Triple-negative breast cancer (TNBC) cells with intact homologous recombination (HR) repair mechanism can survive treatment with Olaparib, which further limits the clinical application of PARP1/2 inhibitors. Previous studies have demonstrated that inhibition of indoleamine 2,3-dioxygenase (IDO) can enhance the sensitivity of human tumor cells to PARP1/2 inhibitors. However, the mechanisms underlying their synergistic effects in the treatment of TNBC remain unclear. Herein, we demonstrate that the combination of Olaparib and Epacadostat significantly reduces the proliferation of BRCA-proficient MDA-MB-231 and MDA-MB-468 cells compared to either monotherapy. Mechanistically, Epacadostat reduces intracellular kynurenine and NAD+ levels, thereby sensitizing TNBCs to PARP1/2 inhibition and significantly amplifying Olaparib-induced DNA damage. Furthermore, Epacadostat and Olaparib synergistically increase cellular reactive oxygen species (ROS), leading to DNA oxidative damage and apoptosis. In vivo, Epacadostat and Olaparib significantly suppressed MDA-MB-468 tumor growth compared to the monotherapy groups, while promoting an increase in phosphorylated H2AX. Notably, the dual inhibition of IDO1 and PARP1/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1/2 represents a promising combination therapy for BRCA-proficient TNBC.

Background/Objectives: Programmed death ligand 1 (PD-L1) is often overexpressed in triple-negative breast cancer (TNBC), where it helps the tumor evade the immune system and promotes tumor growth. Interleukin-24 (IL-24) is recognized for its anti-tumor activity, although its role in immune regulation remains unclear. In this study, we examined the role of IL-24 in regulating PD-L1 and its anti-cancer activity in TNBC cells.

Inflammatory and nested testicular sex cord tumor (IN-TSCT) is a recently characterized malignant neoplasm within the spectrum of testicular sex cord-stromal tumors. Previously misclassified as Sertoli cell tumor, not otherwise specified, or as seminoma, this entity has emerged as a distinct clinicopathologic and molecular subtype defined by recurrent EWSR1::ATF1 gene fusions and a potentially aggressive clinical course. Patients most commonly present with unilateral painless testicular enlargement, and radiologic findings are typically nonspecific. Histologically, tumors demonstrate solid and nested growth patterns, epithelioid cytology with eosinophilic to clear cytoplasm, prominent hyalinized stroma, and a conspicuous inflammatory infiltrate. Immunophenotypically, tumors express sex cord-stromal markers, including steroidogenic factor-1 (SF-1) and inhibin, and frequently co-express epithelial membrane antigen and CD30 while lacking germ cell tumor markers. Molecular studies indicate fusion-driven oncogenesis associated with low tumor mutational burden. Published cases suggest that IN-TSCT may exhibit aggressive clinical behavior, including metastatic spread in a subset of patients; however, the total number of reported cases remains very limited, and the true metastatic risk and prognostic spectrum have not yet been clearly defined. This review synthesizes the available literature to provide a comprehensive clinicopathologic and molecular overview of this emerging tumor entity.

Background/Objective: Although most melanocytic lesions are diagnosed as benign or malignant by histopathologic evaluation, with or without the aid of immunohistochemistry, diagnosis may remain uncertain in a minority of cases. Assessment of copy number abnormalities (CNAs) may provide sufficient additional evidence to favor either a benign or malignant diagnosis in both pediatric and adult cases and in melanocytic lesions of various subtypes, including Spitzoid, mucosal, and acral. CNAs are common in melanomas, while they are rare, with few exceptions, in benign lesions. Detection of CNAs by fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA) has been well established for melanocytic lesions, with advantages and disadvantages for each. The objective of this meta-analysis was to evaluate the utility of CNA testing for the diagnosis of melanoma, across subtypes, when a lesion remains ambiguous after histopathologic and immunohistochemical assessment. In addition, the utility of CNAs to determine prognosis in established diagnoses of melanoma was also evaluated. Methods: The Cancer Genomics Consortium Working Group for Melanocytic Lesions reviewed published data from January 1998 through September 2022 of CNAs in melanocytic lesions detected by either FISH or CMA and conducted a meta-analysis of the findings. Results: Specific abnormalities common in primary cutaneous melanomas of various subtypes and uveal melanomas were enumerated. Differences in CNAs found in primary versus metastatic lesions were also determined, and published evidence for prognosis was summarized. Conclusions: The working group established evidence-based recommendations for the use of CNA testing for evaluation of ambiguous melanocytic lesions.

Soft-tissue sarcomas (STSs) comprise a rare, heterogeneous group of mesenchymal malignancies in which histologic grade remains the strongest determinant of outcome, metastatic risk, and therapeutic strategy. Intermediate/high-grade STSs exhibit a pronounced propensity for early distant relapse, yet growing evidence indicates that metastatic behaviour is not uniform. Within this spectrum, an oligometastatic phenotype, characterised by a limited number of metastases, often confined to the lung, has emerged as a clinically and biologically distinct state associated with more indolent metastatic kinetics and improved survival when treated with aggressive local interventions. However, the criteria that define true oligometastatic STSs remain unsettled, and prospective evidence is lacking. Emerging molecular and immunological correlates provide a potential framework for biological triage. Low genomic complexity (low-risk CINSARC), a B-cell/TLS-rich tumour microenvironment, high immune-cytotoxic signatures, and persistently low or undetectable circulating tumour DNA (ctDNA) are each linked to reduced metastatic competence and may underpin oligometastatic trajectories. Conversely, high chromosomal instability, immunosuppressive microenvironments, and elevated ctDNA levels align with covertly polymetastatic biology despite limited radiographic disease. In this context, artificial intelligence and machinelearning approaches applied to computational genomics, immune profiling, imaging, and liquid-biopsy data offer a powerful strategy to integrate these multi-dimensional features and refine predictions of metastatic behaviour in STS. Oligometastatic STS therefore represents a biologically definable subset amenable to multimodal management integrating local ablative therapies, systemic agents, and immune-based strategies. Prospective, biomarker-stratified trials are needed to validate selection frameworks and optimise treatment sequencing in this evolving therapeutic space.

Background: HER2-low breast cancer is a biologically heterogeneous subgroup in which hormone receptor (HR) expression critically shapes prognosis and treatment, but the underlying regulatory mechanisms remain unclear. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and may contribute to HR heterogeneity. This study aimed to identify deregulated miRNAs and associated gene networks distinguishing HER2-low/HR-positive from HER2-low/HR-negative tumors, elucidating the molecular mechanisms underlying this divergence. Methods: Differential expression analyses of miRNAs and genes were performed using Wilcoxon tests and DESeq2 (|log2FC| > 1; FDR-adjusted p-value < 0.05). Survival analyses were conducted using Cox proportional hazards models to evaluate the individual miRNAs and miRNA signature. Functional enrichment analyses, including GO, KEGG and Reactome pathways, were performed. Correlation analysis and the miRNA target prediction were integrated to identify regulatory interactions. Results: Comparisons between HER2-low/HR-positive and HER2-low/HR-negative tumors identified 165 significantly deregulated miRNAs and 170 strongly deregulated genes. Intersection analysis highlighted miR-9-5p, miR-532-5p and miR-576-5p as specifically associated with HR-negative status. Survival analyses showed non-significant trends for the overall survival and progression-free interval. Functional enrichment analysis revealed hormone-related pathways in HR-positive tumors and immune, inflammatory and proliferative pathways in HR-negative tumors. Integrative correlation and target prediction analyses identified two miRNA-mRNA regulatory axes, miR-576-5p/TGFBI and miR-9-5p/POU2F2. Conclusions: Our study demonstrated that HER2-low breast cancer exhibits distinct miRNA and gene expression profiles, which highlight different transcriptomic profiles according to HR status for the first time. Specific miRNA-gene networks may drive transcriptional heterogeneity, serving as potential biomarkers for stratification and as therapeutic targets. These findings provide insight into the molecular basis of HER2-low tumor diversity and support future development of HR-directed therapeutic strategies.

Non-coding RNAs (ncRNAs) are conserved in the genome of cells across the three domains of life. They comprise a diverse group that are particularly prominent in metazoans where they provide a crucial interface between genes and proteins, participating in key cellular processes at different levels: from control of DNA transcription to modulation of messenger RNA stability to modification of protein activity. The interactions of ncRNAs with one another as well as with other RNAs, DNA and proteins form the basis of a genome-wide regulatory network (GRN). Because of the mutual influence of its components on each other, the GRN is a dynamic system. Further, the GRN imposes constraints on which genes are expressed and when, leading to specific gene-expression patterns or transcriptomes. The configurations of the activities of all gene loci represent self-stabilizing cell states, referred to as "attractor" states, each of which corresponds to a distinct cell type. The cancer cell is also an attractor state that arises from a change in the topography of the epigenetic landscape caused by dysregulation of the GRN. It is proposed that the transition to a neoplastic attractor state is caused by ncRNA alterations, while subsequent somatic mutations of oncogenes and tumor suppressor genes drive cell proliferation and clonal expansion.

Acute myeloid leukemia (AML) is a biologically heterogeneous hematologic malignancy arising from the oncogenic transformation of hematopoietic stem and progenitor cells, resulting in clonal expansion and progressive subclonal diversification. Although considerable advances have deepened our understanding of AML pathogenesis, major challenges persist, particularly regarding relapses and therapeutic resistance. In recent years, exosomes-extracellular vesicles of 30-150 nm in diameter of endosomal origin-have emerged as critical mediators of intercellular communication within the AML tumor microenvironment. These vesicles transport a diverse cargo of proteins, metabolites, and nucleic acids, including mRNA, non-coding RNA species, and DNA, which is selectively packaged during their biogenesis. Circulating exosomes have garnered attention as promising liquid biomarkers for diagnosis, prognosis, and monitoring minimal residual disease, while also representing potential therapeutic targets or delivery platforms. Nonetheless, significant knowledge gaps remain regarding the mechanisms governing exosome biogenesis, cargo selection, and the functional impact on leukemia progression and immune modulation. This review focuses on the role of exosomes in acute myeloid leukemia, with an emphasis on the molecular mechanisms underlying their involvement in pathogenesis, tumor communication, and resistance to therapies, as well as their potential as diagnostic biomarkers.

CDKN2A (p16^INK4a^) is integral to the regulation of the RB-E2F cell-cycle checkpoint and is widely acknowledged as a surrogate marker for high-risk human papillomavirus (HPV)-related cervical neoplasia. Nevertheless, its diagnostic and prognostic significance in uterine corpus endometrial carcinoma (UCEC), a predominantly HPV-independent malignancy, remains inadequately characterized. This study utilized an integrated multi-omics approach to examine CDKN2A dysregulation in cervical squamous cell carcinoma (CESC) and UCEC.

Background: The turnaround of the tumor suppressor p53 protein, the guardian of the genome, is closely regulated to ensure avoidance of its untimely activation, which could lead to the demise of normal cells. Cancer cells often display mutations in the gene TP53 encoding for p53, which interferes with its normal function. Methods: The genomic series of colorectal cancer from the Cancer Genome Atlas (TCGA) was interrogated to discover genomic alterations and determine the mRNA expression of enzymes affecting p53 ubiquitination in colorectal cancers with wild-type and mutant TP53. Results: Genomic alterations of p53-regulating E3 ubiquitin ligases were uncommon in colorectal cancers, the most frequent being mutations in RCHY1. Several p53-regulating E3 ligases were well expressed in subsets of colorectal cancers, two of which, MDM2 and TRIM24, displayed higher mRNA expressions than the normal colorectal epithelia. The former was particularly upregulated in TP53 wild-type colorectal cancers, and the latter was upregulated in both wild-type and mutant TP53 cancers. Upregulation of TRIM24 in TP53 mutant cancers was observed independently of the type of mutations (gain-of-function or other). Among E3 ligases used in proteolysis-targeting chimeras (PROTACs), VHL was upregulated together with its E2-conjugating enzyme UBE2S in colorectal cancers. Conclusions: This survey of p53-targeting ubiquitin ligases provides a roadmap for potential therapeutic strategies working by promoting the destruction of the mutant protein or reactivating its normal function in TP53-mutated colorectal cancers and promoting p53 function by preventing degradation in TP53 wild-type cancers.

To analyze the association between the IRF5 gene variants rs3807135, rs3757385, and rs3778754 and mRNA expression levels in patients from western Mexico diagnosed with melanoma.

Background: Tamoxifen remains the cornerstone of endocrine therapy for hormone receptor-positive breast cancer across Africa. Understanding the factors that influence tamoxifen tolerability is critical, as treatment-related side effects can reduce adherence and compromise therapeutic outcomes. Yet, the contribution of pharmacogenetic variation to tamoxifen-related toxicity remains poorly characterized in African populations. This study, therefore, investigated whether genetic variation in key pharmacogenes influences the risk of treatment-related side effects in a South African breast cancer cohort. Methods: A total of 166 women of Mixed and African Ancestry treated with 20 mg/day tamoxifen at Groote Schuur Hospital, South Africa, were included in the study. Genetic variation across 28 variants in nine pharmacogenes, including CYP2D6, CYP3A4/5, UGT1A4, UGT2B7/15, SULT1A1/2, and SULT1E1, was assessed using various genotyping methods. Associations between genetic and non-genetic factors and tamoxifen side effects were evaluated with logistic regression. Results: Over 70% of participants reported at least one treatment-related side effect. Overall side-effect burden was associated with SULT1A1 copy number variation (p = 0.030) and SULT1E1 rs3736599 (p = 0.042). Musculoskeletal complaints were the most common (40%) and were associated with UGT2B7 rs7439366 (p = 0.040) and CYP3A4 rs2242480 (p = 0.051). Gynecological symptoms affected more than 20% of participants and were linked to SULT1A2*2 (p = 0.050), SULT1E1 rs3736599 (p = 0.016), and UGT2B15 rs4148269 (p = 0.039). Hot flashes were frequent, affecting 33% of patients, but showed no clear pharmacogenetic associations. Conclusions: This study demonstrates that pharmacogenetic variation is associated with interindividual differences in treatment-related side effects, underscoring the need to expand research in African populations to better inform precision endocrine therapy.

Progesterone receptor (PR) regulates gene expression through recruiting coregulators and general transcription factors by activation functions AF1 and AF2. AF1 localizes to the non-conserved and disordered N-terminal domain and is believed to facilitate tissue- and gene-specific activity. Our previous proteomic analysis identified three key residues (K464, K481 and R492) in AF1 that are monomethylated. Methylation mimic mutations KKR → FFF created hypoactive PR, whereas the KKR → QQQ mutation generated hyperactive PR in gene reporter assays. The current study used these mutants to determine the roles of AF1 in PR regulation of cellular activities and global gene regulation in breast cancer cells MCF-7. AF1-FFF mutation attenuated PR regulation of cell proliferation and apoptosis in response to progestin, whereas AF1-QQQ mutation enhanced these effects. AF1-FFF mutation attenuated gene regulation by progestin in ~60% of PR target genes, including genes involved in cell proliferation, hypoxia and TNFα signaling. However, the AF1-FFF mutation had little effect on ligand-independent gene regulation, suggesting distinct mechanisms of gene regulation by liganded and unliganded PR. Intriguingly, impaired activity of methylation mimic mutant PRB-FFF is associated with greater chromatin binding in ChIP-Seq analysis, corresponding to a stronger association between PRB-FFF and Steroid Receptor Coactivator-1 (SRC-1), a member of the p160 family of nuclear receptor coactivators, as was previously reported. In conclusion, PR AF1 is important for the core activities of liganded PR in regulating ~half of target genes and cell proliferation. AF1 monomethylation may modulate PR-chromatin interactions through stronger association with coregulators, thereby decelerating chromatin binding kinetics. This is supported by PRODIGY's prediction of higher binding affinities of monomethylated AF1 and methylation mimic mutant with SRC-1.

Bladder cancer (BCa) is the second most common cancer of the genitourinary tract globally. It has limited treatment options, high recurrence rate, and acquires resistance to platinum-based therapy. Therefore, identifying novel therapeutic targets is urgently needed. Analysis of the TCGA data revealed that the enzyme galactokinase-1 (GALK1) is overexpressed (p < 0.0001) in bladder tumors compared to normal tissue. Our data also confirmed GALK1 protein upregulation in multiple human BCa cell lines and rodent bladder tumors. However, the precise role of GALK1 in BCa progression and effects of its specific inhibitor remain unexamined. In this study, we demonstrate that GALK1 gene silencing using shRNA resulted in a significant reduction in BCa cell proliferation, migration, and invasion. Pharmacological inhibition of GALK1 using small molecule Cpd36 resulted in anticancer efficacy against BCa. Cpd36 inhibited proliferation, migration, and invasion of BCa cells. Further, Cpd36 induced G1 phase cell cycle arrest, apoptosis, mitochondrial membrane depolarization, and ROS production in the BCa cells. Mechanistically, Cpd36-induced reduction in cell proliferation was associated with a decrease in expression of GALK1, PCNA proteins. Inhibition of metastatic potential was accompanied by decreased migration, invasion, and MMP-9 expression. Cell cycle arrest was associated with decrease in Cyclin D1 and increased expression of p21 and p27. Induction of apoptosis was linked with increased expression of cleaved caspase-3 and cleaved PARP, while downregulating p-AKT. Additionally, Cpd36 in combination with cisplatin or gemcitabine showed a strong synergistic effect on BCa cells. Taken together, our findings suggest that GALK1 plays a significant role in BCa cell survival and validates its inhibitors as promising therapeutic options for managing this disease.

Upstream binding transcription factor (UBTF) is a nuclear transcription factor implicated in ribosome biogenesis, yet its pancancer relevance and immunological associations remain incompletely understood. We integrated datasets from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Cancer Cell Line Encyclopedia (CCLE), and cBioPortal databases to characterize UBTF expression, genomic alterations, and prognostic value across 33 cancer types. Immune microenvironment analyses were performed using ESTIMATE and multiple deconvolution algorithms. CRISPR-Cas9-mediated UBTF depletion was conducted in breast invasive carcinoma (BRCA) cell lines to evaluate functional roles. UBTF was broadly upregulated in multiple tumors with recurrent copy number gains. Survival analyses revealed cancer type-dependent prognostic associations. UBTF expression correlated with immune/stromal contexture, checkpoint features, and predicted immunotherapy response. In BRCA, UBTF depletion reduced proliferation and migration while increasing apoptosis. A UBTF-related prognostic signature effectively stratified patient outcomes and was associated with immune infiltration and predicted immunotherapy response. UBTF represents a pancancer biomarker linked to tumor immunity, with validated functional significance in BRCA and potential utility for risk stratification.

Cancer remains a significant challenge to global public health. Preliminary studies indicate that the protein Golgi-associated, Gamma-adaptin Ear Containing, ARF Binding Protein 2 (GGA2) may influence various cancers. However, the potential role of GGA2 in oncogenesis remains unknown. We utilized data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) projects to analyze GGA2 expression levels. Genetic variations and protein expression of GGA2 in human tissues were assessed using the cBioPortal. Gene Set Enrichment Analysis (GSEA) provided deeper insights into GGA2's oncogenic functions. Comprehensive analysis of TCGA datasets combined with ESTIMATE and TIMER tools demonstrated significant correlations between GGA2 expression levels and clinical outcomes, survival metrics, genomic instability markers (microsatellite instability (MSI)/tumor mutational burden (TMB)), and immune microenvironment composition. Functional validation in prostate cancer models employed qRT-PCR quantification, immunoblotting verification, and cellular behavior assessments through colony formation, Transwell migration, and wound closure assays. Our findings suggest GGA2 could serve as a prognostic biomarker in various cancers. Abnormal levels of GGA2 promoter methylation and genetic alterations may contribute to its dysregulated expression in some cancers. Distinctly, GGA2 expression correlates with MSI and TMB across different cancers and is linked to the expression of immune checkpoint genes. Functionally, GGA2 is instrumental in inhibiting oncogenic mechanisms by diminishing the proliferation, colony formation, invasion, and migratory capabilities of prostate cancer cells. Our study shows that the oncogenic role of GGA2 in various cancers and GGA2 could be served as a biomarker of PARD.

Alzheimer's disease (AD) and cancer are both age-related conditions, yet numerous large-scale epidemiological studies have consistently documented an inverse association, with individuals diagnosed with cancer exhibiting a reduced risk of AD and vice versa. Although this relationship has been replicated across diverse populations, its biological basis remains poorly understood. To address this gap, the present study applies a framework that integrates locus-level genetic correlation (rg) with genetically regulated gene expression to clarify the molecular factors contributing to the inverse epidemiological patterns observed between the two diseases. We used the largest available genome-wide association studies (GWAS) (Nmax = 448,150) to quantify local genetic correlations between AD and several age-associated cancers, including breast, prostate, lung, colorectal, melanoma, basal cell carcinoma, bladder, and endometrial cancer. Eight genomic regions showed significant negative local rg, at the 19q13.31-19q13.32 locus demonstrating strong negative correlations across multiple cancers, including breast, prostate, lung, melanoma, and endometrial cancer. To evaluate the contribution of genetically regulated gene expression, we conducted transcriptome-wide association studies (TWAS) using precomputed gene expression weights from cancer tissues (The Cancer Genome Atlas-TCGA), disease-agnostic tissues (Genotype-Tissue Expression-GTEx), and brain tissue (dorsolateral prefrontal cortex-DLPFC). For each AD-cancer pair, we prioritized genes that were nominally significant in both traits (p < 0.05) and exhibited inverse TWAS Z scores. This analysis identified 24 genes with opposite effect directions between AD and at least three cancer types. TWAS signals also aligned with local rg findings at the 19q13.31-19q13.32 region, suggesting that regulatory variation near this locus contributes to shared but opposing genetic effects beyond the canonical APOE signal. Across cancer types, genes inversely associated with AD converged on pathways involved in cell cycle regulation, apoptosis, DNA-damage response, and metabolic processes. These results support the hypothesis that biological mechanisms promoting proliferation and survival in cancer may oppose those contributing to neurodegeneration in AD.

Alterations in tight junction (TJ) organization and dysregulation of cancer stem cell (CSC)-associated markers are increasingly recognized as molecular features linked to colorectal cancer (CRC) progression, heterogeneity and clinical outcome. Bioactive dietary compounds such as spermidine (SPD) and eugenol (EUG) have been proposed as modulators of cancer-related molecular pathways; however, their combined effects on CRC spheroid models relevant to molecular characterization remain insufficiently defined. In the present study, the molecular impact of SPD and EUG, administered individually or in combination, was evaluated in primary and metastatic CRC spheroids. First-generation spheroids derived from Caco-2 and SW620 cells were exposed to SPD, EUG, or SPD+EUG at the time of seeding, and spheroid growth and self-renewal capacity were monitored across successive generations. The expression of TJ- and CSC-associated markers was assessed at both the transcript and protein levels using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting and immunohistochemistry. The combined SPD+EUG treatment was associated with a marked reduction in spheroid area and self-renewal capacity in both CRC models. Baseline molecular profiling revealed higher TJ marker expression in Caco-2 spheroids and enrichment of CSC-associated markers in SW620 spheroids. Treatment-induced modulation of CSC- and TJ-related transcripts was observed; however, transcript-level changes were not consistently mirrored at the protein level, indicating the involvement of post-transcriptional regulatory mechanisms. In particular, Occludin (OCLN), Zonula occludens-1 (ZO-1), CD133, ALDH1A1, SOX2 and VE-cadherin exhibited divergent RNA and protein expression patterns depending on cell type and treatment condition. Collectively, these findings underscore the relevance of three-dimensional CRC spheroid models for molecular profiling studies and highlight the importance of integrating transcript- and protein-level analyses when evaluating bioactive compounds with potential diagnostic and translational relevance in colorectal cancer.

Vitamin B6 is an essential micronutrient whose biologically active form, pyridoxal 5'-phosphate (PLP), acts as a cofactor in metabolic reactions linked to tumorigenesis and also functions as an antioxidant. Low plasma PLP levels are consistently associated with cancer, but studies on dietary intake have yielded conflicting results. Overall, evidence suggests that the effects of vitamin B6 deficiency on cancer are context-dependent, varying with cell type and tumor stage. Accordingly, high expression of PDXK and PNPO, two key genes involved in PLP biosynthesis, is associated with tumor progression in some malignancies, whereas it correlates with improved outcomes in others. This review explores Drosophila melanogaster as a useful model to investigate underlying mechanisms, bypassing the limitations of human studies. Research in Drosophila demonstrates that PLP deficiency promotes cancer by triggering genomic instability. Furthermore, a critical PLP-SHMT gene-nutrient interaction impacting oncogenesis has been established in flies, offering significant therapeutic implications. Finally, studies in Drosophila have shown that PLP deficiency can promote tumor development by also triggering the loss of heterozygosity (LOH). These findings highlight Drosophila as a powerful tool to elucidate the molecular pathways linking vitamin B6 deficiency to cancer.

Neurofibromatosis type 1 (NF1) and NF2-related schwannomatosis (NF2-SWN) are major genetic tumor predisposition syndromes characterized by progressive, often debilitating neoplasms of the peripheral and central nervous systems. Over the past five years, substantial advances in molecular genetics, signaling biology, and targeted therapeutic development have reshaped diagnostic and management paradigms for both disorders. This Perspective synthesizes recent developments, including gene-based reclassification, emergence of MEK inhibitor therapy in NF1, renewed evaluation of bevacizumab and kinase-pathway inhibitor brigatinib, the discovery of a novel TβR1-RKIP pathogenic axis, and a brain-penetrant HDAC inhibitor in NF2-SWN. These insights highlight a shift toward precision-medicine strategies and mechanistically driven therapies poised to redefine future clinical care.