Increased activation of the NLRP3 inflammasome in immune cells, including macrophages, has been implicated in the pathogenesis of multiple chronic inflammatory diseases. Targeted depletion of macrophages has been explored as a cross-disease therapeutic strategy, but without subtype-specific markers, this strategy risks elimination of macrophages with homeostatic functions. In this study, Liu et al. identified a subpopulation of pathogenic macrophages, referred to as Toe-Macs, which are characterized by overexpression of the DNA demethylase TET3 in metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. When induced into the disease microenvironment, Toe-Macs produced proinflammatory cytokines and chemokines. Selective elimination of Toe-Macs attenuated disease progression without any discernible side effects in mouse models of MASH and NSCLC. These findings highlight the role of Toe-Macs in the pathogenesis of chronic inflammatory diseases and provide a rationale for exploring TET3 as a therapeutic target.

Pediatric acute myeloid leukemia (pAML) is comprised of a diverse set of oncogenic drivers (ODs) that have been risk-stratified to inform prognosis and therapeutic decision-making. Despite proteomic, transcriptomic, genetic, and epigenetic characterization of the pAML landscape, questions still remain about why certain ODs have poorer prognoses than others.

Hereditary cancer syndromes are associated with causative pathogenic variants and clinical pathologies. Therapeutic advances have provided proof-of-concept for the actionability of the germline, whereas epidemiologic studies have identified pathogenic germline variants across tumor types regardless of hereditary syndromes. Drug development advances in synthetic lethal approaches, immunotherapeutics, cancer vaccines, and other strategies have led to regulatory approval of multiple agents, supporting the incorporation of universal germline testing. We review the current landscape of germline mutations as cancer drug targets, compare available clinical diagnostics, discuss the development of promising antitumor agents, and envision the future of universal germline testing in cancer medicine.

Precision medicine has transformed oncology by tailoring treatments to the molecular and genetic characteristics of individual tumors. Stem cell-based strategies hold unique potential to complement these approaches by enabling regenerative support, targeted delivery of therapeutics, and novel models for drug screening.

Chordoma represents a central nervous system tumor with an incidence of 8.4 per 10 million individuals in the U.S. Current treatment options include surgical resection and radiotherapy. Despite recent studies demonstrating significant improvement in molecular understanding of disease, treatment options remain limited.

Next-generation sequencing (NGS) has transformed genomics by enabling rapid, high-throughput analysis of DNA and RNA, driving significant progress across multiple fields, such as cancer research, rare disease diagnosis, and personalized medicine. This review discusses the wide-ranging applications of NGS, particularly in identifying genetic variants that guide the development of targeted therapies, improving patient outcomes. The NGS workflow involves crucial steps including data quality control, sequence alignment, and variant calling, supported by both open-source and commercial tools. Cloud-based platforms have further streamlined the storage, management, and processing of the vast datasets generated by NGS technologies. As NGS continues to evolve, ethical challenges, especially concerning genomic data privacy and informed consent, remain critical considerations. Looking ahead, the integration of multi-omics data and the advent of single-cell sequencing hold the potential to deepen our understanding of complex biological processes. Essential databases like dbSNP, COSMIC, and The Cancer Genome Atlas are key resources for interpreting NGS findings and their clinical significance. By effectively utilizing these tools and datasets, researchers can generate new genetic insights with far-reaching implications for advancing human health and understanding disease mechanisms.

The bone is the most common metastatic organ for various urinary system tumors. The immunosuppressive microenvironment of bone metastatic lesions leads to poor patient prognosis, yet its regulatory mechanism remains unclear, necessitating the exploration of novel immune targets. Although the G protein signaling regulator RGS1 is associated with tumor progression and immune cell infiltration, its mechanism of action in the immune microenvironment of bone metastatic carcinoma has not been elucidated. This study aims to clarify its regulatory role in the immune microenvironment of tumor bone metastasis and the function of CD8+T cells. Single-cell RNA sequencing data were collected from bone metastatic lesions of 8 patients with renal cell carcinoma(RCC) and 9 patients with prostate cancer(PCA). A comprehensive analysis yielded 215,864 cells, which were annotated into 20 subsets. Results showed that CD8+T cells and other cell types were enriched in bone metastatic carcinoma tissues. RGS1 was highly expressed in these CD8+T cells, and CD8+T cells with high RGS1 expression exhibited an exhausted phenotype. Moreover, we established a mouse model of PCA bone metastasis and found that overexpression of RGS1 in CD8+T cells led to down-regulation of functional molecules, up-regulation of exhaustion markers, and a reduced antitumor capability. In summary, this study demonstrates that RGS1 is strongly associated with the functional and exhaustion profiles of CD8+T cells in both RCC and PCA bone metastases, offering a novel target and strategy for immunotherapy of PCA bone metastasis.

Glioblastoma is the most common and deadly brain cancer, known for its rapid progression and heterogeneity at microscopic and macroscopic levels. This heterogeneity is influenced by factors such as tumor cell density, involvement of normal tissue, and gene expression profiles. Mutations in EGFR gene are associated with shorter recurrence intervals and poorer survival outcomes in GBM patients. Non-invasive imaging techniques like MRI can provide valuable insights into EGFR mutations. To reduce the risks of brain biopsies and sampling errors, this study introduces an AI-based decision support system (DSS) for classifying EGFR mutations in GBM patients through automated segmentation of tumorous regions using MRI. The DSS employs deep neural networks (Inception ResNet-v2, DenseNet-121, and ResNet-50) trained on a GBM dataset from Memorial Hospital in Istanbul, which includes three MRI input types: expert segmented, without segmentation, and without tumor. Information criteria (IC) were used to guide model selection by balancing predictive performance and structural complexity. DenseNet-121 showed superior performance, with accuracy scores of 0.952, 0.942, and 0.938 for expert segmented, without segmentation, and absence of tumor inputs, respectively. Precision and recall metrics were also highest for DenseNet-121, especially with expert-segmented inputs. A multivariate statistical analysis confirmed significant differences across model performances. The results underscore the value of integrating information criteria into deep learning pipelines to enhance model robustness and interpretability in medical imaging applications.

Ferroptosis is an iron-dependent form of regulated cell death induced by hyperoxidation of polyunsaturated fatty acids (PUFAs) in cytoplasmic membrane phospholipids. Recent research has identified four key regulatory pathways of this process, with glutathione pathway (SLC7A11/SLC3A2)/GSH/GPX4 being the most central and well-studied. Functioning of all ferroptosis control systems is supported by the multilevel network of protein-coding and regulatory genes, whose dysregulated expression could trigger tumor cell transformation. Ferroptosis, alongside with other types of programmed cell death, plays a pivotal role in pathogenesis of many cancers, including non-small cell lung cancer (NSCLC). This review provides a comprehensive overview of the molecular mechanisms of ferroptosis and summarizes experimental evidence demonstrating involvement of the ferroptosis-associated non-coding RNAs (microRNAs and long non-coding RNAs) in the development and progression of NSCLC. Special emphasis is placed on the potential application of anti-ferroptotic and pro-ferroptotic non-coding RNAs in NSCLC therapy, focusing on targeted modulation of their expression to induce ferroptosis in tumor cells.

Discrepancies in cancer sequencing data continue to pose significant challenges for accurate mutation detection, potentially resulting in misdiagnoses and suboptimal treatment strategies. Although deep learning (DL) has emerged as a transformative approach for identifying and rectifying these errors, there remains a lack of comprehensive evaluation of DL architectures, performance benchmarks, and clinical translation. In this systematic review of 78 studies (2015-2024), We synthesize recent advancements in DL methodologies for identifying genomic discrepancies, demonstrating that convolutional and graph-based architectures currently achieve state-of-the-art performance in variant calling and tumor stratification. DL models reduce false-negative rates by 30%-40% compared to traditional pipelines, with methods such as MAGPIE prioritizing pathogenic variants with 92% accuracy. However, challenges such as data scarcity, batch effects, and the interpretability of "black-box" models persist. We propose a future research roadmap advocating federated learning to enhance data privacy and attention mechanisms to improve model transparency. By bridging bioinformatics and oncology, this review offers actionable insights to expedite the deployment of DL in precision cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is an exceptionally lethal malignancy, with high percents of patients presenting with liver metastases (LM). However, the mechanisms driving liver metastases remain critical bottlenecks requiring urgent exploration.

Single nucleotide polymorphisms (SNPs) located in the genes participating in the steroid hormone metabolism pathway may influence the outcomes of androgen deprivation therapy (ADT) in prostate cancer (PCa) patients, but findings on the Chinese population remain limited.

Recent advancements in risk stratification have greatly improved outcomes in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite favorable prognostic indicators, including the absence of cytogenetic abnormalities and minimal residual disease (MRD) negativity, relapse remains a major clinical concern.

Black patients with pancreatic ductal adenocarcinoma (PDAC) are less likely to have a major pathologic response (MPR) after neoadjuvant chemotherapy (NAC). Data suggest lower baseline carbohydrate antigen 19-9 (CA 19-9) among Black patients. Whether CA 19-9 nonproduction contributes to racial differences in NAC response was evaluated, and the biological mechanisms underlying the reduced response in CA 19-9 nonproducers (CAnonprod) were investigated.

Dendritic cells (DCs) play a crucial role in the coordination of immune responses and have emerged as a potential target for cancer immunotherapy. However, existing DC-based immunotherapies face several clinical challenges, including suboptimal manipulation strategies, poor cross-presentation, and impaired migration. Besides, the complex tumor milieu drives DCs towards a tolerogenic state, leading to immune evasion and cancer progression. Hence, innovative engineering strategies emerging from a thorough understanding of the genetic and molecular aspects of the factors driving DCs to an immune-compromised status will benefit cancer immunotherapy. Taking advantage of the multiplexing potential of gene editing methods such as CRISPR/Cas9 and viral vectors will ensure multiple genome modifications in DCs that can result in higher migration, cross-presentation, and immune-activating cytokine production in a single manipulation step. Such precise DC modifications with high accuracy require the involvement of nanocarrier formulations with high surface functionalization and targeting potential. In this regard, our review provides a comprehensive summary of critical tumor-induced dysfunctions in DCs and promising genome engineering strategies, highlighting nanocarrier-based approaches to mitigate these challenges.

Ferroptosis is an iron-dependent form of programmed cell death driven by the accumulation of lipid peroxides. KHSRP, an RNA-binding protein, is known to orchestrate diverse cellular processes, including cell differentiation, proliferation, and lipid metabolism. However, its potential role in modulating ferroptosis in cancer remains unclear. In this study, we found that elevated KHSRP expression was associated with poor prognosis in colorectal cancer (CRC) patients. Knockdown of KHSRP significantly elevated lipid peroxidation, increased malondialdehyde (MDA) accumulation, and reduced glutathione (GSH) levels, ultimately triggering ferroptosis in CRC cells. Mechanistically, we discovered that KHSRP interacts with the splicing factor hnRNPM, which directly binds to GPX4 mRNA. Critically, hnRNPM overexpression effectively rescued the decrease in GPX4 expression and the ferroptotic phenotype induced by KHSRP knockdown. These results suggest that the KHSRP-hnRNPM complex binds to GPX4 mRNA and acts as a key regulator of its post-transcriptional fate to sustain GPX4 expression. Overall, our results uncover a novel regulatory mechanism whereby high KHSRP expression protects CRC cells from ferroptosis. Targeting the KHSRP-hnRNPM-GPX4 axis to overcome ferroptosis resistance represents a promising therapeutic strategy for CRC.

Melanoma is an aggressive malignancy with one of the highest mortality rates among skin cancers. Radiotherapy is a common treatment modality, but radioresistance remains a significant challenge. The stimulator of interferon genes (STING) pathway has been implicated in antitumor immunity and cancer treatment, yet its role in melanoma radiosensitivity is poorly understood.

PRDM15, a member of the PRDM family, is critically involved in embryonic development, cell differentiation, and tumorigenesis. However, its specific regulatory mechanisms in tumorigenesis remain poorly understood. This study demonstrates that PRDM15 is significantly upregulated in colorectal cancer (CRC) tissues and positively correlates with advanced pathological staging. Knockdown of PRDM15 inhibits p53-dependent cell proliferation by arresting cell cycle progression and promoting apoptosis, thereby suppressing colorectal carcinogenesis both in vitro and in vivo. Furthermore, PRDM15 depletion enhances the sensitivity of HCT116 cells to the chemotherapeutic agent 5-Fluorouracil (5-FU). Mechanistically, PRDM15 functions as a novel negative regulator of p53, exerting its oncogenic effects by transcriptionally downregulating USP10, which in turn destabilizes p53. These findings underscore the critical role of the PRDM15-USP10-p53 axis in CRC progression, offering new insights into the molecular mechanisms driving CRC and identifying potential therapeutic targets for intervention.

Nectin-4-MMAE is an innovative antibody-drug conjugate (ADC) that combines a Nectin-4-targeting monoclonal antibody with monomethyl auristatin E (MMAE), a potent microtubule inhibitor, demonstrating substantial therapeutic promise. While previous research has primarily focused on Nectin-4-targeted therapies in urothelial carcinoma, their potential efficacy in gastric cancer (GC) has yet to be thoroughly investigated. To bridge this knowledge gap, this study seeks to investigate the therapeutic effects of Nectin-4-MMAE in GC and examine the mechanistic role of autophagy in the treatment of Nectin-4-positive gastric cancer. Apoptosis and autophagy induced by NECTIN-4-MMAE were validated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay, flow cytometry (FCM), transmission electron microscopy (TEM), confocal microscopy, and Western blotting (WB). Gene enrichment analysis was performed based on RNA Sequencing (RNA-seq) data. Finally, the antitumor effects of NECTIN-4-MMAE, with or without the autophagy inhibitor, were confirmed in a mouse xenograft model. Our findings indicate that Nectin-4-MMAE induces both apoptotic cell and protective autophagy. Notably, the combination of Nectin-4-MMAE with autophagy inhibitors demonstrated a markedly stronger inhibitory effect on gastric cancer cells than Nectin-4-MMAE alone. These results suggest a viable therapeutic approach for treating Nectin-4-positive gastric cancer through the combinatorial use of Nectin-4-MMAE with autophagy inhibitors.

Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression of deleted pro-apoptotic genes, recovered mitochondrial priming and sensitivity to killer T cells or ICIs. In mice, pharmacologically reducing the apoptotic threshold of ICI persisters prevented relapses. Thus, CNVs can drive the evolution of resistance to ICIs in melanoma, with tumor cell-intrinsic apoptotic threshold representing a target to curtail persister evolution.