Chemotherapy is a cornerstone of cancer treatment that significantly improves patient survival. However, the emergence of chemoresistance remains a leading cause of cancer-related mortality. RUNX3, a transcription factor that functions as a tumor suppressor in several cancers (e.g., gastric, colorectal, liver, and lung cancers), plays a key role in regulating tumor cell behavior. It exerts its effects by modulating oncogenic signaling pathways, controlling the cell cycle, promoting apoptosis, and influencing epithelial-to-mesenchymal transition (EMT) and cellular differentiation. Moreover, RUNX3 modulates tumor chemosensitivity through a wide range of mechanisms, including the regulation of apoptosis, drug efflux, cell cycle dynamics, oxidative stress, cancer stem cell properties, EMT, and metabolic reprogramming. RUNX3 could act as a promising therapeutic target for overcoming chemoresistance and a potential biomarker for predicting chemotherapy response. In this review, we summarize current knowledge on the expression patterns and clinical significance of RUNX3 across different malignancies, discuss the molecular mechanisms by which it influences chemoresistance, and therapeutic strategies aimed at modulating RUNX3 expression to reverse chemoresistance. Targeting RUNX3 holds potential to enhance tumor chemosensitivity and offers new avenues for combating chemoresistance in cancer treatment.
Heterogeneous nuclear ribonucleoprotein C (HNRNPC), a core member of the RNA-binding protein (RBP) family, modulates multiple molecular processes including RNA splicing, stability regulation, translation, and non-coding RNA regulatory networks, thereby extensively participating in the onset and progression of various human diseases. This review systematically elucidates the molecular functional characteristics of HNRNPC, encompassing its core regulatory role in RNA metabolism, post-translational modification patterns, and protein complex synergy mechanisms. It comprehensively summarizes the abnormal expression profiles and pathogenic mechanisms of HNRNPC in multi-system diseases such as tumors, neuropsychiatric diseases, reproductive and metabolic diseases, infectious and inflammatory diseases. Furthermore, this review deeply discusses the clinical application potential of HNRNPC as a diagnostic biomarker, prognostic predictor, and therapeutic target, as well as current research hotspots and unresolved scientific questions. Existing studies have demonstrated that HNRNPC regulates target gene expression in an N6-methyladenosine (m⁶A)-dependent or independent manner, exerting either oncogenic or protective effects in disease pathogenesis. Abnormal HNRNPC expression is closely associated with disease progression and poor clinical prognosis. With the in-depth development of epitranscriptomics research, HNRNPC is expected to become a core molecular target for the precision diagnosis and treatment of multiple diseases, providing important theoretical support for the mechanistic research and clinical translation of HNRNPC-related diseases.
Colorectal cancer (CRC) progression remains a major clinical challenge, emphasizing the need to uncover regulatory mechanisms. Succinyl-CoA ligase GDP-forming subunit beta (SUCLG2), a mitochondrial enzyme in the tricarboxylic acid cycle, is implicated in various cellular processes, but its role in CRC is not well understood. SUCLG2 was identified through integrated bioinformatics analysis of CRC datasets, followed by multi-omics clinical validation. Its function was assessed via in vitro and in vivo assays, and mechanisms were explored using transcriptomic, metabolomic, and epigenetic approaches. SUCLG2 expression was significantly downregulated in CRC, correlating tightly with advanced TNM stage and poor prognosis. Functional assays demonstrated that SUCLG2 restricts CRC cell proliferation and xenograft tumor growth. Mechanistically, SUCLG2 reactivated GADD45G transcription through S-adenosylmethionine (SAM)-dependent epigenetic remodeling, reducing intracellular SAM levels, suppressing DNA methyltransferase (DNMT) activity, and alleviating GADD45G promoter hypermethylation. GADD45G was established as a critical downstream mediator of the SUCLG2/p53 signaling axis, as its knockdown abrogated the tumor-suppressive effects of SUCLG2. Clinical validation confirmed a robust positive correlation between SUCLG2 and GADD45G expression, alongside a negative correlation with GADD45G promoter methylation in CRC patients. Our findings establish SUCLG2 as a tumor suppressor that acts via a SAM‑DNMT epigenetic axis to demethylate GADD45G and reactivate p53‑mediated growth inhibition, highlighting SUCLG2 as a promising prognostic biomarker and therapeutic target for CRC.
Mediator complex subunit 1 (MED1; also known as TRAP220 and PBP) is a non-DNA-binding transcriptional co-regulator whose apparently opposing roles in cancer cannot be inferred from expression level alone. This review advances an evidence-weighted, locus- and complex-centered framework to reconcile the MED1 paradox. We distinguish causal genetic and mechanistic data from clinicopathological associations and propose that MED1 output is determined by lineage-specific transcription-factor recruitment, genomic occupancy, signaling-dependent modification, chromatin state, and cellular context. Direct evidence supports MED1-dependent oncogenic transcription in estrogen receptor-driven breast cancer, androgen receptor-driven prostate cancer, E2A-PBX1-positive B-cell acute lymphoblastic leukemia, and hepatocyte tumor models. In contrast, MED1 loss promotes invasive behavior in defined non-small-cell lung cancer and melanoma models, whereas findings in colorectal and bladder cancer remain largely correlative. We further evaluate MED1 enrichment at super-enhancer-associated assemblies and transcriptional condensates, emphasizing that enrichment does not by itself establish structural or functional necessity. Finally, we assess indirect pharmacologic strategies and RNA-based suppression, noting the absence of a clinically validated MED1-selective inhibitor or degrader. By shifting the focus from pan-cancer expression to partner-, locus-, and model-specific dependency, this framework defines testable biomarkers and therapeutic hypotheses for selectively targeting oncogenic MED1 complexes while preserving physiological MED1 functions.
Photodynamic therapy (PDT) is a light-activated treatment that induces tumor cell death through the production of reactive oxygen species (ROS). There is emerging evidence that PDT can also elicit systemic antitumor immunity (abscopal effect) through the mechanisms of immunogenic cell death and immune reprogramming. The aim of this review was to systematically evaluate preclinical evidence of the abscopal and systemic immune responses induced by PDT. Following preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines, PubMed, Scopus, Web of Science, and Embase were searched up to September 2025. Eligible studies included animal models assessing distant tumor regression or systemic immune activation following PDT, with or without combination therapies. Twenty-four preclinical studies met the inclusion criteria. PDT consistently induced local tumor regression and immune activation, evidenced by damage-associated molecular pattern release, calreticulin exposure, and cytotoxic CD8-positive T lymphocyte infiltration. Several studies demonstrated clear abscopal effects, particularly when PDT was combined with programmed cell death protein-1/programmed death ligand 1 blockade or adjuvants. Reported cytokine upregulation, including interleukin-6, interferon-gamma, and tumor necrosis factor-alpha, confirmed robust systemic immune activation. Preclinical and early clinical studies suggested that PDT could be used to induce systemic, immune-mediated tumor control, similar to the abscopal effect. Optimizing treatment parameters and combination with immunotherapies may allow PDT to develop from a local, cytotoxic treatment to a systemic cancer immunotherapy.
Hepatocellular carcinoma (HCC) ranks among the malignancies with the highest mortality rates worldwide. Owing to the lack of effective diagnostic and therapeutic strategies, patient prognosis generally remains poor. MicroRNAs (miRNAs) function as both oncogenes and tumor suppressors, exerting precise regulatory control over diverse biological behaviors in HCC through multiple pathways. This review summarizes how miRNAs modulate the activation of critical signaling cascades, including the Wnt/β-catenin, PI3K/AKT/mTOR, TGF-β/Smad, and MAPK/ERK pathways, by targeting numerous genes. Furthermore, miRNAs contribute to HCC pathogenesis and progression by reshaping the tumor microenvironment and inducing metabolic reprogramming. Given their pivotal regulatory roles in HCC, we also comprehensively evaluate the diagnostic and therapeutic potential of miRNAs as clinical targets and highlight the major challenges currently impeding their translation.
The tumor immune microenvironment of lung adenocarcinoma (LUAD) is characterized by pronounced heterogeneity; however, practical tools capable of simultaneously dissecting its immunobiological characteristics and predicting therapeutic response remain scarce. Given the close association between immune infiltration-related genes and LUAD tumorigenesis, progression, and immunotherapy efficacy, this study aimed to construct an immune infiltration-related gene signature and develop an integrated model that incorporates prognostic indicators, molecular subtyping, and immunotherapy efficacy prediction. We obtained RNA-sequencing data and clinical information for LUAD cohorts from the TCGA and GEO databases, and retrieved 547 immune infiltration-related genes from the CIBERSORTx platform. Using differential expression analysis, Cox regression, and least absolute shrinkage and selection operator (LASSO) regression, we constructed a prognostic model based on immune infiltration-related genes and validated it across multiple independent cohorts. We further compared differences between high and low-risk groups in molecular pathways, tumor stemness features, the immune microenvironment, tumor mutational burden, immunotherapy responsiveness, and drug sensitivity, and performed in vitro cellular experiments to functionally validate key genes. We developed and validated a prognostic model comprising 13 immune infiltration-related genes, and its risk score emerged as an independent prognostic factor in multivariable Cox analysis. LUAD patients were stratified into two distinct risk groups: the high-risk group was characterized by enhanced cell-cycle and DNA-replication pathways, increased stemness features, higher tumor mutational burden, and an immunosuppressive microenvironment, whereas the low-risk group showed stronger immune infiltration, higher immune checkpoint expression, and higher predicted responsiveness to immunotherapy. In vitro functional assays confirmed that SKA1 exerts an oncogenic role in LUAD, significantly enhancing LUAD cell proliferation, migration, and invasion. We developed a robust prognostic model based on immune infiltration-related genes that effectively predicts the prognosis and immunotherapy response of patients with LUAD, reveals two distinct immuno-biological phenotypes, and deepens our understanding of LUAD heterogeneity. This model provides a key molecular basis for LUAD molecular subtyping and for formulating individualized therapeutic strategies.
Distant metastasis is the leading cause of cancer-related mortality, and inflammation plays a significant role in promoting cancer metastasis. Patients undergoing surgery are generally more susceptible to bacterial infection due to surgical trauma and immunological dysfunction. However, the extent to which bacterial inflammation contributes to tumor progression remains unclear. We conducted an integrative analysis of colorectal cancer patients who underwent curative surgery and experimental animal models to investigate the impact of anastomotic leakage on oncological outcomes. Using a cecal ligation and puncture (CLP) mouse model, we analyzed NK cell infiltration and activity in peripheral blood and liver tissues under infectious inflammatory conditions, together with NET deposition in metastatic niches. Finally, we examined the efficacy of NET degradation or CTSG inhibition in restoring NK cell-mediated tumor cytotoxicity and preventing tumor metastasis in two distinct mouse models of severe infection. Postoperative infectious complications were associated with increased metastatic recurrence. In mouse models, infection-induced NETs impaired NK cell proliferation and function. Mechanistically, NET-associated CTSG contributed to reduced surface NKp46 expression, a key activating receptor on NK cells. Disruption of NETs or pharmacological inhibition of CTSG restored NK cell cytotoxicity and suppressed metastatic colonization. NET-associated CTSG undermines NK cell-mediated tumor surveillance, contributing to infection-driven metastasis. Targeting the NET-CTSG axis may offer a novel therapeutic strategy to prevent postoperative metastatic progression.
Metabolic reprogramming is a hallmark of breast cancer (BrCa), with alterations in glycolysis, glutamine metabolism, and the urea cycle contributing to tumour progression. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, shifts metabolism toward oxidative phosphorylation and has been proposed as a therapeutic agent. While isotope tracing is well-established, natural isotope abundance (δ¹³C, δ¹⁵N) is emerging as a biomarker of metabolic alterations in cancer. We investigated the relationship between isotope composition and metabolism in BrCa using two BALB/c mouse mammary tumour models (V14 and 4T1) and assessed the effects of DCA treatment using metabolomics, lipidomics and isotopomics. V14 and 4T1 tumours exhibited isotopic patterns similar to human tumours, with δ¹³C enrichment and δ¹⁵N depletion relative to non-cancerous mammary tissue. V14 tumours were more δ¹⁵N-depleted than 4T1, reflecting differences in nitrogen metabolism. Multivariate analysis integrating isotopic, metabolomic, and lipidomic data revealed isotopic features as key discriminators between tumours and normal tissues. Compared to V14, 4T1 tumours were enriched in TCA intermediates, sphingolipids, and amino acids, whereas V14 tumours showed elevated glutaminolytic and nitrogenous metabolites. DCA treatment differentially affected tumour growth, with V14 tumours more sensitive than 4T1. DCA altered nitrogen metabolism, increasing the arginine-to-ornithine ratio, and modulating δ¹⁵N values in a tumour-specific manner increasing V14 and decreasing 4T1 δ¹⁵N values. DCA had little effect on δ¹³C. δ¹³C values were primarily determined by the balance between lipid and TCA cycle metabolites, rather than glycolytic flux. δ¹⁵N variation was linked to nitrogen metabolism, including urea cycle intermediates and sphingolipid composition, with a potential role for choline-related fractionation in δ¹⁵N depletion. Altered gene expression of Hacd2 and Acot12 in V14 tumours after DCA treatment was reflected in shorter fatty acid tails in phosphatidyl cholines, supporting the lipidomics data. These findings support the hypothesis that cancer-associated metabolic reprogramming influences natural isotope abundance. Correlations between isotope shifts and metabolic signatures highlight the potential of lipid-derived δ¹⁵N as a biomarker of tumour metabolic state, with implications for noninvasive metabolic profiling in BrCa.
Nanoparticle-mediated photodynamic therapy (PDT) is gaining increasing attention as a complementary strategy to enhance the efficacy of immune checkpoint blockade (ICB) in solid tumors. PDT induces reactive oxygen species-mediated cytotoxicity and immunogenic cell death, promoting antigen release, dendritic cell maturation, and remodeling of the tumor microenvironment to support systemic antitumor immunity. However, clinical outcomes remain constrained by hypoxia, suboptimal photosensitizer delivery, and limited intratumoral nanoparticle penetration. Recent advances in multifunctional biodegradable nanocarriers engineered to co-deliver photosensitizers together with oxygen-generating or oxygen-carrying components, and immunomodulatory agents have shown potential to overcome these barriers and enhance antitumor immune responses in preclinical settings. In this review, we critically evaluate the current landscape of nanotechnology-enhanced PDT combined with ICB, outline emerging design principles that may improve therapeutic specificity and immune activation, and highlight translational implications for clinical application. We further discuss the role of artificial intelligence (AI) in guiding PDT parameters, predicting immune checkpoint responsiveness, and informing rational nanoplatform design. Finally, persisting challenges, including standardized characterization, regulatory harmonization, scalable manufacturing, and long-term biosafety, are considered, emphasizing the need for coordinated multidisciplinary efforts to advance nanotechnology-assisted PDT-immunotherapy combinations toward clinically viable cancer treatments.
Solute carrier (SLC) transporters play a central role in tumor metabolism by mediating the uptake of amino acids and sugars required for cancer cell growth and survival. Their proper function is crucial for maintaining cellular homeostasis, and their dysregulation contributes to metabolic reprogramming, tumor progression, and therapy resistance. Recent studies have identified non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, as key regulators of SLC transporter expression and function. This review provides a focused and comprehensive overview of the intricate regulatory networks between ncRNAs and amino acid and sugar transporters within the SLC family, highlighting their implications in cancer. We summarize current evidence on direct and indirect regulatory mechanisms, including transcriptional, post-transcriptional, and epigenetic pathways, and discuss how these interactions reshape cancer metabolism. We highlight existing knowledge gaps, such as context-dependent regulation, indirect regulatory networks, and limited mechanistic validation in vivo. Finally, we discuss the therapeutic potential and challenges of targeting ncRNA-SLC networks. A deeper understanding of these interactions may facilitate the development of novel therapeutic approaches aimed at improving cancer treatment outcomes.
Vascular adhesion protein-1 (VAP-1), also known as amine oxidase copper-containing 3 (AOC3), is a multifunctional molecule with dual adhesive and enzymatic activities, and can regulate leukocyte trafficking, redox signaling, and stromal interactions within the tumor microenvironment. Evidence from both experimental and clinical investigations has demonstrated the aberrant expression of VAP-1 in a wide range of cancers and its correlation with tumor progression and outcomes. Elevated tissue levels of VAP-1 are generally associated with aggressive behavior and unfavorable survival in gliomas and breast, colorectal, and ovarian cancers, whereas altered circulating levels in gastric and thyroid cancers may have adjunctive diagnostic relevance when interpreted alongside conventional biomarkers, imaging findings, and clinicopathological features. Preclinical studies have documented the therapeutic advantages of VAP-1, as the inhibition of its enzymatic activities can suppress angiogenesis, reduce the infiltration of immunosuppressive myeloid cells, and restore antitumor immunity, with synergy observed in combination with immune checkpoint inhibitors. Moreover, novel molecular imaging strategies using VAP-1-specific ligands may support theranostic applications, offering opportunities for patient stratification and real-time assessment of therapeutic responses in selected contexts. This review gathers evidence on the involvement of VAP-1 in the pathogenesis of cancers and its diagnostic and therapeutic applications. The integration of data from basic and translational studies will underscore both the opportunities and challenges of targeting VAP-1 and guide future studies of the applications of targeting VAP-1 in the clinical setting.
Digestive system cancers, including malignancies of the oral cavity, esophagus, stomach, liver, pancreas, and colorectum, rank among the most prevalent tumors worldwide, with persistently high incidence and mortality. Notch signaling is a highly conserved pathway that orchestrates essential cellular processes such as differentiation, proliferation, and development; its dysregulation has been increasingly linked to various diseases, particularly digestive system cancers. Accumulating evidence indicates that aberrant Notch signaling is closely associated with the development of these malignancies, where it influences tumor initiation, progression, metastasis, and therapy resistance. Notably, depending on cellular context, Notch signaling may also exhibit tumor-suppressive effects in certain digestive system cancers. Understanding the role of Notch signaling in these tumors is essential for the development of more effective therapeutic strategies. Currently, multiple preclinical studies are investigating agents targeting the Notch pathway. This review summarizes current evidence on Notch signaling in digestive system cancers and points to open questions that warrant further study to inform future therapeutic strategies.
Galectin-3 (LGALS3), a β-galactoside-binding lectin, plays a pivotal role in regulating physiological and pathological processes in hepatocellular carcinoma (HCC). This study integrates multi-omics analytics and structure-based drug screening to evaluate Galectin-3 inhibitors for HCC treatment. Transcriptomic data and immunohistochemistry confirmed elevated Galectin-3 expression in HCC tissues, with Kaplan-Meier analysis showing its association with poor survival. Single-cell RNA sequencing revealed Galectin-3’s role in immune regulation, cancer stemness, and epithelial-mesenchymal transition. Structure-based screening identified 68 compounds with significant interactions with key Galectin-3 binding sites. Molecular dynamics simulations confirmed stable complex formation between Galectin-3 and inhibitors GB1107 and Pimasertib. In vitro assays demonstrated both compounds significantly inhibited HCC cell viability, colony formation, and migration dose-dependently. GB1107 exhibited stronger cytotoxicity at lower doses, while Pimasertib induced greater apoptosis at higher concentrations. Both compounds effectively downregulated stemness and epithelial-mesenchymal transition markers. These findings suggest Galectin-3 inhibition by GB1107 and Pimasertib disrupts oncogenic pathways, reducing tumor growth and metastatic potential, and offering promising therapeutic strategies for HCC management.
Combined hepatocellular-cholangiocarcinoma (CHC) is a rare primary liver cancer with low incidence and poor prognosis. CHC can develop distant metastasis (DM) at an early stage, which severely shortens the survival time of patients. We aimed to use machine learning (ML) to construct a decision-making system to assess risk factors for the development of DM in CHC patients. 1180 CHC patients from the SEER database between 2000 and 2020 were collected and randomized into the train set and internal test group in a 7:3 ratio. Patients diagnosed with CHC at our hospital between 2011 and 2018 were also collected as the external validation set (N = 125). Patients with CHC were divided into a metastasis group and a non-metastasis group according to the occurrence of DM. Univariate and multivariate logistic regression analyses were conducted to evaluate the risk factors influencing DM of CHC patients in the training set. We screened the feature variables based on random forest (RF) and forward feature importance sequences. Then we incorporated them into six ML algorithms for constructing machine learning models and used 10-fold cross-validation for internal validation. Receiver operating characteristic (ROC) curves, precision-recall curve (PRC), calibration curve (CC), and confusion Matrix (CM) were used to evaluate the predictive ability of the models. We determined the importance ranking of risk factors for DM in CHC patients using Shapley additive explanations (SHAP) and further used SHAP to analyze the interpretability of the black-box model. Finally, we built a web risk calculator based on the optimal performance model to facilitate its clinical application. A total of six variables were selected for constructing the decision model. Extreme gradient boosting (XGB) obtained the most significant recognition ability, with ROCAUC = 0.863, accuracy of 0.802, sensitivity of 0.875, and PRAUC of 0.642 in the internal test set. 10-fold cross-validation results showed that the ROCAUC of XGB was 0.989, with a standard error of 0.019. The SHAP method revealed that node, surgery, age, grade, primary site, and race are the top 6 key variables that contribute to the occurrence of DM in CHC. In addition, the analysis of two typical cases proved the reliability of the model. The XGB model outperforms other machine learning methods in recognizing the occurrence of distant metastases in CHC patients, and has a high degree of utility and reliability to inform clinical treatment decisions for patients.
Tumor heterogeneity is driven by genomic and transcriptomic variation, as well as by extensive protein diversification through post-translational modifications (PTMs), which generate distinct functional proteoforms. These combinatorial modifications reshape signaling, metabolism, and therapeutic response, adding a regulatory layer that conventional proteomics often fails to capture. Recent advances in mass spectrometry and open-modification analysis have enabled systematic profiling of pan-modification proteoforms. This emerging framework provides a deeper mechanistic basis for understanding and resolving tumor heterogeneity. This review explores the integration of multiple PTMs in shaping proteoform identity and the subsequent reprogramming of oncogenic signaling pathways. The impact of advanced analytical frameworks, such as top-down proteomics and spatially resolved mapping, on contemporary tumor biology is assessed. Additionally, we discuss the clinical implications of proteoform-centric biomarkers regarding therapeutic interventions and resistance. By reframing proteomic regulation in terms of pan-modification and proteoform diversity, this review outlines a foundational framework for next-generation precision oncology that interprets proteins not as single entities but as dynamic assemblies of functionally encoded molecular states.
The neuronal pentraxin receptor (NPTXR) is mainly expressed in the cytoplasm of a subset of neuronal cells in the cerebral cortex. While NPTXR may be involved in mediating uptake of synaptic material during synapse remodeling or synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses during embryonic development, NPTXR expression has recently been shown to be elevated in tissues from patients with gastric cancer. NPTXR protein expression was evaluated in human cancer and healthy tissue samples. We then generated antibody–drug conjugates based on YB-800 (YB-800ADCs), a fully humanized monoclonal antibody selectively targeting NPTXR. The cross-reactivity of YB-800 and YB-800ADCs were assessed, as well as their tumor inhibitory effects in experimental tumor models. NPTXR protein was highly and consistently expressed in human tissue samples from multiple cancer types but only minimally expressed, if at all, in healthy tissues. Treatment with YB-800ADCs inhibited tumor cell proliferation/survival in engineered HEK293 cells overexpressing the human NPTXR. YB-800ADCs were also found to have pronounced anti-tumor effects in mice bearing NPTXR-expressing HEK293 tumors at well-tolerated doses. Initial anti-tumor findings were further confirmed using a naturally occurring NPTXR-expressing human bladder PDX model. NPTXR is an oncofetal protein that is highly expressed in multiple human cancers but minimally expressed in healthy tissues. We have established NPTXR as a new tumor marker and have developed antibody–drug conjugates using YB-800, a novel, first-in-class, humanized monoclonal antibody targeting the human NPTXR. Initial results demonstrate that YB-800ADCs have pronounced anti-tumor effects in vivo in NPTXR-expressing cancer cells. Continued evaluation of YB-800ADCs is warranted.
A substantial proportion of patients with melanoma brain metastases (MBM), especially those symptomatic at therapy start, continue to respond poorly to currently available systemic therapies, including immune checkpoint inhibitors. Durable systemic treatment options beyond established regimens remain limited for this patient population. Drug repurposing offers a rapid translational path for identifying novel therapeutic strategies. Thioridazine, a phenothiazine antipsychotic with known blood–brain barrier permeability, has shown anticancer effects in several malignancies but has not previously been evaluated in MBM. This study investigates the anti-tumoral potential and underlying mechanisms of thioridazine in patient-derived MBM cell lines. Cytotoxic, anti-proliferative, and anti-migratory effects of thioridazine were assessed in four MBM cell lines (H1, H2, H3, H10) using monolayer and soft agar viability assays, live-cell imaging, and clonogenic assays. Potential off-target toxicity was evaluated using fetal rat brain organoids (FRBOs). Mechanistic effects were examined using Annexin V/PI flow cytometry, Western blotting of apoptosis- and autophagy-related proteins (cleaved PARP1, cleaved caspase-3, Bcl-2, p62, LC3A/B), and confocal microscopy to assess autophagosome formation and lysosomal dynamics. Thioridazine reduced viability of MBM cells in a dose-dependent manner, with IC50 values ranging from 8.7 to 12.0 µM. Anchorage-independent growth was similarly inhibited. FRBOs displayed no treatment-associated cytotoxicity at MBM-relevant doses in vitro. Thioridazine markedly suppressed MBM cell proliferation, migration, and clonogenic growth in a dose-dependent manner. Apoptosis induction was inconsistent across cell lines, with variable activation of cleaved PARP1, cleaved caspase-3, and Bcl-2. In contrast, autophagy-associated markers p62 and LC3A/B were consistently upregulated, accompanied by intracellular accumulation of punctate autophagosomes and altered lysosomal morphology, indicating impaired autophagic flux. Thioridazine demonstrates robust anti-tumoral activity in MBM cells in vitro while sparing healthy brain organoid tissue. Its cytotoxic effects appear independent of classical apoptosis and instead correlate with disrupted autophagic flux and altered lysosomal dynamics. These findings highlight thioridazine as a promising candidate for therapeutic repurposing in MBM and support further investigation into its autophagy-modulating mechanisms.
Lung cancer remains one of the most prevalent and lethal malignancies worldwide, resulting in approximately 1.5 million deaths annually. Currently, more than 75
Fusion genes, arising from aberrant genomic rearrangements, represent critical oncogenic drivers with distinct oncogenic functions. Although relatively uncommon in breast cancer, accumulating evidence suggests that fusion genes contribute to tumor initiation, progression, and therapeutic resistance. This review first summarizes the molecular mechanisms underlying fusion gene formation, their frequency and subtype distribution, and advances in detection technologies in breast cancer. We then discuss how fusion genes reprogram oncogenic signaling pathways and mediate resistance to conventional and targeted therapies. Finally, we evaluate their translational potential as diagnostic biomarkers and therapeutic targets, emphasizing opportunities for precision oncology. By integrating current insights, this review underscores the multifaceted roles of fusion genes in breast cancer biology and highlights their promise for guiding the development of more effective, personalized treatment strategies.
