Exosomes are small extracellular vesicles that mediate intercellular communication and, in cancer, carry cargo that both reflects the donor tumor cell and influences recipient cells within local and distant microenvironments. Exosomal proteins and microRNAs have been reported individually across many cancer types, but rarely compared on a common basis; in this review, previously reported molecules from eight cancer categories-blood, breast, colon, kidney, liver, lung, prostate, and stomach-were compiled from curated repositories and re-analyzed within a single functional framework. In total, 3643 exosomal proteins (523 hematologic, 3120 solid-tumor) and 627,225 miRNA-target pairs, derived from 350 unique microRNAs, were organized using Gene Ontology, KEGG, and PANTHER annotation. Across cancers, proteins converged on a reproducible core-signaling, transport, cytoskeletal organization, and extracellular interaction-dominated by binding, catalytic, and transporter functions localized to membrane, vesicle, and extracellular compartments. Comparisons between hematologic and solid malignancies revealed both shared cancer-associated functions and context-dependent patterns linked to tissue origin and disease ecology. Together, these findings indicate that integrated protein-and-microRNA profiling offers a useful framework for understanding tumor communication, refining cancer classification, and advancing biomarker discovery, while underscoring that harmonized workflows, independent validation, and mechanistic follow-up remain necessary before descriptive enrichment outputs can support clinically robust applications.

This work reports the synthesis, characterization and in vitro evaluation of three organometallic triorganotin(IV) complexes bearing a dicarbamido-bis-organosilane benzoate ligand as potential anticancer agents against colorectal cancer cells. The complexes, Sn(IV)-biSi-1, Sn(IV)-biSi-2 and Sn(IV)-biSi-3, differ in the alkyl groups directly bound to the Sn(IV) center (methyl, n-propyl and isopropyl, respectively). Their structures were confirmed by 1H, 13C and 119Sn NMR spectroscopy, FTIR and ESI-MS, supporting monodentate carboxylate coordination and a solvent-dependent Sn(IV) coordination environment. Biological assays in HCT116 cells showed that the final bis-organosilane complexes were markedly more active than their aminobenzoate intermediates and, under several conditions, more effective than cisplatin. Sn(IV)-biSi-2 and Sn(IV)-biSi-3 reduced cell viability to approximately 30% at 0.5 μM after 5 days and to about 11% and 7%, respectively, at 12.5 μM. In repeated-treatment assays, these complexes maintained antiproliferative activity more efficiently than cisplatin, limiting resistance-like cell recovery. Western blot analysis revealed increased γ-H2AX, p53, cleaved caspase-3 and cleaved PARP, indicating DNA damage-associated apoptotic signaling. Overall, these results identify bis-organosilane triorganotin(IV) benzoates, especially Sn(IV)-biSi-2 and Sn(IV)-biSi-3, as promising metal-based anticancer candidates that sustain antiproliferative activity after repeated exposure in colorectal cancer cells and may contribute to strategies aimed at therapy-resistant colorectal tumors.

The primary aim of this review is to summarize current evidence from clinical and pre-clinical studies on endogenous molecular biomarkers associated with radiosensitivity and radioresistance in cervical cancer, including patients treated with photon-based radiotherapy, cervical cancer cell lines, and xenograft models, and to evaluate the association of these biomarkers with radiotherapy response, residual disease, recurrence and survival, and experimental measures of radiosensitivity. A systematic literature review was conducted for studies published over the last 10 years that evaluated associations between genomic, epigenetic, or protein biomarkers and radiotherapy response or survival outcomes in cervical cancer. Eligible studies included in the current analysis summarize clinical, translational, and pre-clinical studies in correlation with photon-based radiotherapy. Research focusing exclusively on non-coding RNAs, exogenous radiosensitizers, or non-photon modalities was excluded. In total, 112 studies were identified, and 46 of them met the inclusion criteria. The identified biomarkers clustered into several key biological processes: DNA damage response and cell cycle regulation, cancer stemness, hypoxia and microenvironment, epigenetic and transcriptional regulation, and signaling pathways, including exosome-mediated communication. Most markers were linked to radioresistance and adverse outcomes, whereas a smaller subset was associated with increased radiosensitivity. A limited group of biomarkers was linked to clinical outcomes such as local control, residual disease, or survival, and emerging multi-marker protein signatures suggested that combinatorial approaches may outperform single-marker strategies. Radiosensitivity in cervical cancer is regulated by a network of biological pathways. Validated, integrated biomarker panels that capture DNA repair proficiency, stemness, hypoxia adaptation, and key signaling pathways are needed to improve risk stratification and enable biomarker-guided radiosensitization.

Identifying immunotherapy biomarkers for colorectal cancer (CRC) beyond MSI-high status is challenging. We evaluated CREBBP/EP300 and POLE/POLD1 mutations as candidate markers using public cohorts (MSK-CHORD, n = 5493; TCGA, n = 528; MetTropism, n = 24,496; ICI-treated, n = 1610). Regression with SHAP attribution, survival analyses, and pan-cancer transcriptomic profiling (n = 7628) were performed. CREBBP/EP300 mutations were independently associated with TMB-high MSS tumors (p < 0.00001). The co-mutation group (CREBBP/EP300 + POLE/POLD1; CoMut) was the strongest predictor of elevated TMB level (β = 3.63; p < 10-16; exp(β) = 37.7) with a median TMB of 155.9 vs. 7.4 and 5.4 Mut/Mb in single-mutation groups. CoMut also associated with improved survival (HR = 0.57, p = 0.035). In the ICI-treated cohort, both single-mutation groups (CREBBP/EP300-MUT-only; POLE/POLD1-MUT-only) and showed longer overall survival than wild type (34 and 28 vs. 17 months; p < 0.05), but only CREBBP/EP300 mutations independently reduced mortality risk (HR = 0.71, p = 0.0025). All groups shared immune-inflammatory transcriptomic enrichment. These findings support CREBBP/EP300 mutations as candidate immunotherapy biomarkers, and co-mutations with POLE/POLD1 define a TMB-high MSS subgroup that could refine TMB testing, pending prospective validation.

This study assessed the prevalence and clinical relevance of p16INK4a, p53, HER2, and Nectin-4 protein expression in primary vaginal cancer (PVC), with HER2 and Nectin-4 representing potentially druggable targets. A total of 34 patients with PVC from the University Medical Center Mainz biobank were included. Immunohistochemistry was used to evaluate the expression of p16, p53, HER2, and Nectin-4: p16, p53, and HER2 staining results were dichotomized (positive vs. negative; mutant vs. wildtype staining pattern), whereas Nectin-4 expression was assessed using an immunoreactive score (IRS) based on staining intensity and the proportion of positive tumor cells. Univariate analyses were performed to identify intergroup differences, and survival analyses were conducted using the log-rank test. Negative p16 expression was significantly associated with adenocarcinomatous histology (p = 0.0211), but neither p16 nor p53 status showed prognostic relevance. HER2 positivity was detected in 14.7% of tumors and was significantly associated with adenocarcinoma (p = 0.0001), p16 negativity (p = 0.0035), and younger age (p = 0.0483). Based on IRS, strong total Nectin-4 expression was observed in 20.59% and moderate membranous Nectin-4 expression in 17.65% of cases. No significant associations were found between HER2 or Nectin-4 expression and clinical outcomes; however, a limited statistical power of the survival analysis due to the low number of events (n = 10 deaths) should be considered. This analysis demonstrates a notable prevalence of HER2 and Nectin-4 expression in PVC.

Homer proteins (Homer1-3) are scaffold proteins that mediate protein-protein interactions in signal transduction; however, the role of Homer3 in breast cancer (BC), particularly triple-negative breast cancer (TNBC), remains poorly defined. Here, we investigated the clinical relevance and functional significance of Homer3 in BC and TNBC. Publicly available datasets from TCGA and GEO were analyzed to evaluate associations between Homer3 expression and patient outcomes using Kaplan-Meier survival analysis. Pathway enrichment analysis and gene set variation analysis (GSVA) were performed to identify signaling programs associated with Homer3 co-expressed genes. Functional roles were examined using stable TNBC cell lines with Homer3 knockdown or overexpression, followed by assays for cell proliferation, clonogenic growth, migration, invasion, and wound healing. We found that Homer3 expression was elevated in breast tumors compared with normal tissues and was associated with poor prognosis in both BC and TNBC. Homer3 expression was higher in TNBC than in non-TNBC subtypes and negatively correlated with estrogen receptor (ER) and progesterone receptor (PR) expression. Functionally, Homer3 depletion suppressed TNBC cell proliferation, clonogenic capacity, migration, invasion, and wound healing, whereas Homer3 overexpression produced reciprocal effects. Pathway analyses revealed that Homer3 co-expressed genes were enriched in cell cycle-related pathways and Hallmark MYC signaling, which were associated with adverse clinical outcomes. Consistently, Homer3 knockdown selectively reduced key proliferative cell-cycle regulators. Collectively, these findings demonstrate that Homer3 is associated with aggressive phenotypes and MYC- and cell cycle-linked proliferative programs in breast cancer, particularly in TNBC. Survival analyses are presented as exploratory findings, supporting the biological relevance of Homer3 in TNBC. These findings suggest that Homer3 may represent a potential therapeutic vulnerability.

Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal gland for which no curative treatment options exist in advanced stages. Analyzing the ACC cohort of The Cancer Genome Atlas, we identified that expression of the mRNA-stabilizing protein Embryonic-Lethal-Abnormal-Vision-Like RNA-Binding Protein 1 (ELAVL1) was negatively associated with patient survival. To investigate the functional role in ACC, we generated a CRISPR/Cas9-mediated ELAVL1 knockout (KO) in the ACC cell lines NCI-H295R and HAC15 and performed Next-Generation RNA Sequencing (NGS) to characterize transcriptomic changes. In NCI-H295R, NGS analysis revealed 3468 upregulated genes and 3458 downregulated genes in ELAVL1-deficient cells compared with controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified significant enrichment of aldosterone biosynthesis-related genes and enriched downregulation of genes associated in with "pathways in cancer." Functionally, ELAVL1-KO cells exhibited impaired colony-forming ability, indicating reduced proliferative or clonogenic potential. Steroid profiling of cell culture supernatants further demonstrated increased aldosterone synthesis and decreased cortisol and androgen production in the KO cells, consistent with the observed transcriptional changes. Given that hypercortisolism is an established negative prognostic factor in ACC, these data suggest that ELAVL1 may represent a potential therapeutic target worth further investigation for modulating steroidogenesis in ACC patients.

Here, we report the identification of a previously unrecognized population of tumor-induced podoplanin-positive (PDPN+) cells in clear-cell renal cell carcinoma (ccRCC) that exhibit features of under-differentiated lymphatic endothelial cells (LECs). These PDPN+ cells lack a complete repertoire of canonical LEC markers, including VE-cadherin, LYVE1, and VEGFR3, and fail to form functional lymphatic vessels, indicating a dysplastic phenotype. We termed these cells dysLECs and found that these cells are induced by BMP10 produced specifically by tumor cells. In turn, dysLECs secrete CXCL13, which promotes tumor cell proliferation and metastasis. Ligand-receptor analyses revealed a highly tumor-specific reciprocal signaling circuit: kidney tubule cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene uniquely express BMP10, a TGF-β family cytokine, whereas its receptor ALK1 is restricted to dysLECs; conversely, dysLECs produce CXCL13, while VHL mutant kidney tubule cells uniquely express its receptor, CXCR5. Pharmacological inhibition of ALK1 reduced CXCL13 production and suppressed the hyperplastic phenotype of VHL mutant tumor cells in vivo, whereas BMP10 neutralization inhibited tumor growth and metastasis in an orthotopic ccRCC xenograft model. Collectively, these findings identify a dysplastic population of PDPN+ lymphatic-like endothelial cells and define a tumor-specific BMP10-CXCL13 signaling axis that drives ccRCC progression, uncovering a previously unrecognized therapeutic vulnerability in this disease.

Oxidative stress in the tumor microenvironment, which is its own intrinsic property, is frequently utilized to deal with the drug-targeting issue in the nanoparticle drug delivery system. For this purpose, reactive oxygen species (ROS)-sensitive nanoparticles encapsulating doxorubicin (DOX) and chlorin e6 (Ce6) were synthesized for treatment of MDA-MB-231 breast cancer cells. Hyaluronic acid (HA) with a reductive end was conjugated with methoxy poly(ethylene glycol) (PEG) using thioketal diamine (ThdNH2) linkage (HA-b-PEG copolymer). Then, Ce6 were conjugated to the carboxylic acid group of HA via ThdNH2 (HA(Ce6)-b-PEG copolymer). DOX was physically incorporated to make DOX-incorporated HA(Ce6)-b-PEG copolymer nanoparticles (DOX-NP). HA(Ce6)-b-PEG copolymer nanoparticles (empty NP) and DOX-NP have a tiny particle size, less than 200 nm, with spherical morphology. They were responsively disintegrated according to the hydrogen peroxide (H2O2) concentration, then the release rate of Ce6 or DOX was accelerated, indicating that empty NP and DOX-NP have ROS sensitivity. DOX-resistant MDA-MB-231 cells were prepared by continuous treatment of DOX for three months. DOX-NP were efficiently internalized into the cells while intra-cellular delivery of DOX itself was inhibited. DOX-NP has higher anticancer activity against DOX-resistant MDA-MB-231 cells than that of DOX itself since cells were resistant to DOX itself. Under light irradiation, DOX-NP significantly decreased the viability of DOX-resistant MDA-MB-231 cells while DOX itself did not properly affect cell viability. Empty NP also efficiently inhibited cell viability rather than that of Ce6 itself while both of them did not affect the cell viability in the absence of light irradiation. Furthermore, empty NP showed higher ROS generation than that of Ce6 itself. DOX-NP more efficiently induced apoptosis/necrosis than DOX itself. In DOX-resistant MDA-MB-231 cell-bearing mice, DOX-NP was efficiently delivered to tumor tissue. DOX-NP greatly inhibited the growth of tumors under light irradiation, more than that of DOX itself or empty NP. In conclusion, DOX-NP showed promising antitumor activity against DOX-resistant MDA-MB-231 cells.

Pancreatic ductal adenocarcinoma (PDAC) has two principal molecular subtypes-classical and basal-like-with divergent prognosis and chemotherapy response, yet transcriptomic classifiers rarely generalize across cohorts or quantify per-patient uncertainty. We trained a classical-versus-basal-like classifier on CPTAC-PDAC (n = 140) and externally validated it on histology-filtered TCGA-PAAD (n = 150). Twelve algorithms were benchmarked under stratified nested cross-validation with four-method consensus feature selection; domain adaptation (naive transfer, CORAL, and ComBat), four conformal procedures (split, weighted, CV+, and Conformal Risk Control), and a four-method consensus explainable-AI framework (SHAP, LIME, permutation importance, and decision-curve ablation) with pathway enrichment were then evaluated. Top models reached a cross-validated AUROC ≈ 0.96 and external AUROC 0.913-0.938 (top-3 ensemble 0.961); batch correction did not improve transfer, indicating minimal residual batch effect. Consensus explainability recovered keratinization biology and nominated five candidate genes (GSDMC, A2ML1, PIP5K1B, IL20RB, and AKR7L) beyond the Moffitt signature. All four conformal procedures plateaued near 0.85 coverage at α = 0.05 under zero-shot transfer, whereas local recalibration on a small target sample restored nominal coverage. We present a transparent, externally validated, uncertainty-aware and TRIPOD+AI-compliant PDAC subtype classifier, best deployed as a calibrated decision-support tool with site-specific recalibration.

Chronic inflammation and cyclooxygenase (COX)-2-mediated prostanoid signaling contribute to melanoma progression, yet their modulation by natural products remains poorly defined. We examined the effects of dogwood fruit extracts-Japanese cornel (Cornus officinalis) and two European cultivars ('Uholok', 'Yantarnyi')-on temporal prostanoid dynamics in A375 (primary tumor-derived) and MeWo (metastasis-derived) mela-noma cells. Dynamic changes rather than static levels were modeled using GAMLSS or zero-inflated Gamma models to assess time, cell line, cornel type, and dose effects. Untreated A375 cells showed time-dependent increases in PGE2, PGF2α, thromboxane B2, and 13,14-dihydro-PGE1, consistent with inducible COX-2 activation, whereas MeWo cells maintained consistently high prostanoid levels, reflecting constitutive COX-2 expression. Cornus extracts modulated these trajectories in a cell- and dose-dependent manner. In A375, low concentrations allowed prostanoid accumulation, while higher doses flattened or reversed these increases; Japanese cornel produced the strongest inhibition, whereas European cultivars showed weaker or cultivar-specific effects. MeWo cells were less responsive, with significant changes emerging only at higher doses. PGD2 and 6-keto-PGF1α remained largely unchanged, indicating selective targeting of COX-2-dependent prostanoids. Extracts also reduced accumulation of downstream prostanoids, including 15-deoxy-Δ12,14-PGJ2 and 13,14-dihydro-PGE1, particularly in A375 cells. These differences highlight a stronger susceptibility of early-stage melanoma to phytochemical intervention and support cultivar-dependent bioactivity linked to phytochemical composition. In summary, Cornus extracts selectively attenuate time-dependent trajectories of tumor-promoting prostanoids-most effectively with Japanese cornel-while sparing homeostatic mediators, warranting further investigation on their potential for melanoma chemoprevention or adjunctive therapy.

Glioblastoma (GBM) is a highly aggressive primary malignant brain tumor, featuring diffuse infiltrative growth and poor clinical outcomes, which underscores the need to delineate the molecular mechanisms driving its malignant progression. COP9 signalosome subunit 7B (COPS7B), a core component of the conserved COP9 signalosome complex, is significantly upregulated in GBM tissues; however, its biological function and regulatory mechanism in GBM remain largely elusive. Here, we found that elevated COPS7B expression was positively correlated with glioma pathological grade and adverse prognosis in histologically and molecularly confirmed GBM patients. Functional assays demonstrated that COPS7B markedly promoted the proliferation, migration, and invasion of GBM cells in vitro, while COPS7B knockdown exerted the opposite suppressive effects. Mechanistically, we identified clusterin (CLU) as a key downstream functional effector of COPS7B in GBM. COPS7B upregulated CLU protein abundance by enhancing the translation efficiency of CLU mRNA, without altering its transcriptional level or protein stability. Functional rescue experiments further confirmed that CLU is indispensable for COPS7B-mediated malignancy-driving phenotypes in GBM, and transcriptomic analysis revealed that the progression-promoting effect of CLU was tightly associated with the activation of tumor-related signaling cascades, including the ERK and MAPK pathways, as well as the regulation of cell growth, invasion, and migration. Collectively, this study not only reveals a critical role of COPS7B in driving GBM malignant progression but also delineates a novel COPS7B-CLU regulatory axis that drives GBM aggressive phenotypes via activation of mitogenic signaling, suggesting candidate targets for further translational investigation.

Lymphoma remains a major hematological malignancy associated with treatment resistance and systemic toxicity, highlighting the need for novel anticancer agents derived from natural products. In this study, dicentrine (5), an aporphine alkaloid isolated from Stephania venosa, was investigated for its anti-lymphoma activity in Raji and Ramos cells. Among the isolated compounds, dicentrine (5) exhibited the strongest cytotoxic activity, with IC50 values of 9.03 ± 0.53 and 5.16 ± 0.44 µg/mL in Raji and Ramos cells, respectively, while demonstrating favorable selectivity toward lymphoma cells relative to peripheral blood mononuclear cells (PBMCs). Dicentrine (5) significantly suppressed c-Myc and phosphorylated c-Myc expression, reduced lymphoma cell proliferation, and decreased total viable cell numbers in a dose-dependent manner. Cell cycle analysis revealed G0/G1 arrest in Raji cells and G2/M arrest in Ramos cells. Furthermore, dicentrine (5) induced apoptosis, as evidenced by increased Annexin V-positive populations and elevated cleaved caspase-3 expression. Molecular docking analysis demonstrated strong binding affinities of dicentrine (5) toward Akt, PI3K, caspase-3, and caspase-9, while network pharmacology identified AKT1 and the PI3K/Akt signaling pathway as potential targets associated with lymphoma suppression. Western blot analysis further demonstrated that dicentrine (5) significantly reduces total Akt protein expression. Overall, the present findings indicate that dicentrine (5) suppresses lymphoma progression by inhibiting cell proliferation and promoting apoptotic cell death, highlighting its potential as a promising natural therapeutic candidate for lymphoma.

Artificial intelligence (AI) has emerged as a promising tool for inferring molecular biomarkers directly from digitized histopathologic slides. However, the current evidence in gastrointestinal and hepatobiliary cancers remains fragmented across tumor types and biomarker categories. Relevant studies were systematically identified and screened according to the PRISMA 2020 statement. PubMed, Embase, Web of Science Core Collection, Scopus, and IEEE Xplore were searched from 1 January 2015 to the date of search. Eligible studies involved gastrointestinal or hepatobiliary malignancies, used histopathology images, applied AI-based methods, and reported molecular biomarker prediction or inference. A total of 110 studies were included. Most studies focused on colorectal, gastric, liver, and pancreatic cancers, with microsatellite instability, mutation status, molecular subtypes, and tumor mutational burden being the most commonly investigated targets. Model architectures evolved from conventional convolutional neural networks to multiple-instance learning and transformer-based methods. While many studies reported promising predictive performance, direct comparison across studies remained challenging because of substantial heterogeneity in datasets, model architectures, and validation strategies. AI-based molecular biomarker identification from pathologic slides shows substantial promise in gastrointestinal and hepatobiliary cancers, but current evidence is constrained by heterogeneity and limited validation. Standardized, multicenter studies are needed before routine clinical implementation.

Mesothelioma is a rare, aggressive malignancy with poor prognosis. B7-H3 (CD276), an immune checkpoint molecule, and CD163-positive tumor-associated macrophages (TAMs) contribute to tumor progression and immune evasion. This study evaluated the prognostic impact of B7-H3 expression and CD163-positive TAM infiltration. This single-center retrospective study included 94 patients diagnosed with malignant mesothelioma between 2011 and 2024. B7-H3 expression was assessed using the H-score method and dichotomized at the cohort median. CD163-positive TAM density was quantified in hotspot high-power fields. Overall survival (OS) was analyzed using Kaplan-Meier, log-rank, and multivariable Cox regression analyses. Median OS was 10.15 months (IQR: 4.88-19.66). High B7-H3 expression was associated with shorter OS, whereas high CD163-positive TAM density was associated with longer OS. In multivariable analysis, B7-H3 expression, CD163 expression, tumor localization, recurrence status, and treatment status were independently associated with overall survival. Combined biomarker analysis showed the worst OS in the CD163-low/B7-H3-high group and the best OS in the CD163-high/B7-H3-low group. High B7-H3 expression was independently associated with shorter overall survival, whereas high CD163-positive TAM infiltration was associated with longer overall survival in this cohort. The combined B7-H3/CD163 profile may identify distinct prognostic subgroups and highlights the tumor immune microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate below 10%. Cancer-associated fibroblasts (CAFs) promote epithelial-mesenchymal transition (EMT) and metastasis, yet the specific CAF subtypes and molecular axes driving PDAC progression remain incompletely understood. Here, using multi-omics data from PDAC samples, we identified a malignant ductal subpopulation, termed Ductal-T0, characterized by the highest EMT activity and prominent acquisition of myofibroblastic CAF (myCAF)-like transcriptional programs. Computationally, we predicted that myCAF-secreted THBS2 and FN1 engage the ITGA3/ITGB1/SDC1/SDC4 receptor axes in Ductal-T0 cells, which could activate TNF, NF-κB, TGF-β, and PI3K-AKT-signaling pathways to promote EMT. Pseudotime trajectory and velocity analyses suggested that Ductal-T0 cells exhibited the highest propensity to acquire myCAF-like features among all ductal subpopulations. Survival analysis revealed that an increased proportion of Ductal-T0 cells and elevated abundance of THBS2-ITGA3/ITGB1 and THBS2-SDC1 ligand-receptor pairs were significantly associated with poor prognosis. Spatial transcriptomics further revealed that myCAFs and Ductal-T0 cells co-localized at the tumor margin, which may contribute to reduced immune cell presence via dense extracellular matrix (ECM) barrier formation-a computationally inferred model of EMT-associated immune exclusion and metastatic progression-and identify THBS2 as a promising candidate for future therapeutic investigation to disrupt CAF-tumor crosstalk in PDAC.

Cancer stem cells (CSCs) drive therapeutic resistance, metastasis, and tumor recurrence through reversible transitions among stem-like, differentiated, epithelial, and mesenchymal states, which are sustained by interconnected epigenetic mechanisms. To our knowledge, this is the first review to integrate curcumin-mediated regulation of DNA methylation, chromatin remodeling, and non-coding RNAs within a single CSC plasticity framework and to propose the concept of an "epigenetic collapse of CSC plasticity" as a mechanistic explanation for how curcumin may weaken stemness, state switching, and adaptive treatment resistance. Evidence was critically evaluated through structured searches of PubMed/MEDLINE, Scopus, Web of Science Core Collection, Google Scholar, and citation tracking, while direct curcumin-epigenetic evidence was distinguished from independent CSC evidence and inferential mechanistic links. Curcumin has been reported to modulate DNMT1 and locus-specific DNA methylation; regulate HDACs, p300/CBP, EZH2, H3K27me3, and BMI1; and alter selected microRNA, long non-coding RNA, and circular RNA pathways, with comparatively stronger evidence involving the miR-34 family, miR-200c, miR-21, H19, and circHN1. However, current evidence is constrained by the predominance of bulk cancer-cell models, heterogeneous formulations and exposure conditions, and the scarcity of epigenetic rescue experiments combined with rigorous functional CSC assays. By unifying previously fragmented epigenetic evidence, this review advances a new evidence-weighted model in which curcumin may suppress CSC persistence not through a single molecular target, but by destabilizing the multilayer epigenetic circuitry that enables plasticity. Curcumin should therefore be regarded as a context-dependent, multilayer epigenetic modulator rather than an established CSC-eradicating therapy, and its translational relevance requires validation in prospectively defined CSC models with pharmacologically justified delivery and exposure conditions.

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent malignancy worldwide. Moreover, ESCC remains poorly characterized at the molecular level, which contributes to limited therapeutic options and an overall poor prognosis. In this context, HMGA family members, which are overexpressed in tumors but almost absent in healthy adult tissues, seem to represent promising therapeutic targets. These proteins act by binding to AT-hook DNA-binding motifs and may regulate the expression of several genes associated with tumor progression. Therefore, integrating in silico, translational, and in vitro approaches, we investigated the functional consequences of blocking HMGA2-DNA interaction in ESCC tumor progression by using netropsin, a site-specific ligand for AT-rich DNA regions. Our results demonstrate that netropsin treatment significantly reduced cell viability, migration, and cell cycle progression, thereby promoting apoptosis. Furthermore, netropsin treatment was capable of partially reverting Epithelial-Mesenchymal Transition (EMT) activation associated with HMGA2 expression, by downregulating EMT activators, such as Slug and Twist. Finally, the netropsin treatment sensitizes ESCC cells to chemotherapeutic treatment with 5-Fluorouracil. Taken together, our findings highlight that AT binding-specific blockade could be correlated with the inhibition of HMGA2 and may reveal a promising approach to better understand ESCC progression.

Next-generation sequencing (NGS) has become a cornerstone of precision oncology in colorectal cancer (CRC), although its role in routine patient stratification remains incompletely defined. This retrospective single-centre study characterised the molecular landscape of clinically selected CRC patients undergoing routine NGS and explored associations between genomic alterations and clinicopathological features. 97 eligible patients who underwent targeted NGS using two validated sequencing platforms were selected. Demographic, clinicopathological, and molecular data were integrated, and associations were evaluated using descriptive statistics, exploratory association testing, principal component analysis, and multiple correspondence analysis. At least one reportable genetic alteration was identified in 91 patients (93.8%), comprising 198 alteration events across multiple cancer-related genes. The most frequently altered genes with pathogenic or likely pathogenic variants were TP53 (55.7%), KRAS (40.2%), PIK3CA (18.6%), and BRAF (11.5%), while microsatellite instability was detected in 19.1% of evaluable tumours. Exploratory analyses identified associations between selected molecular alterations and clinicopathological characteristics. However, these were generally modest, frequently limited by small subgroup sizes, and none survived Benjamini-Hochberg correction. Principal component analysis demonstrated substantial molecular heterogeneity without defining distinct clinicopathological subgroups. Routine targeted NGS provides detailed molecular characterisation of CRC and generates information relevant to biomarker-informed clinical decision-making in real-world practice. However, targeted panels alone were insufficient to establish robust molecular subgroups in this retrospective cohort. These findings highlight the biological complexity of CRC and support larger prospective studies incorporating broader molecular profiling to improve precision patient stratification and optimise personalised therapeutic strategies.

Lung cancer ranks first in both incidence and mortality among all malignancies, and tumor microenvironment (TME)-induced CD8+ T cell exhaustion is a critical factor driving immune evasion and compromising the efficacy of immunotherapy. MicroRNAs (miRNAs), as key post-transcriptional regulators, shuttle between lung cancer cells and CD8+ T cells via extracellular vesicles (EVs), serving as critical communication hubs that reshape the TME. This review systematically synthesizes recent literature to summarize the regulatory patterns of miRNAs on functions of lung cancer cells and CD8+ T cells, and dissect the molecular mechanisms underlying miRNA-mediated bidirectional crosstalk between these two cell types. This review focuses on the dual-pronged immune evasion strategy employed by lung cancer cells to counteract CD8+ T cells. On the one hand, lung cancer cells aberrantly express endogenous miRNAs, such as miR-20a, miR-149-5p, and miR-326, to remodel their surface ligands and establish immune camouflage. On the other hand, they actively secrete EVs enriched in specific miRNAs, including miR-7108-3p, miR-651-5p, and miR-24-3p, which directly suppress CD8+ T cell function. Furthermore, lung cancer cells secrete additional miRNAs, notably miR-6794-5p, miR-708-5p, and miR-1234-3p, to reprogram other TME components, namely tumor-associated macrophages (TAMs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). These reprogrammed cells, in turn, indirectly attenuate CD8+ T cells through a relay-like mechanism via immunosuppressive cytokines or surface checkpoint molecules produced by these cells. In addition, competing endogenous RNA (ceRNA) networks formed by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in lung cancer cells regulate miRNA activity at multiple levels, further impairing the immune effector functions of CD8+ T cells. Conversely, activated CD8+ T cells also secrete miRNA-containing EVs, which deliver these miRNAs to tumor cells, thereby inhibiting tumor progression. Elucidation of this miRNA-based bidirectional communication network will not only advance our understanding of immune evasion mechanisms in lung cancer but also provide novel insights into cell-free immunotherapeutic approaches based on CD8+ T cell-derived vesicles.