LIMD1, a tumour suppressor located at chromosome 3p21.3, is frequently lost in non-small-cell lung cancer, yet its role in tumour-immune interactions remains unclear. Here, we show LIMD1 loss increases PD-L1 protein abundance across multiple lung cancer models and primary airway epithelial cells. Mechanistically, LIMD1 restrains PD-L1 through post-transcriptional and post-translational mechanisms. LIMD1 loss can relieve microRNA-mediated repression of the CD274 3'UTR, and LIMD1 loss can also disrupt ARIH1-PD-L1 association, reduce PD-L1 polyubiquitination, and stabilise PD-L1 protein without a commensurate increase in CD274 transcript levels in isogenic models. Functionally, LIMD1-deficient tumour cells suppress CD8+ T-cell activation in vitro and show enhanced sensitivity to PD-1/PD-L1 blockade in tumour-PBMC co-culture assays. Analysis of TRACERx non-small-cell lung cancer samples revealed clonal LIMD1 loss of heterozygosity in ∼40% of lung adenocarcinomas, where it is associated with increased tumour PD-L1 expression. Across independent patient cohorts receiving immune checkpoint blockade, low LIMD1 expression was enriched among responders. We identify LIMD1 as a tumour-intrinsic regulator of PD-L1 turnover and suggest that tumour suppressor loss can shape immune checkpoint biology and influence immunotherapy response.

Molecular classification has refined risk stratification in endometrial cancer and is now incorporated into the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system. However, prospective real-world data on its impact on multidisciplinary tumor board (MDT) decision making remain limited. We evaluated the impact of molecular information on adjuvant treatment recommendations in stage I to II endometrial cancer.

Breast cancer represents a major public health burden in Sudan, where most patients are diagnosed at advanced stages and access to comprehensive diagnostic and molecular services remains limited. Current treatment strategies are largely extrapolated from non-African populations, despite the substantial genetic diversity across African populations that may significantly influence drug response, efficacy, and toxicity. Pharmacogenomics offers a promising approach to optimize breast cancer therapy through genetically informed treatment decisions; however, its clinical application in Sudan and across Africa remains limited. This narrative review synthesizes published evidence on pharmacogenetic determinants influencing breast cancer treatment, with a particular focus on African and Sudanese populations. Relevant studies published between 2005 and 2026 were identified through searches of PubMed, Google Scholar, and PharmGKB. A qualitative synthesis was conducted to summarize key pharmacogenes, population-specific genetic variability, and their potential clinical and therapeutic implications. Considerable interethnic variability has been reported in pharmacogenes involved in drug metabolism and transport, including CYP2D6, CYP3A4, CYP2B6, DPYD, and ATP-binding cassette transporter genes. African populations exhibit distinct allele frequency patterns that may substantially affect drug disposition, therapeutic efficacy, and toxicity, particularly for endocrine therapies and commonly used chemotherapeutic agents. These differences limit the direct applicability of pharmacogenomic data derived from European and Asian populations and underscore the need for population-specific evidence. Integrating pharmacogenomics into breast cancer management has the potential to improve treatment effectiveness and safety in Sudan. Achieving this goal requires the generation of locally relevant pharmacogenomic data, strengthened diagnostic and laboratory infrastructure, and a stepwise, context-appropriate incorporation of pharmacogenomic principles into clinical practice. Such an approach is important to support equitable and effective precision oncology for Sudanese and African populations.

Motivated by the rising incidence of cancers at younger ages, this study compares tumor genomic alterations between adolescents and young adults (AYAs; 18-39 years) and non-AYAs (40 years and older) and explores the relationship with continuous age in patients with relapsed/refractory ovarian, breast, and colorectal cancers accrued to the NCI-MATCH trial.

Metronomic chemotherapy with oral capecitabine + vinorelbine (Cape + VNL) provides synergistic cytostatic activity and antiangiogenic and immunomodulatory effects, potentially offering prolonged disease control with limited toxicity in HER2-negative metastatic breast cancer (MBC). However, efficacy in the real-world (RW) setting, especially in late lines, and the impact of dihydropyrimidine dehydrogenase (DPYD) polymorphisms on dose reduction and safety remain limited.

Chemoradiotherapy (CRT) is a standard treatment for rectal cancer, yet patients show marked variability in response. Identifying reliable biomarkers that predict CRT response remains an unmet clinical need.

Ropeginterferon alfa-2b, a novel monopegylated interferon with improved pharmacokinetics, has emerged as a promising cytoreductive agent for managing polycythemia vera (PV). Despite increasing adoption, evidence synthesis of its efficacy and safety compared to standard care remains limited. The manuscript aimed to evaluate the efficacy of ropeginterferon alfa-2b in comparison to standard treatment options, including hydroxyurea and phlebotomy, in achieving complete hematologic response, partial molecular response (PMR), and reducing JAK2V617F allele burden in patients with PV.

There is a growing number of research suggesting that there is an association between gut microbiota and central nervous system (CNS) tumor. However, the causal relationships and the mediation effects of inflammatory proteins in the associations are unclear. We extracted genetic variants associated with gut microbiota, inflammatory proteins, and 4 subtypes of CNS tumors from published genome-wide association studies and performed a Mendelian randomization analysis to identify potential causal effects. The inverse variance weighted method was used as the main method. Mediation analysis and single-cell RNA-seq analysis were performed to explore the mediation effects and the expression in cells. This study identified 73 gut microbial taxa and 11 inflammatory proteins that were significantly associated with CNS tumors. The inflammatory proteins may act as intermediate mediators in the potential causal association between gut microbiota and 4 CNS tumor subtypes. Mediation analysis suggested that CX3CL1 may partially mediate the relationship between gut microbiota and Glioblastoma, while Eotaxin, CSF-1, IL-15RA and the other 5 cytokines may serve as subtype-specific potential mediators for the remaining 3 tumor types. Our research supports a hypothesized "gut-immune-brain" axis that may mediate the effects of gut microbiota on different CNS tumor subtypes, with distinct immune proteins implicated for each. These findings strongly suggest potential targets for microbiome therapy and immune therapy, though the underlying mechanistic links require experimental validation.

Mitochondria activate immunity, but the role in cancer is unknown. Here, we report that transgenic expression of Parkin, a regulator of mitochondrial fitness, induces inflammation and interferon (IFN) gene signatures, suppresses prostate cancer formation and generates CD8+ and CD20+ intraprostatic immune aggregates. These had hallmarks of mature tertiary lymphoid structures (TLS), expressing markers of B cell maturation (CXCL13, CCL21), germinal center formation (BCL6, GL7), mature dendritic cells (MHC-II/CD208) and high endothelial venules (LYVE-1). Parkin TLS showed high Ig gene expression, recruitment of CXCR5+ follicular T helper cells and expansion of CD69+/KLRG1+ effector T cells. Conditioned medium from Parkin-positive cells expanded memory B and plasma cells, increased IgG1 production, and sustained B and T cell migration. Finally, conditional expression of Parkin induced TLS formation, upregulated Ig chains and inhibited prostate cancer growth, in vivo, whereas Parkin reconstitution in IFNAR1, CD8 or CD20 knockout mice had no effect. Therefore, mitochondrial immunity orchestrates antitumor responses, and TLS formation contributes to tumor suppression.

The molecular mechanisms by which KMT2A-rearranged (KMT2A-r) leukemias maintain the oncogenic FLT3 expression remain largely unclear, limiting therapeutic opportunities. Here, we identify the RNA binding protein MBNL1 as an unexpected positive regulator of FLT3 by DepMap dataset exploration and combinatorial CRISPR screens. MBNL1 promotes leukemia cell survival in cell lines and primary tumors by sustaining FLT3 expression in a KMT2A-r context-dependent manner. Mechanistically, we discover that MBNL1 recognizes a structured single-stranded DNA (ssDNA) element containing five consecutive guanines within the FLT3 enhancer, through MBNL1's zinc finger domains and the carboxyl-terminal unstructured region. Such MBNL1 protein/ssDNA interaction was evident in KMT2A-r leukemia using ChIP-seq and KAS-seq. Mutations of key amino acids of MBNL1's ssDNA binding surface or the critical guanines in ssDNA markedly abrogate the protein-ssDNA interactions. These findings implicate MBNL1 as a distinct FLT3 activator by recognizing a structured enhancer ssDNA element, highlighting an unexpected role for RNA binding proteins in transcriptional regulation through direct ssDNA recognition.

Melanoma plasticity drives immune evasion and therapy resistance through dynamic cell-state transitions beyond genetic alterations. Although epigenetic remodeling is central to this process, its impact under therapeutic pressure remains unclear. We profiled longitudinal biopsies from patients with melanoma treated in the phase 1b NIBIT-M4 epi-immunotherapy trial [NCT02608437, DNA (cytosine-5)-methyltransferase 1 inhibitor plus anti-CTLA-4] using single-cell multiome and spatial transcriptomics. Seven malignant meta-programs were identified, including a rare Wnt/β-Catenin melanocytic state and a dedifferentiated neural crest-like state enriched in nonresponders. Spatial analyses showed that homotypic clustering stabilizes resistant programs, with neural crest-like cells forming compact niches. Responders displayed enrichment of antigen presentation/interferon program and coordinated T and B cell expansion, whereas nonresponders retained stable neural crest-like clusters. Epigenetic therapy reactivated transposable elements, priming innate immunity and enhancing immunogenicity. Nuclear factor of activated T cells, cytoplasmic 2 (NFATC2) emerged as a master regulator of neural crest-like states and resistance; its perturbation promoted differentiation and immunogenicity. These findings define mechanisms of resistance and nominate β-Catenin and NFATC2 as therapeutic vulnerabilities.

Epidermal Growth Factor Receptor (EGFR) is often present on the cell surface of a wide variety human malignancies, including non-small-cell lung cancer (NSCLC), glioblastoma (GBM), pancreatic ductal carcinoma (PDC), and castration-resistant prostate cancer (CRPC). Efforts to optimize immunotherapies targeting EGFR are limited by murine intolerance of human EGFR. To overcome this obstacle, we developed C57BL/6 mice in which a truncated variant of human EGFR (hEGFRt), lacking the ligand binding domain and cytoplasmic domain, is expressed from the CAG regulatory elements comprised of the CMV enhancer, β-actin promoter, and β-globin poly-adenylation signals. Cetuximab, a high-affinity, clinically available anti-human EGFR antibody, retains affinity for hEGFRt. The hEGFRt cDNA in the CAG-hEGFRt transgene is flanked by loxP sites to enable its excision thereby reducing interaction of hEGFRt-directed immunotherapies with normal tissues. The CAG-hEGFRt(f/f) transgene is abundantly expressed in hematopoietic lymphoid and myeloid cells, with low-level expression evident also in non-hematopoietic liver, lung, kidney, and brain. Mx1-Cre-mediated transgene excision in adult mice reduces hEGFRt ~ 5-fold in blood mononuclear cells. CAG-hEGFRt(f/f) adult mice are tolerant of syngeneic NSCLC, GBM, prostate, and PDC lines expressing hEGFRt. These mice retain hEGFRt tolerance after transgene deletion. CAG-hEGFRt(f/f) mice provide a new and important tool for the development of immunotherapies targeting hEGFR.

Atezolizumab plus bevacizumab (ATZ/BEV) is a standard first-line therapy for advanced hepatocellular carcinoma (HCC); however, many patients do not achieve meaningful tumor regression. The temporal and spatial immune remodeling associated with ATZ/BEV remains poorly understood.

In recent years, chronic lymphocytic leukemia (CLL) has undergone a radical change in the therapeutic landscape, allowing for the complete omission of chemotherapy in favor of targeted drugs. This reflects the improved understanding of the pathogenesis and biology of the disease, including both the genetic landscape of the leukemic clones and the crucial role of the numerous connections with the tumor microenvironment (TME). Regarding the latter, both in the bone marrow and in the lymph nodes, tissue architecture and function are reshaped by the lymphoid infiltrate to co-opt surrounding bystander cells, thereby supporting leukemic cell proliferation and survival. In this review, we explore the peculiarities of the CLL TME and how they translate into remarkable changes in the lymph nodal structure and in the inter-cellular interactions. We will elaborate on the potential that new multi-omics technologies might have in understanding the complex interplay occurring between CLL cells and TME.

Prostate-specific antigen (PSA) screening lacks specificity, particularly within the 4-10 ng/mL diagnostic gray zone, leading to unnecessary prostate biopsies and overtreatment. Here, we developed and validated a streamlined urine DNA methylation assay for non-invasive prostate cancer (PCa) detection and biopsy decision-making. Tissue-based Methylated DNA Immunoprecipitation Sequencing (MeDIP-seq) was integrated with large-scale public methylome cohorts to identify PCa-specific hypermethylated regions. Candidate markers were further refined by targeted bisulfite sequencing (TBS) and translated into quantitative PCR (qPCR) assays using post-prostatic massage urine samples. In a retrospective development cohort of 348 participants, stepwise marker selection and logistic regression modelling generated a compact two-gene methylation assay comprising ADD3_2 and GSX2_2. The model was then evaluated in an independent prospective multicenter cohort of 200 participants. The assay achieved robust diagnostic performance, with areas under curve (AUC) of 0.86 in the development cohort and 0.91 in the validation cohort, while maintaining specificity above 90%. Performance was preserved in the PSA gray zone and for clinically significant PCa (csPCa). Decision curve analysis (DCA) indicated that integrating this tool could safely avert approximately 55% of unnecessary biopsies without compromising cancer detection. This simple qPCR-based two-gene urine methylation assay provides a scalable, cost-effective and non-invasive complement to PSA-based PCa screening.

Despite advances in treating acute lymphoblastic leukemia (ALL), resistance to asparaginase (ASNase) remains a major clinical hurdle. Recent evidence suggests that leukemic cells may evade ASNase-induced cytotoxicity by upregulating the glutamate/aspartate transporter EAAT1 (SLC1A3). This study aimed to evaluate whether pharmacological inhibition of EAAT1 using UCPH-101 could enhance the inhibitory effects of ASNase in T-ALL models.

High-level MET gene amplification is a rare but potentially actionable alteration in gastric cancer. Previous phase III trials of MET-targeted therapies enrolled broadly MET-positive populations without prospective selection for high-level MET amplification, and no MET-directed therapy is currently established for this disease. Here, we report a 74-year-old woman with heavily pretreated metastatic gastric adenocarcinoma harboring high-level MET amplification (copy number 21) identified by comprehensive genomic profiling. Following expert panel review, the patient received capmatinib through the BELIEVE trial (NCCH1901; jRCTs031190104) and achieved a confirmed partial response at 8 weeks, with a 43.7% reduction in the sum of target lesion diameters. The response was maintained at 16 weeks; disease progression was observed at 24 weeks, with a progression-free survival of approximately 5.5 months. In the context of a literature review of MET-targeted therapies in gastric cancer, this case supports further investigation of selective MET inhibition in gastric cancer with high-level MET amplification, a rare molecular subset not prospectively enriched in previous clinical trials.

Targeted immunotherapies have transformed the treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), yet their efficacy depends on sustained expression of lineage-associated surface antigens. This review examines how antigen-directed pressure reshapes the biology of resistance, distinguishes canonical antigen escape from lineage plasticity, and clarifies the genomic contexts, diagnostic challenges, and therapeutic implications of these distinct escape routes.

Total neoadjuvant therapy (TNT) has emerged as a key treatment paradigm for locally advanced rectal cancer, reducing distant metastasis rates and facilitating organ preservation in selected patients. However, treatment response remains heterogeneous, highlighting the need for biomarkers that can guide treatment selection and optimise outcomes. This narrative review synthesises the current evidence regarding tumour-intrinsic genomic biomarkers associated with response to neoadjuvant therapy, encompassing somatic mutations, germline polymorphisms, gene expression profiles, mismatch repair (MMR) status, protein expression, epigenetic markers, and circulating tumour-derived biomarkers across conventional chemoradiotherapy (CRT) and TNT paradigms. Across the reviewed literature, individual somatic mutations, including KRAS, TP53, and BRAF, demonstrated limited reproducibility as predictive biomarkers, although KRAS mutations were recurrently associated with lower pathological complete response (pCR) rates in CRT-era cohorts. Germline polymorphisms in DNA repair (XRCC1) and folate metabolism (MTHFR) genes showed inconsistent associations with treatment response. In contrast, transcriptomic biomarkers demonstrated greater biological coherence, with proliferative, epithelial-mesenchymal transition, and metabolic signatures frequently associated with treatment resistance, while multi-gene classifiers generally outperformed single-gene markers. Among currently available tumour-intrinsic biomarkers, MMR deficiency was the most consistently reported biomarker associated with reduced response to fluoropyrimidine-based regimens, including TNT, although TNT-specific evidence remains comparatively limited. Dynamic circulating tumour DNA (ctDNA) monitoring, particularly ctDNA clearance during or after therapy, was consistently associated with pathological response and long-term oncologic outcomes across reviewed studies, whereas baseline ctDNA levels showed limited predictive value. Overall, the reviewed literature suggests that biomarker research in rectal cancer has evolved from single-gene analyses towards pathway-level and dynamic biomarkers. The integration of transcriptomic signatures, MMR status, and dynamic ctDNA monitoring may represent a promising strategy for personalising neoadjuvant therapy, improving patient selection for organ-preserving approaches, and enhancing oncologic outcomes in locally advanced rectal cancer. Nevertheless, the evidence base remains heterogeneous, and further prospective validation, assay standardisation, and evaluation within contemporary TNT cohorts are required before these biomarkers can be routinely incorporated into clinical decision-making.

Extranodal involvement (ENI) is incorporated into routine risk assessment for diffuse large B-cell lymphoma (DLBCL), but treating ENI as a single binary adverse feature may conceal clinically relevant heterogeneity in extranodal burden, anatomical distribution, treatment feasibility, and immune-molecular context. We evaluated ENI as a burden- and site-aware phenotype rather than as a uniform descriptor. We retrospectively studied 710 adults with newly diagnosed DLBCL treated with first-line immunochemotherapy between June 2011 and December 2024. Outcomes were analyzed according to ENI status, number of extranodal sites, and involved organs. Targeted sequencing was available in 176 tumors, and RNA sequencing was performed in 107 quality-controlled tumor samples. Clinical models were interpreted as adjustment models because ENI burden overlaps with established risk factors; site-specific and molecular analyses were prespecified as exploratory and were interpreted with attention to available-case denominators, treatment heterogeneity, sparse subgroups, and multiplicity. ENI was associated with inferior overall survival (OS) and progression-free survival (PFS) in unadjusted analyses. Multisite ENI was enriched for adverse baseline features, including advanced Ann Arbor stage, elevated lactate dehydrogenase (LDH), higher International Prognostic Index (IPI), and impaired performance status. After multivariable adjustment, the independent prognostic contribution of ENI burden was attenuated, indicating substantial clinical overlap with systemic disease burden and host fitness. Several anatomical sites showed candidate adverse signals, but rare-site estimates were limited by small subgroup sizes, wide confidence intervals, and multiple testing. Targeted sequencing and RNA-seq suggested heterogeneous genomic and immune-transcriptional patterns across ENI categories; these results should be regarded as hypothesis-generating because of tissue availability, tumor-only sequencing in many cases, modest molecular sample sizes, and lack of orthogonal immune validation. ENI in DLBCL is best interpreted as a clinically heterogeneous disease descriptor rather than a single uniform prognostic category. ENI burden and anatomical distribution provide useful descriptive and prognostic context, but they should be interpreted alongside established clinical risk, treatment intensity, censoring patterns, tissue-sampling constraints, and molecular ascertainment limitations. Exploratory genomic and immune-transcriptional correlates identified in this study require prospective multicenter validation with harmonized staging, treatment-intensity annotation, matched-normal sequencing, and spatial or cellular immune profiling before ENI-informed biological or therapeutic stratification can be applied clinically.