The molecular analysis of urine cell-free DNA offers a noninvasive tool to advanced bladder cancer (BC) management. Assessment of somatic copy number aberration (SCNA) and DNA methylation analysis have emerged as promising approaches for BC detection. Here, we developed an integrated analysis to assess both SCNA and targeted methylation changes from the same template molecules, which we named the integrated sequencing-based copy number and methylation analysis in urine (iSECURE) method.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare yet highly aggressive subtype of non-small cell lung carcinoma (NSCLC) with limited therapeutic options. We conduct a comprehensive proteogenomic analysis of LCNEC using tumors and paired normal adjacent tissues from 107 patients (81 pure LCNEC and 26 combined LCNEC). APOBEC mutational signatures strongly correlate processes of tumor initiation and immune suppression, and KEAP1 mutations correlate with metabolic reprogramming in LCNEC combined with NSCLC. A conflicting relationship is observed between neuroendocrine and immune phenotypes. We identify three LCNEC subtypes with unique prognosis features, microenvironment dysregulation, genetic alterations, and potential therapeutic targets. Interleukin-33 (IL-33) emerges as a critical therapeutic biomarker associated with enhanced T cell infiltration and antitumor activity. We further optimize recombinant IL-33 (rIL33) with site-directed mutagenesis and develop PEGylated rIL33, demonstrating its prolonged circulation time in cynomolgus monkeys and superior immune agonist activity in mouse models. Overall, this study offers insights into LCNEC biology and provides promising innovative immunoagonist therapy strategies for lung cancer.

Myasthenia gravis (MG) presents a clinical challenge where autoantibody titers poorly predict disease severity, and thymectomy provides inconsistent benefits. We hypothesized that thymic B cells acquire survival mechanisms that bypass canonical tolerance checkpoints, enabling persistence independent of antigen-specific selection. Using single-cell RNA sequencing, V(D)J repertoire analysis, and spatial transcriptomics to generate the largest MG atlas to date (237,661 cells), we identified a tolerance checkpoint swap in MG pathogenesis. Pathological class-switched B cells within thymic germinal centers exhibited reduced antigen presentation (CD74 and CD1C) and diminished CD40 costimulation while up-regulating TNFRSF17 to engage BAFF-driven survival. This shift allows polyclonal autoreactive B cells to evade stringent selection and seed peripheral sites. T follicular helper cells supported this reprogramming via increased TNFSF13B and CHGB expression, with the latter facilitating dopamine-mediated synaptic acceleration. These findings offer insight into clinical paradoxes in MG and point to the BAFF-BCMA axis as a potential therapeutic target and biomarkers for disease activity.

Remodeling of fatty acid metabolism is increasingly recognized as a critical feature of tumor progression, yet the contribution of very long-chain fatty acid (VLCFA) remains incompletely understood. The elongation of VLCFAs, which is mediated by four consecutive enzymes in the endoplasmic reticulum (ER), has been implicated in tumor progression. However, the molecular mechanisms underlying VLCFA elongation enzymes and their specific contributions to tumorigenesis remain largely elusive. Here, we demonstrate that trans-2-enoyl-CoA reductase (TECR) is upregulated in colorectal cancer (CRC). Structural and biochemical analyses revealed a conserved catalytic mechanism for TECR-mediated trans-2-enoyl-CoA reduction. Moreover, we show that TECR forms a stable complex with 3-hydroxyacyl-CoA dehydratase (HACD), to cooperatively drive VLCFA elongation. A unique U-shaped loop in HACD is critical for recognizing TECR. Disruption of the HACD-TECR interaction interface significantly suppresses CRC cell growth. Collectively, these findings elucidate the molecular mechanism of HACD-TECR-mediated VLCFA elongation and suggest a potential therapeutic strategy for CRC treatment by modulating VLCFA metabolism.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Current treatments often fail to eradicate AML; therefore, new therapeutic strategies are essential. Here, we reveal that RNA terminal uridylyl transferase enzymes 4 and 7 (TUT4/7) are druggable therapeutic targets, whose genetic deletion suppresses AML growth, induces apoptosis, and improves the survival in leukemic mouse models. Notably, a preclinical TUT4/7 inhibitor promotes cell death in samples from patients with AML and synergizes with venetoclax. Mechanistically, TUT4/7 inactivation suppresses mevalonate pathway gene expression, compromising the cholesterol synthesis pathway. Current AML therapies often cause severe hematopoietic toxicity. Although Tut4/7 deletion results in inflammatory activation throughout the hematopoietic system, this is permissive to a normal life span and Tut4/7 deficiency does not compromise HSPC function. Together, these findings identify TUT4/7 as druggable targets, whose inactivation suppresses AML while sparing normal hematopoiesis. In combination with venetoclax, this represents a promising therapeutic strategy.

Acute myeloid leukemia/myelodysplastic syndromes (AML/MDSs) carrying p53 mutations are refractory to various standard therapies. Arsenic trioxide (ATO) may be effective in restoring function to p53 structural mutants. Here, we report that mutant p53 rescued by ATO treatment strengthened interferon responses triggered by the DNA hypomethylating agent decitabine by transactivating interferon regulatory factor 7 (IRF7) directly. Decitabine also increased the transactivation activity of ATO-rescued mutant p53 by inducing p53-serine-20 phosphorylation and blocking p53-inhibitory mouse double minute 2 homolog (MDM2). ATO and decitabine together killed p53-mutant AML cells and suppressed tumor growth in cell line-derived xenografts. In a first-in-human pilot clinical trial for testing the combination of ATO and decitabine (PANDA-T0 trial, NCT03855371), which enrolled five patients with AML/MDS harboring p53 structural mutations, the ATO and decitabine regimen produced manageable adverse events, and four of the five treated patients achieved complete remission at the level of the bone marrow, associated with p53 activation and interferon response. In 103 p53-mutant patients whose samples were deposited in Ruijin AML/MDS sample repository, 48 distinct p53 missense mutants were identified, 21 of which were classified as ATO and decitabine regimen applicable because of their competencies in activating p53 and interferon responses upon cotreatment. This study establishes an alternative treatment regimen for patients with p53-mutant AML/MDS and provides a proof-of-concept framework for p53-targeted therapy that differentiates between p53 mutations.

Silencing of the Cysteine dioxygenase-1 (CDO1) tumor suppressor gene by aberrant DNA methylation contributes to gastric carcinogenesis. Despite evidence that Helicobacter pylori (H. pylori) infection induces aberrant DNA methylation in the gastric mucosa, CDO1 promoter methylation has not been well characterized in H. Pylori positive (HPP) patients with chronic gastritis. This study aimed to investigate the CDO1 promoter methylation levels in patients with chronic gastritis with and without H. pylori infection, in comparison with gastric tumors. The quantitative analysis of CDO1 promoter methylation and CDO1 immunopositivity was performed in 45 primary gastric tumors, 17 biopsy samples of HPP chronic gastritis, 23 H. Pylori negative (HPN) chronic gastritis, and 15 normal gastric mucosa samples (control group). CDO1 expression was evaluated by immunohistochemistry, and promoter methylation levels were determined using quantitative methylation-specific PCR following bisulfite conversion. CDO1 promoter methylation levels were significantly higher in the gastric cancer (GC) group compared to the HPN chronic gastritis and control groups (p < 0.001). No significant difference was observed between the GC and HPP chronic gastritis groups. However, CDO1 promoter methylation levels were significantly higher in the HPP group compared to the HPN group (p = 0.049). No significant differences in CDO1 immunopositivity were observed among the study groups. ROC analysis demonstrated good discriminative ability of CDO1 methylation between GC and non-cancer cases (AUC = 0.83), whereas its performance was more limited in distinguishing GC from HPP chronic gastritis (AUC = 0.67). CDO1 promoter methylation is increased in GC and HPP chronic gastritis, suggesting that H. pylori-associated chronic inflammation may be associated with early epigenetic alterations. Although no direct correlation with protein expression was observed, our findings suggest that while CDO1 methylation may be informative for identifying cancer-related epigenetic changes, it may be insufficient as a standalone biomarker in high-risk inflammatory conditions. Further studies are needed to clarify its clinical utility, particularly in high-risk populations.

Gastric cancer remains a major cause of cancer-related mortality worldwide, with tumor recurrence and distant metastasis being primary contributors to poor prognosis; however, the underlying molecular mechanisms are not fully understood. CD93, a type I transmembrane glycoprotein, has been implicated in tumor angiogenesis and metastasis in various solid cancers, yet its role in gastric adenocarcinoma (STAD) requires further elucidation.

The tumor microenvironment is proposed to have an essential role in the growth and therapeutic response of glioblastoma. Vessel formation or angiogenesis has been an important target of different therapeutic strategies. In the past, we described that targeting telomere protection through abrogation or inhibition of the TRF1 shelterin telomere protein in a GBM model is sufficient to delay tumor growth and progression. Here, we set out to address whether Trf1 deletion only in endothelial cells has an impact on GBM growth and progression. Although we saw a tendency to a decrease in CD31-positive cells in GBM tumors where Trf1 was deleted, which was concomitant with a tendency to increased global DNA damage and increased telomere induced DNA damage foci in endothelial cells, as expected from telomere unprotection, this was not sufficient to delay tumor growth and progression. These findings suggest that TRF1-dependent telomere protection in endothelial cells is not a major limiting factor for PDGF-driven GBM at tumor initiation and progression.

Genetic ancestry may complement biological, behavioral, and clinical factors in understanding colorectal cancer (CRC) disparities; yet, ancestry-informed analyses in CRC remain limited.

Clinical benefit from adjuvant capecitabine in patients with early-stage triple-negative breast cancer (eTNBC) and deleterious BRCA1/BRCA2 mutation (BRCAm) is not well characterized. This retrospective, observational study explored the real-world effectiveness of adjuvant capecitabine in patients with eTNBC by BRCAm status.

Ultra-low-pass whole-genome sequencing (ULP-WGS) of cell-free DNA (cfDNA) offers a cost-efficient strategy for cancer detection, but its clinical application is limited by extreme data sparsity and poor model generalization. We developed Fragmentia-AI™ WGS, a mutation-calling-independent framework that uses a transformer-based multiple-instance learning architecture with sequential fine-tuning across tumor fraction (TF) strata to extract latent cancer-associated signals from ULP-WGS data. Model performance was evaluated in multiple independent cohorts, including a pan-cancer test set covering 17 cancer types, an external public dataset generated on a different sequencing platform, and a technical variability cohort with heterogeneous pre-analytical and experimental conditions. Clinical relevance was assessed by correlating model predictions with progression-free survival (PFS) in patients with advanced non-small cell lung cancer receiving chemoimmunotherapy. Sequential fine-tuning across TF strata significantly improved performance in low-TF samples, achieving a 35.6% relative increase in AUC compared with high-TF-only training (0.884 vs. 0.652). In the independent test cohort, the model achieved an overall AUC of 0.930, with consistent performance across TF strata and cancer types. External validation confirmed robust cross-platform generalizability (AUC: 0.929; sensitivity: 0.78; specificity: 0.92). The model maintained stable classification performance despite score fluctuations associated with pre-analytical and technical variables. Importantly, model-negative status, defined as a prediction score below the training-derived cutoff, remained significantly associated with improved PFS compared with model-positive status (HR = 0.49, 95% CI: 0.29-0.82) after multivariable adjustment. Collectively, this framework enables robust cancer detection and clinically meaningful risk stratification from highly sparse cfDNA sequencing data.

This study evaluated the diagnostic performance of CDO1 and ZSCAN12 methylation in paired endometrial (Em) and exfoliated cervical (Cx) samples for detecting endometrial cancer (EC) and endometrial atypical hyperplasia (EAH).

Previous studies have extensively examined the associations between CD133 gene polymorphisms (rs10022537, rs2286455, rs2240688, and rs3130) and cancer risk, but have yielded inconsistent results. This study aimed to investigate the potential contributions of these polymorphisms to the susceptibility of liver, lung, and gastric cancers through a replicated case-control study and a subsequent systematic meta-analysis. A total of 480 patients with liver cancer, 550 patients with lung cancer, 460 patients with gastric cancer, and 800 healthy controls from the Hubei population were enrolled. Sanger sequencing assay was applied to genotype the four target CD133 gene polymorphisms. The case-control study revealed that rs10022537 was significantly associated with the risk of liver cancer but not with the risk of lung or gastric cancer. In contrast, rs3130 was significantly associated with both lung and liver cancer risk, whereas no association was observed with gastric cancer risk. rs2240688 exhibited a significant association exclusively with lung cancer risk, and rs2286455 showed no significant association with any of the three cancer types. The meta-analysis further demonstrated that rs3130 was significantly associated with lung cancer risk in the Chinese population, and rs2240688 was significantly associated with gastric cancer risk. No significant association was found for rs10022537 or rs2286455 with liver, lung, or gastric cancer risk. Collectively, these findings suggested that rs3130 and rs2240688 in the CD133 gene may serve as susceptibility factors for risk of lung cancer and gastric cancer, respectively. Further validation studies in larger and more diverse populations are warranted.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by significant inter- and intra-tumoral heterogeneity. Its varied response to radiotherapy limits clinical outcomes, yet the underlying molecular determinants remain poorly understood.

A new type of regulated cell death known as Necrosis by Sodium Overload (NECSO) has been discovered recently. There is growing evidence indicating that NECSO is essential in both anti-tumor immune responses and the proliferation of cancer cells. Nonetheless, the underlying mechanisms and clinical relevance of NECSO are still not well understood, especially regarding its prognostic significance in kidney renal clear cell carcinoma (KIRC).

Although chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable success in hematological malignancies, its therapeutic efficacy in solid tumors remains limited by several challenges, including insufficient tumor infiltration, T cell exhaustion and the immunosuppressive tumor microenvironment (TME). CRISPR/Cas, a third-generation gene editing technology developed in recent years, is characterized by its simplicity and high efficiency. This technology has demonstrated broad application potential across multiple fields and has emerged as a powerful tool for improving CAR-T cell therapy. In this review, we summarize recent advances in the application of CRISPR/Cas gene editing technology to enhance the antitumor activity of CAR-T cells against solid tumors. We also discuss the key challenges currently faced and systematically propose potential strategies for overcoming the limitations.

Germline predisposition gene mutations may influence outcomes in patients undergoing hematopoietic stem cell transplantation (HSCT).

The therapeutic landscape for advanced non-small cell lung cancer (NSCLC) has been transformed by immune checkpoint inhibitors (ICIs), yet significant response heterogeneity necessitates robust, dynamic predictive biomarkers. Conventional tissue-based markers, such as PD-L1 expression and tumor mutational burden (TMB), are hindered by their invasive nature and inability to capture the dynamic tumor-host immune interplay. This review synthesizes the paradigm shift toward a dynamic, multi-parametric framework for precision immuno-oncology. We highlight the clinical utility of the liquid biopsy toolbox-including circulating tumor DNA (ctDNA) for molecular residual disease (MRD) monitoring, circulating tumor cells (CTCs), and extracellular vesicles (EVs) in reflecting systemic immune status. Furthermore, we explore biological insights from multi-omics profiling, covering genomic drivers of resistance (e.g., STK11/KEAP1), immunometabolic crosstalk, and systemic inflammatory indicators like the NLR/PLR ratio. The potential of radiomics and pathomics to extract spatial signatures via artificial intelligence (AI) is discussed to address whole-tumor heterogeneity. Finally, we emphasize the integration of these disparate data streams through multimodal AI and Explainable AI (XAI) to construct high-fidelity predictive models. This integrated approach aims to overcome standardization hurdles and enable personalized, adaptive management in NSCLC immunotherapy.

This study aimed to evaluate the efficacy of a single-test, targeted DNA next-generation sequencing (NGS) panel in classifying endometrial carcinoma (EC) into molecular subtypes and to compare its performance with that of the established Sanger sequencing + immunohistochemistry (Sanger + IHC) molecular classification.