastoma vs. pediatric control retina) and (iii) multivariate Cox proportional hazards regression analysis using the GEPIA3 online platform. Results: LRP2 expression was uniformly reduced across retinoblastoma and all UM subtypes versus control. CUBN expression decreased in retinoblastoma and epithelioid melanoma, was retained in spindle melanoma, and increased in mixoid-cell melanoma. CAV1 expression was increased in epithelioid melanoma but reduced in retinoblastoma, mixoid, and spindle melanomas. GIPC1 and DAB2IP expression were preserved in epithelioid melanoma yet significantly reduced in retinoblastoma and mixoid/spindle melanomas. In TCGA-UVM, higher CAV1 and GIPC1 mRNA expression was associated with worse overall survival (p ≈ 0.025 and 0.036), whereas LRP2, CUBN, and DAB2IP expression were not significant. GEO analyses revealed no significant differences for the five genes in UM cell lines versus melanocytes (GSE62075). However, in retinoblastoma (GSE208143), LRP2 was downregulated, while CUBN, CAV1, GIPC1, and DAB2IP were upregulated. Conclusions: Endocytic/signaling proteins exhibit distinct, subtype-linked expression in ocular tumors. Integration with public datasets highlights CAV1 and GIPC1 as adverse survival correlates in UM and positions LRP2/CUBN/DAB2IP dysregulation as features of ocular tumor biology, nominating candidate biomarkers and mechanistic targets. Full article

Cutaneous melanoma remains one of the most aggressive tumors, yet the role innate immunity plays in its progression remains poorly understood. Effector elements with high regulatory potential, capable of both promoting and inhibiting tumor growth—mast cells (MCs), are of particular interest. This includes quantitatively characterizing the interactions between tryptase-positive mast cells (MCs) with atypical Melanin—A⁺ cells and describing their spatial phenotype, in relation to the stage of cutaneous melanoma. A retrospective analysis was carried out on samples retrieved from 128 patients with cutaneous melanoma (AJCC 8th edition: IA–IIID). Histological analysis, histochemistry (toluidine blue, Giemsa), and diplex /multiplex IHC for tryptase and Melan-A were performed; as well as Fluorescence imaging, 3D reconstructions and quantitative mapping in QuPath v 0.6.0. Proximity was assessed by the nucleus-to-nucleus distance: <10 μm (contact), 10–20 μm (paracrine zone), >20 μm (out of interaction). The relative amount of MCs in the intratumoral zone was lower than in the intact dermis, with a simultaneous increase in their absolute density per mm² in the melanoma microenvironment, maximum in the peritumoral area and most pronounced at stage II. Three types of interactions were identified: (i) juxtaposition without secretion, (ii) degranulation of MCs directed to tumor cells, (iii) melanosecretion of Melanin—A⁺ cells directed towards MCs, followed by phagocytosis of melanocores. An inverse intratumoral connection between the number of MCs and the number of Melanin—A⁺ cells was noted; MCs with elongated forms, extensive contacts and polarized tryptase secretion, including granule localization near/at the nuclei of adjacent cells, were frequently observed. The obtained data indicate stage-region-dependent bidirectional cross-talk between melanin and MCs, forming tissue spatial signals, potentially useful as biomarkers and targets for personalized therapy. Full article

Background: Retinoid-binding proteins (RBPs) regulate retinoid metabolism and signaling, but their roles across human cancers remain incompletely defined. Methods: We conducted a comprehensive analysis using bioinformatics tools and experimental validations, examining RBP expression profiles across cancer types based on data from The Cancer Genome Atlas (TCGA). We employed survival analysis using the Kaplan–Meier method and utilized single-cell RNA sequencing (scRNA-seq) to investigate the roles of RBP4 and RBP7 in the tumor microenvironment. Results: Our analysis revealed significant downregulation of RBPs in multiple cancers, with RBP4 and RBP7 showing notable expression variations linked to tumor stages and grades. Cox analysis identified RBP4 as a protective gene in kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), and mesothelioma (MESO), while RBP7 exhibited protective effects in breast cancer (BRCA) and uveal melanoma (UVM). Conclusions: This pan-cancer and single-cell integrative analysis highlights the complex roles of RBPs in cancer progression and their potential as prognostic biomarkers, particularly RBP4 and RBP7 in breast cancer. These findings warrant further investigation into the functional mechanisms of RBPs, which may provide valuable strategies for therapeutic interventions. Full article

Annexin A1 (ANXA1), a calcium-dependent phospholipid-binding protein, is considered a key modulator of cancer biology. Numerous pieces of evidence support its multifaceted involvement in tumor progression, metastatic dissemination, immune escape, and resistance to therapy in various malignancies, such as melanoma, along with liver, lung, and digestive tract tumors, including stomach and colorectal cancer (CRC). Although colon and rectal cancer (RC) exhibit overlapping characteristics, they are classified as separate clinical entities due to differences in tumor biology and therapy approaches. Moreover, locally advanced rectal cancer (LARC) raises clinical challenges due to variable treatment responses and its therapy resistance, preventing successful treatment and patients’ recovery. Considering ANXA1’s involvement in chemoresistance, further investigation is currently focused on ANXA1-targeted therapies. This review aims to update the knowledge on ANXA1, as a CRC predictive and prognostic biomarker, with involvement in therapy resistance, highlighting its significance in LARC patients. Through emerging evidence, our research provides valuable insights into the potential of ANXA1’s clinical utility and its prospective value as a target in chemoresistance approaches. Full article

The gut microbiome is an established predictor of response to immune checkpoint inhibitors (ICI) in melanoma, and antibiotic exposure prior to ICI initiation is a validated negative prognostic factor. About half of melanoma patients harbor BRAF mutations and are treated with BRAF/MEK inhibitors (BRAFi/MEKi). While the detrimental impact of antibiotics is well described in the ICI setting, their effect on BRAFi/MEKi efficacy remains unknown. We retrospectively analyzed 49 advanced BRAF-mutant melanoma patients treated with BRAFi/MEKi. Antibiotic-exposed patients were compared with non-exposed patients across three time windows: within 30, 60, or 90 days before and after therapy initiation. Outcomes included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Among the cohort, 41% had antibiotic exposure within ±30 days, 53% within ±60 days, and 57% within ±90 days. Baseline characteristics were comparable between groups, except for worse ECOG scores in antibiotic-exposed patients. Across all windows, ORR, PFS, and OS were comparable between groups. Unlike what was observed in the ICI setting, antibiotic use did not negatively affect outcomes with BRAFi/MEKi. Despite small sample size, these findings suggest that the detrimental prognostic impact of antibiotics is specific to immunotherapy, highlighting the importance of evaluating the microbiome as a predictive biomarker across treatment contexts. Full article

Artificial intelligence (AI) has emerged as a transformative tool in histopathology, offering new opportunities to enhance prognostic accuracy and guide immunotherapy in cutaneous melanoma. The prognostic significance of tumor-infiltrating lymphocytes (TILs) is well established, yet their manual assessment remains subjective, labor-intensive, and often confined to selected tissue regions. Recent AI-based approaches enabled automated and reproducible quantification of TIL density and spatial immune profiling across whole-slide images, providing a more comprehensive view of the tumor immune microenvironment. In melanoma, these methods have demonstrated the potential to predict response to immune checkpoint blockade, with spatially resolved TIL profiling emerging as a particularly powerful prognostic and predictive biomarker. This review summarizes recent advances in AI-driven histopathologic analysis of cutaneous melanoma, focusing on automated TIL quantification and spatial immune profiling, and highlights how these innovations refine prognostic evaluation and improve the prediction of immunotherapy outcomes. Full article

Background: N6-methyladenosine (m6A) modification plays a crucial role in tumor biology; however, the function of the methyltransferase adaptor WTAP in melanoma remains poorly understood. Methods: We analyzed WTAP expression and its clinical relevance using TCGA-SKCM and GTEx datasets, followed by immunohistochemical validation in melanoma tissues. The biological effects of WTAP were assessed through gain- and loss-of-function experiments in melanoma cell lines. Weighted gene co-expression network analysis (WGCNA) and LASSO regression were used to identify key WTAP-related genes. Results: WTAP expression was significantly decreased in melanoma compared with normal skin and was negatively correlated with tumor progression and poor survival. Functionally, WTAP overexpression suppressed melanoma cell proliferation and migration, whereas its knockdown produced the opposite effects. Bioinformatic analyses and rescue experiments identified KLF9 as a potential downstream effector of WTAP. WTAP depletion reduced KLF9 mRNA and protein levels, while overexpression restored them. Moreover, MeRIP-qPCR confirmed that WTAP promotes m6A enrichment on KLF9 mRNA, suggesting a post-transcriptional regulatory mechanism. Conclusions: Our findings reveal a novel WTAP–KLF9 axis that mediates melanoma suppression through m6A-dependent regulation. This study provides new insight into the context-specific role of WTAP in melanoma and suggests it may serve as a potential biomarker or therapeutic target. Full article

Targeted therapies, including treatment with inhibitors of BRAF^V600 and MEK kinases, have improved outcomes in advanced melanoma. However, most patients relapse due to acquired resistance, underscoring the need for new drug targets. This study evaluated PRI-724, a CBP/β-catenin inhibitor, in patient-derived drug-naïve melanoma cells and their trametinib- or vemurafenib-resistant counterparts. While PRI-724 has demonstrated efficacy in preclinical models and clinical trials in different cancer types, its potential in melanoma has not been previously assessed. We found that treatment with PRI-724 downregulated survivin and other CBP/β-catenin target proteins, reduced invasiveness, and induced apoptosis in drug-naïve and trametinib- and vemurafenib-resistant cells. Trametinib-resistant melanoma cells showed the greatest sensitivity to PRI-724, indicating that CBP/β-catenin transcriptional activity may represent a new therapeutic vulnerability. Transcriptomic and immunoblotting analyses revealed the highest survivin levels in vemurafenib-resistant cells, which may underlie their reduced responsiveness to PRI-724. Bioinformatic analyses (TCGA and GSE50509) confirmed that a high survivin level predicts poor prognosis and reduced response to treatment. The results of the study point to the potential of PRI-724 as a chemotherapeutic agent for the treatment of melanoma. Its efficacy might depend on CBP/β-catenin transcriptional activity in melanoma cells, and further evaluation of this signaling with survivin as a biomarker is therefore warranted. Full article