搜索结果：Cancer gene therapy

Cancer remains one of the leading causes of death worldwide, and the limitations of conventional therapies such as surgery, chemotherapy, and radiotherapy underscore the urgent need for innovative therapeutic strategies. While advances in early detection and treatment have improved outcomes in some regions, challenges such as micrometastasis, tumor relapse, and multidrug resistance continue to hinder long-term success. The multifactorial nature of cancer-driven by complex genetic mutations, diverse tumor microenvironments, and adaptive cancer cell behavior- demands more precise and effective solutions. Recent breakthroughs in molecular biology and genetic engineering have led to the emergence of genome editing technologies that offer promising avenues for targeted cancer therapy. This review highlights the evolution and application of key genome editing platforms, including meganucleases, zinc finger nucleases (ZFNs), transcription activator- like effector nucleases (TALENs), and the CRISPR/CAS9 system. Meganucleases were among the earliest tools with site-specific cutting ability, but limited versatility. ZFNs and TALENs offered greater modularity and target specificity through protein-DNA interactions. The CRISPR/CAS9 system revolutionized genome editing with its RNA-guided targeting, allowing for higher efficiency, simplicity, and flexibility in gene modification. These tools have enabled researchers to disrupt oncogenes, repair tumor suppressor genes, and manipulate signalling pathways involved in tumor progression, resistance, and metastasis. Moreover, ongoing advancements in delivery systems and gene repair mechanisms have further enhanced their therapeutic potential. We also discuss their translational potential from bench to bedside and explore future perspectives on how these technologies may revolutionize precision oncology, ultimately contributing to more effective treatment outcomes.

Virus-like particles (VLPs) are spontaneously generated from viral capsid proteins. VLPs imitate genuine viruses visually and physiologically, but lack viral DNA. Various VLP designs provide structural and functional appeal. Spontaneous polymerization of viral capsid proteins may result in the formation of VLPs with geometrical symmetry, which are often icosahedral, spherical, or rod-like. Moreover, functionalized VLPs may precisely target cancer cells and recruit macrophages to destroy them. The ability to target tumors for therapeutic drug delivery through VLP-based delivery platforms in novel and intriguing aspects related to cancer treatment is the primary goal of VLP design. Cancer therapies require precise targeting of diagnostic or therapeutic elements to tumor cells while avoiding healthy cells and tissues. VLPs offer an innovative approach as site-specific drug delivery systems, reducing systemic toxicity and minimizing injury to healthy cells. Immunotherapy, which boosts the host's immune system, has fewer side effects. Cancer vaccines aim to induce an immune response that provides protection against tumor cells. Due to their naturally fitted particle size and repetitive structural order, VLPs may be employed as a vaccine without any adjuvant. Recombinant VLP structures can be enhanced by including antigenic epitopes of viruses or different disease-related antigens, and targeting peptides to the interior and exterior surfaces, making them potential tools for future immunizations with preventive and regenerative qualities. Additionally, VLP-based delivery strategies may enhance immunogenicity and provide a more effective and safer approach to managing solid cancers with fewer side effects compared to chemotherapy or radiation. However, the production of chimeric VLPs still faces challenges, such as the need for more reliable preclinical animal models and associated costs. Despite these obstacles, ongoing research will improve VLP-based technologies and increase their potential advantages. This review aims to provide basic information on VLPs and outline current studies on their use as drug and vaccine delivery systems in different cancers, highlighting their potential as a promising cancer treatment strategy. The key terms in the literature search-including drug delivery, gene therapy, multi-capsid VLPs, and virus-like particles (VLPs)-were searched in international databases, namely Web of Science, PubMed, and Scopus from 2003 to 2022.

Although targeted therapy significantly improves the prognosis of gastric cancer patients, the availability of cancer targeted drugs in clinical practice is still limited. In order to identify potential therapeutic targets for gastric cancer, Mendelian randomization (MR) analysis based on aggregated data was conducted. Specifically, cis eQTL data were obtained from the whole blood and gastric cohorts of GTEx Consortium V8 as exposure variables. Obtain cancer summary statistical data representing outcome variables from the FinnGen database. Using co localization analysis to evaluate whether common single nucleotide polymorphisms (SNPs) are associated with cancer risk and gene expression. Ultimately, thrombospondin-3(THBS3) was identified as a significant gene in both cohorts, supported by consistent colocalization evidence. Subsequently, a dual sample MR analysis was conducted to investigate the correlation between gene expression and gastric cancer risk, and the results also confirmed the relationship between THBS3 gene expression and gastric cance risk. In addition, a meta-analysis was conducted showing that THBS3 is a gene with poor cancer prognosis. Cell studies indicate that inhibiting THBS3 expression can reduce cell proliferation, enhance sensitivity to gastric cancer-related drugs, and lower MVP gene expression may linked to drug resistance. It also influences tumor growth signaling, metabolic pathways, and cell adhesion processes. In summary, based on the research results of SMR, colocalization, dual sample MR, meta-analysis, and other analysis methods, there is convincing evidence to support the view that THBS3 has important prospects as a feasible therapeutic target gene for cancer.

Triple-negative breast cancer (TNBC) is one of the most aggressive molecular subtypes of breast cancer and immune-checkpoint blockade therapy has markedly changed the treatment landscape for this malignancy. Tumour-infiltrating lymphocytes (TILs) and tumour mutational burden (TMB) predict patient response to treatment with immune checkpoint inhibitors and reflect patient outcomes. The present study aimed to develop a TIL-based prognostic model, create a list of immune-related genes (IRGs) to inform clinicians of possible outcome predictions and generate a clinically relevant estimate of potential benefit from immunotherapy in TNBC. The present study included a cohort of 130 patients that were classified into two groups, namely TMBhigh/CD8+ T-cell-rich and TMBlow/CD8+ T-cell-poor. Differential expression analysis using the 'edgeR' package identified IRGs associated with survival. The identified IRGs were included in a univariate Cox analysis to derive a prognostic signature. In addition, the present study examined how the signature genes were associated with immune cell infiltration using the Tumour IMmune Estimation Resource database. The final four-gene signature, C-X-C motif chemokine ligand 13 (CXCL13), latent TGF-β binding protein 2, placental growth factor and transporter associated with antigen processing binding protein-like (TAPBPL), stratified risk robustly: Patients in the high-risk group had significantly worse overall survival compared with low-risk patients in both prognostic and validation models. Compared with high-risk patients, low-risk patients had greater infiltration of CD8+ T cells, M1 macrophages, resting dendritic cells and activated CD4+ T cells and less infiltration of both M0 and M2 macrophages. Higher CXCL13 and TAPBPL expression levels were significantly associated with higher CD8+ T-cell counts and inversely associated with M0 and M2 macrophage counts. The overall risk score and CXCL13 expressions were all positively correlated with multiple immune checkpoint genes, while TAPBPL expression correlated positively with CTLA4, TIM3 and TIGIT. In summary, the present study provided a TMB- and T-cell infiltration-based IRG signature that is prognostic and may potentially support the prediction of immunotherapy responsiveness in TNBC in the future.

Concurrent development of therapy-related acute myeloid leukemia (t-AML) and lymph node tuberculosis (LNTB) following comprehensive anti-tumor therapy for locally advanced lung squamous cell carcinoma (LSCC) is extremely rare in clinical practice. This is not a new biological concept but represents a rarely documented clinical scenario in the setting of neoadjuvant chemoimmunotherapy, surgery, and anti-PD-1 maintenance therapy. Herein, we systematically summarize the clinical features, pathogenesis and individualized therapeutic strategies of these two concurrent rare complications based on a single rare case and the latest relevant literature, to provide a reference for clinical diagnosis and treatment. A 54-year-old male patient was initially diagnosed with locally advanced LSCC. After four cycles of neoadjuvant therapy with carboplatin, albumin-bound paclitaxel and pembrolizumab, the tumor lesion regressed markedly. Thoracoscopic right upper lobectomy was then performed, followed by maintenance immunotherapy with single-agent pembrolizumab postoperatively. Four months after maintenance therapy, the patient developed abnormalities on routine blood work, low-grade fever, fatigue and superficial lymphadenopathy. t-AML was confirmed by bone marrow aspiration, immunophenotyping, gene mutation and cytogenetic examinations, accompanied by breast cancer susceptibility gene 2 (BRCA2), DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A), and isocitrate dehydrogenase 2 (IDH2) mutations, and positivity for lysine (K)-specific methyltransferase 2A partial tandem duplication (KMT2A-PTD). Meanwhile, LNTB was diagnosed by lymph node aspiration pathology combined with tuberculosis-specific assays. The patient was treated with an optimized quadruple anti-tuberculosis regimen (HZEM), and induction chemotherapy for AML with VA regimen (venetoclax plus azacitidine) plus revumenib, and supportive therapy. Subsequently, the patient achieved partial remission of leukemia, with no uncontrollable severe adverse events. In this case, LSCC was managed with neoadjuvant therapy, thoracoscopic right upper lobectomy and postoperative maintenance therapy with single agent pembrolizumab. The development of t-AML is primarily driven by cytotoxic DNA damage induced by chemotherapeutic agents, whereas the potential contribution of immune checkpoint inhibitors remains largely speculative. The potential contribution of immune checkpoint inhibitors via immune microenvironmental disturbance remains largely speculative and insufficiently documented by current clinical evidence. The impaired immune function caused by comprehensive anti-tumor therapy may further elevate the risk of LNTB. The overlapping clinical manifestations of the two concurrent diseases substantially increase diagnostic difficulty. Timely and thorough bone marrow examination, lymph node pathological biopsy and tuberculosis-specific screening are the keys to early and accurate diagnosis.

Macrophage polarization and endoplasmic reticulum (ER) stress play critical yet incompletely understood roles in cancer progression and therapeutic resistance. Here, we conduct a systematic pan-cancer analysis of macrophage polarization and ER stress-related genes (MPERSRGs) by integrating multi-omics data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and single-cell RNA sequencing datasets across 33 cancer types. We identify distinct expression patterns of seven core MPERSRGs (CEBPB, NUPR1, ATF3, CASP3, TNFSF10, BRSK2, NOD2) that correlate significantly with tumor stage, immune infiltration, and patient prognosis. Employing 117 machine learning algorithm combinations, we develop a robust five-gene prognostic signature (FAM83A, RHOV, CPS1, STRIP2, SLC2A1) for lung adenocarcinoma (LUAD) with area under the curve values of 0.692, 0.688, and 0.614 for 1-, 3-, and 5-year overall survival, respectively. Single-cell transcriptomic analysis of 86,378 cells reveals three functionally distinct fibroblast subpopulations (MFAP5+, MATK+, HP+) with differential MPERSRG expression profiles, with MFAP5 + fibroblasts showing the highest enrichment in epithelial-mesenchymal transition and angiogenesis pathways. Cell-cell communication analysis identifies fibroblasts and epithelial cells as the most interactive populations, with the CLEC2C-KLRB1 ligand-receptor pair mediating the strongest signaling between mast cells and NK cells. Drug sensitivity predictions across multiple databases identify vorinostat, nilotinib, olaparib, and paclitaxel as potential therapeutic agents showing differential efficacy based on MPERSRG expression stratification. These findings establish MPERSRGs as key determinants of tumor-immune interactions and provide actionable biomarkers for risk stratification and precision therapy selection in cancer.

Cuproptosis, a copper-dependent form of programmed cell death, has been implicated in the progression of various cancers. However, the role of LOXL2 - a cuproptosis-related gene (CRG) - and its prognostic value in thyroid cancer (THCA) remain largely unexplored. We systematically investigated the prognostic significance of CRGs in THCA through an integrative approach combining bioinformatics screening and experimental validation. Expression profiling of all identified CRGs was performed using The Cancer Genome Atlas (THCA cohort) to assess their transcriptional alterations and associations with patient prognosis. Pathway enrichment, immune infiltration, and drug sensitivity analyses were subsequently conducted to explore the functional relevance of these genes. CRGs exhibiting significant differential expression and prognostic correlation were selected for in vitro functional validation using EdU proliferation, CCK-8, and Transwell assays to elucidate the role of LOXL2 in THCA progression. Additionally, we evaluated the antitumor effects of cuproptosis inducers on THCA cells to explore the therapeutic potential of targeting cuproptosis. Systematic expression analysis identified four CRGs (MT1A, MT1F, LOXL2, and MT1M) that were significantly dysregulated in THCA tissues compared to normal counterparts. Based on the expression patterns of these four genes, THCA patients were stratified into low-risk and high-risk groups. Notably, the high-risk group exhibited significantly lower immune scores and poorer overall survival. Pathway analysis revealed alterations in glycerolipid metabolism and oxidative phosphorylation in the high-risk group. Among the four genes, LOXL2 showed the strongest correlation with THCA prognosis. Functional assays demonstrated that LOXL2 knockdown significantly suppressed THCA cell viability, proliferation, migration, and invasion. Importantly, treatment with cuproptosis activators exerted potent anticancer effects against THCA cells. Our study indicates that LOXL2 may serve as a potential biomarker for cuproptosis-related pathways and represents a potential therapeutic target in THCA. Furthermore, our findings suggest that pharmacologically targeting cuproptosis-related genes may provide a promising therapeutic strategy for the management of THCA.

Nucleic acid-based nanotherapeutics hold great promise for tumor treatment, yet face challenges in drug loading capacity, stability during delivery, and controlled intracellular release. Herein, we propose a carrier-free, tumor microenvironment (TME)-responsive nanoplatform (FAM NPs-FA) constructed via coordination-driven self-assembly of Survivin antisense oligodeoxynucleotide (ASO), methotrexate (MTX), and Fe3+ ions. The resulting nanocomposites demonstrate high drug loading, enhanced serum stability, and intrinsic synergistic activity by integrating chemodynamic, gene, and chemotherapeutic therapies. Upon cellular uptake by tumor cells, the acidic TME triggers disassembly of the nanoplatform, releasing Fe3+, Survivin ASO, and MTX. Intracellular glutathione reduces Fe3+ to Fe2+, which catalyzes hydrogen peroxide to generate highly cytotoxic hydroxyl radicals for chemodynamic therapy (CDT). Meanwhile, the released Survivin ASO specifically silences Survivin mRNA, suppressing anti-apoptotic protein expression, and accelerating tumor cell apoptosis. Moreover, combined with the chemotherapeutic effects of MTX, this nanoplatform demonstrates exceptional synergistic therapeutic efficacy against tumors while minimizing adverse impacts on healthy tissues, thus opening a versatile and effective carrier-free platform for TME-responsive synergistic cancer therapy integrating gene regulation, reactive oxygen species generation, and chemotherapy.

There are relatively well-substantiated concepts regarding the differences in the clinical course of metastatic colorectal cancer depending on the primary tumor localization: right- and left-sided (including rectal). However, many clinical trials demonstrate clear differences in the selected efficacy of adjuvant chemotherapy in the treatment of rectal versus colon cancer. We hypothesize that there are significant differences in long-term outcomes between patients with metastatic rectal cancer (RC) and those with left-sided colon cancer (LSCC) that may depend on the genetic profile of the primary tumor. 155 patients with synchronous metastases of LSCC and 96 patients with RC were selected for clinical analysis. The TCGA database was used to obtain information on mRNA expression from the "Comprehensive molecular characterization of human colon and rectal cancer" study. 153 patients with LSCC and 41 patients with RC were included in this analysis. Clinical analysis characterized by a significantly more favorable course of the disease after I and I+II lines of chemotherapy for RC group, which may be associated with a higher expression of EBI3, IL-17A, and SOCS1 in the primary tumor. Also, the RC group is characterized by a higher sensitivity to anti-VEGF therapy, which can be explained by a higher expression of VEGF-A, VEGF-D, and KDR-VEGFR2 compared to the LSCC group. Our study shows that when analyzing the effectiveness of antitumor therapy in patients with colorectal cancer, it is necessary to distinguish not only between groups with cancer of the right and left colon, but also to consider rectal cancer as a third independent group.

Breast cancer is the leading cause of cancer-related deaths in women, primarily due to distant metastasis. Metabolic reprogramming plays a critical role in tumor growth and spread, but the metabolic mechanisms underlying metastasis in breast cancer remain unclear. The primary objective of this study is to identify molecular targets mediating breast cancer progression and to evaluate whether targeting the metabolic reprogramming represents a potential therapeutic strategy. To uncover key metabolic regulators involved in breast cancer progression, we analyzed high-throughput RNA sequencing data and identified Paired Like Homeodomain 1 (PITX1) as a frequently upregulated oncogene. Its expression was further validated by immunohistochemistry, quantitative PCR, and western blotting across various metastatic breast cancer tissues. The correlation between PITX1 expression and patient survival was also evaluated. Functional assays were conducted to explore the role of PITX1 in promoting breast cancer proliferation and metastasis. As this study is primarily based on mechanistic cellular and bioinformatic analyses rather than clinical intervention trials, traditional clinical effect size metrics are not directly applicable. However, we have now ensured that all major findings include quantitative effect measurements (e.g., fold changes, hazard ratios where applicable, correlation coefficients) together with corresponding statistical significance values to improve clarity and transparency. Elevated PITX1 expression was significantly associated with poorer overall survival, distant metastasis-free survival, relapse-free survival, and post-progression survival in breast cancer patients. Silencing PITX1 significantly reduced breast cancer cell proliferation and suppressed glycolysis. Mechanistically, we found that PITX1 transcriptionally activates Phosphofructokinase platelet (PFKP), a key glycolytic enzyme, thereby enhancing glycolytic flux to promote tumor growth and metastatic capacity. Notably, isoliquiritigenin was identified as a small-molecule inhibitor that targets the PITX1-PFKP axis, downregulating glycolysis and consequently suppressing breast cancer progression. Our findings uncover a novel oncogenic mechanism by which PITX1 promotes breast cancer progression and metastasis through glycolytic reprogramming. Targeting the PITX1-PFKP axis with isoliquiritigenin offers a promising therapeutic strategy for breast cancer treatment.

Immune checkpoint inhibitors like pembrolizumab exhibit variable efficacy in metastatic gastric cancer (GC). This study aimed to identify molecular drivers of pembrolizumab response, explore mechanisms of immune checkpoint inhibitors (ICIs) efficacy, and develop a prognostic signature. Transcriptomic analysis of pembrolizumab-treated GC (TIGER database) identified 165 response-associated differentially expressed genes (DEGs). Functional annotation and single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) revealed that responder-upregulated genes (R-DEGs) were enriched in immune activation pathways and mainly localized to CD8 + T/NK cells. In contrast, non-responder-upregulated genes (D-DEGs) were linked to extracellular matrix (ECM) remodeling and mainly expressed in fibroblasts/endothelial cells. CellChat analysis demonstrated that key DEGs mediate immune-stromal crosstalk via MHC-I and collagen/laminin signaling. A prognostic signature (Lasso-StepCox[forward] Riskscore; LSR: APOD, APOH, BATF2, GJA1, MAGED1, SLC5A1, SLCO2A1, VWF, VCAN) was derived and validated in four independent GC cohorts from the GEO and Cancer Genome Atlas (TCGA) database. Multi-omics analyses showed that LSR-high tumors exhibited aggressive clinicopathological features, increased stromal components, reduced cytotoxic immune infiltration, diminished tumor mutational burden (TMB), and poorer prognosis. Immunohistochemistry (IHC) and spatial transcriptomics in GC showed that stromal VWF/VCAN expression correlates with reduced CD8⁺ T cell granzyme B expression, suggesting T cell dysfunction. High VWF expression in GC predicted poor survival, and a combined VWF/VCAN score showed enhanced prognostic stratification. This study highlights stromal-immune crosstalk as a driver of pembrolizumab resistance and provides a signature as a clinical tool for prognosis and personalized therapy in metastatic GC.

In the current study, an optimum formulation of alginate-functionalized and PEGylated niosomes (Nio) co-encapsulated with letrozole (Let) and berberine (Ber) was observed for potential preclinical treatment of breast cancer to combat multidrug resistance and reduce drug doses. The incorporation of alginate (AL) and polyethylene glycol (PEG) enabled tunable network architecture, improved colloidal stability, and sustained release behavior of the formulated system. Nio-Let/Ber@PEG and Nio-Let/Ber@AL formulations showed desired entrapment efficiencies of 86.12 and 91.34 for Let and 71.32 and 75.12 for Ber, respectively. Drug release profiles showed that sustained and slower release rates were observed for coated niosomes (Nio-Let/Ber@PEG and Nio-Let/Ber@AL) compared to uncoated niosomes (Nio-Let/Ber). MTT assay showed the IC50 of coated niosomes was much lower than the uncoated formulation and free drugs for MCF-7 and MDA-MB-231 breast cancer cell lines. Moreover, coated niosomal formulations significantly increased the rate of apoptosis induction and cell cycle arrest compared to uncoated niosomes. Also, gene expressions of Bax and caspase 3/8/9 increased while the gene expression of Bcl2 (anti-apoptotic) decreased after treatment with coated niosomes compared to uncoated ones. Taken together, this preliminary research indicated that the co-delivery of Let and Ber through coated niosomal formulations (Nio-Let/Ber@PEG and Nio-Let/Ber@AL) was an efficient controlled dual-drug delivery system to increase the effectiveness of breast cancer therapy.

Breast cancer remains one of the most prevalent malignancies among women worldwide, and despite advances in therapy and treatment options, tumour relapse and metastasis remain major clinical challenges, largely driven by the breast cancer stem cells (BCSCs) niche that resists conventional treatments and regenerates tumours. In breast cancer, where approximately 30% of patients who initially respond to treatment ultimately relapse and die of metastatic disease, targeting BCSCs is critical for improving patient outcomes. Cyclin-dependent kinase inhibitor 1A/p21 (CDKN1A/p21) is a multifunctional protein that is known primarily for its role in regulating the cell cycle in response to DNA damage. However, in this study, we aimed to explore the role of CDKN1A/p21 in the survival and expansion of BCSCs. We used three-dimensional in vitro models to assess the influence of CDKN1A/p21 expression on the survival of BCSCs both under basal conditions and after oxidative damage. Spatial transcriptomics analysis and chromatin immunoprecipitation-quantitative PCR (qPCR) were used to investigate the role of CDKN1A/p21 in the regulation and control of BCSC gene expression signatures. We demonstrated that alterations in CDKN1A/p21 expression affect the ability of breast cancer cells to grow and survive after oxidative damage. Mechanistically, we found that CDKN1A/p21 directly binds to the promoter and regulates the expression of CD44, SPP1, and TMSB10, a combination gene signature that is associated with a greater probability of recurrence and metastasis in breast cancer patients. We propose that changes in gene regulation mediated by CDKN1A/p21 possibly contribute to cancer stem cell survival after oxidative damage, thus making CDKN1A/p21 a promising target for future drug discovery projects aimed at addressing the issue of therapeutic resistance and breast cancer metastasis.

In vivo Chimeric Antigen Receptor (CAR)-T cell therapy reprograms a patient's own T cells directly inside the body, bypassing the complex and costly traditional manufacturing process. This is achieved by systemically delivering viral or non-viral vectors that genetically modify endogenous T lymphocytes to produce functional CAR-T cells de novo. By eliminating ex vivo cell processing, this strategy can simplify workflows, reduce costs, improve accessibility, and allow faster treatment. Key delivery platforms include engineered lentiviral and adeno-associated viral (AAV) vectors for lasting CAR expression and targeted lipid nanoparticles (LNPs) for transient mRNA delivery. Emerging technologies like biomaterial scaffolds and ultrasound stimulation further enable localized and spatiotemporally controlled T cell engineering. Clinically, early trials in relapsed/refractory multiple myeloma and B-cell malignancies have shown strong antitumor responses, even without preconditioning chemotherapy. Remaining challenges comprise achieving precise T cell targeting, overcoming the immunosuppressive tumor microenvironment, preventing antigen escape, and managing safety risks such as vector genotoxicity or LNP reactogenicity. Future translation will depend on combining synergistic regimens, refining vector design, and implementing tunable safety controls. The aim of the study is to highlight how in vivo CAR-T therapy is evolving from concept to clinical reality, poised to redefine adoptive cell therapy as a scalable and widely applicable pharmacologic intervention.

Esophageal cancer (EC) ranks among the most lethal gastrointestinal malignancies. Due to challenges in early diagnosis, molecular heterogeneity, and therapeutic resistance, patient prognosis remains extremely poor, necessitating the development of novel biomarkers and therapeutic targets. As a core effector of the Hippo signaling pathway, the potential significance of Yes-associated protein 1 (YAP1) has garnered increasing attention. This paper aims to systematically summarize the multi-omics research, molecular mechanisms, and preclinical/translational evidence for YAP1, covering its activation pathways, biological functions, clinical significance, and therapeutic strategies. We elucidated YAP1's multidimensional regulatory network in EC, including Hippo-dependent and -independent mechanisms, cross-regulation with environmental risk factors, and its role in malignant phenotypes such as cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), and metastasis. The potential of YAP1 as a diagnostic, prognostic, and predictive biomarker is evaluated, alongside summarizing its role in mediating chemotherapy, radiotherapy, and immune tolerance mechanisms, along with recent advances in targeted therapies. This provides a theoretical foundation for subsequent basic research and precision medicine translation. As a potential hub in the EC signaling network, it is considered to play a key role in driving tumor progression and treatment resistance through multiple pathways. Targeting YAP1 holds broad clinical promise but faces challenges including functional duality, subtype heterogeneity, and complex resistance mechanisms. Future efforts should focus on developing highly selective inhibitors, integrating multi-omics technologies and innovative models to advance clinical translation and provide new strategies for precision treatment of EC patients.

Partial epithelial-mesenchymal transition (p-EMT) is a dynamic cellular state associated with metastasis and adverse outcomes in multiple cancers, but its prognostic significance in ovarian cancer remains unclear. This study aimed to develop and validate an ovarian cancer-specific transcriptomic signature based on p-EMT-related genes, and to determine whether this signature can improve prognostic stratification and overall survival prediction across independent cohorts. A pan-cancer p-EMT gene set was curated from ten published studies. Using transcriptomic and clinical data from TCGA-OV (n = 488), a six-gene p-EMT signature was developed via LASSO regression to generate a patient-specific risk score. The score was integrated with clinical variables to construct a prognostic nomogram and validated in the external GEO cohort GSE140082 (n = 380) and GSE165808 (n = 51). A six-gene p-EMT transcriptomic signature (ADAM9, ANXA8L1, FSTL3, RABAC1, TPM4, and TWIST1) was significantly associated with overall survival (OS) and stratified patients into high- and low-risk groups (adjusted HR = 1.74, p < 0.001). Incorporation with age and FIGO stage in a nomogram improved predictive performance, with AUCs of 0.727, 0.700, and 0.656 at 1-, 3-, and 5-year OS, respectively. External validation in GSE140082 and GSE165808 confirmed model robustness, yielding 3-year AUCs of 0.630 and 0.826, respectively, demonstrating preserved prognostic value across independent cohorts and disease stages. This six-gene p-EMT transcriptomic signature demonstrates prognostic value in ovarian cancer and offers potential for individualized risk stratification and clinical decisionsupport.

Triple-negative breast cancer (TNBC) still poses an important clinical challenge due to its aggressiveness, notwithstanding the increasing amount of treatment options. While radiation therapy (RT) is important for TNBC management, dose-limiting side effects limit its efficacy. FLASH-RT, delivered with ultra-high dose rates, has shown anti-tumour effects comparable to conventional dose rate RT (CONV-RT) but with reduced normal tissue side effects, offering the potential of dose escalation to treat aggressive tumour subtypes such as TNBC. In this study, we investigated TNBC responses to FLASH-RT across gene transcription, immune infiltration, and anti-tumour efficacy. Using subcutaneous and orthotopic 4&#x202f;T1 and MDA-MB-231 murine TNBC models, female BALB/c or Swiss nude mice received single (14 or 20&#x202f;Gy) or fractionated (5&#x202f;&#xd7;&#x202f;5.2 or 10&#x202f;&#xd7;&#x202f;3&#x202f;Gy) doses of either CONV-RT (0.2&#x202f;Gy/s) or FLASH-RT (5-5.79&#x202f;&#xd7;&#x202f;10&#x2076; Gy/s). Tumour growth was monitored, and 4&#x202f;T1 tumours were collected at 24&#x202f;h, 5&#x202f;days, and 2&#x202f;weeks post-irradiation for histology, flow cytometry, and bulk RNA sequencing. All regimens demonstrated iso-efficacy between FLASH and CONV-RT in delaying tumour growth. RNA sequencing revealed that, 24&#x202f;h post-irradiation, FLASH-RT significantly preserved expression of chemokines (NES&#x202f;=&#x202f;2.516), including CXCL9, 10 and 11 which are critical for T cell function. Additionally, FLASH-RT retained interferon alpha and gamma signalling (NES&#x202f;=&#x202f;2.998; 3.235) via the ISGF3 complex, resulting in interferon-stimulated genes expression. While CONV-RT downregulated these genes, histology and flow cytometry showed no differences in immune cell infiltration between modalities. We hypothesize that FLASH-RT's conserved expression of negative regulators of interferon type I and II (NES&#x202f;=&#x202f;2.108 and 1.784 respectively), but also negative regulators of inflammation (NES&#x202f;=&#x202f;1.88), including PD-L1 and IL18BP, may underlie this discrepancy. In summary, while FLASH-RT and CONV-RT are equally effective in delaying tumour growth and modulating the immune response in murine TNBC, transcriptomic analysis uncovered distinct immunomodulatory profiles, suggesting nuanced mechanisms that warrant further investigation.

c&#x2011;Myc, a member of the MYC family, is an extensively studied proto&#x2011;oncogenic transcription factor that plays crucial roles in various biological processes of tumor cells, including proliferation, cell cycle regulation, DNA damage repair, metabolic reprogramming, differentiation and genomic maintenance. Furthermore, in cancer therapeutics, c&#x2011;Myc may serve as a key factor influencing targeted drug efficacy and tumor drug resistance. This review comprehensively summarizes the structural characteristics of c&#x2011;Myc and its roles and key molecular mechanisms across various malignancies, as well as current strategies for c&#x2011;Myc&#x2011;targeted therapies and related clinical trials. Additionally, the existing challenges in c&#x2011;Myc research are discussed and future research directions are being outlined. The synthesis aims to provide novel insights for fundamental research, offer new perspectives for precision cancer therapy in clinical practice and ultimately bring renewed hope for cancer treatment.