Macrophage-mediated phagocytosis plays a critical role in the elimination of cancer cells and shaping antitumor immunity. However, the tumor-intrinsic pathways that regulate cancer cell sensitivity to macrophage-mediated phagocytosis remain poorly defined. In this study, we performed a genome-wide CRISPR screen in murine pancreatic cancer cells cocultured with primary macrophages and identified that disruption of the tumor-intrinsic pyrimidine synthesis pathway enhances phagocytosis. Mechanistically, we discovered that macrophages inhibit the pyrimidine salvage pathway in tumor cells by upregulating Upp1-mediated uridine degradation through cytokines TNF-α and IL-1. This shift increased tumor cells' reliance on de novo pyrimidine synthesis. As a result, tumor cells with impaired de novo pyrimidine synthesis showed depleted UMP and displayed enhanced exposure of phosphatidylserine (PtdSer), a major "eat-me" signal, thereby promoting macrophage-mediated phagocytosis. In multiple pancreatic cancer models, Cad-deficient tumors exhibited markedly reduced tumor burden with increased levels of phagocytosis by macrophages. Importantly, the Cad-mediated suppression of pancreatic cancer was dependent on TAMs and cytokines IL-1 and TNF-α. Pharmacological inhibition of DHODH, which blocks de novo pyrimidine synthesis, similarly decreased tumor burden with enhanced phagocytosis in pancreatic cancer models. These findings highlight the critical role of the tumor-intrinsic pyrimidine synthesis pathway in modulating macrophage-mediated antitumor immunity, with potential therapeutic implications.

DNA damage and repair are central to the onset of cancer, aging, and aging-related diseases. Rare genetic defects in the nucleotide excision repair pathway, such as those causing the cancer-prone disorder xeroderma pigmentosum (XP) or the progeroid condition Cockayne syndrome, highlight the dramatic consequences of unrepaired DNA lesions. In this issue of the JCI, two related papers from Ogi and coworkers - Fassihi et al. and Nakazawa et al. - describe a new XP clinical entity, XP-J, linked to a pathogenic variant in the p52 subunit of the transcription-repair complex TFIIH. The studies' characterization of XP-J and the p52ΔC variant opened unexpected possibilities to ameliorate the molecular defect in another subunit of TFIIH that causes a different, more severe repair syndrome: trichothiodystrophy. This commentary provides a broader historical, medical, and molecular context for the intricate genotype-phenotype relationship between compromised repair and its clinical consequences and discusses next steps for the advances reported.

Oral squamous cell carcinoma (OSCC) is a devastating disease with an increasing incidence. Among the commonly dysregulated pathways in oncogenesis are the phosphatidylinositol 3-kinase / protein kinase-B/ mammalian target of rapamycin (PI3K/AKT/mTOR) and apoptotic pathways. Buparlisib, a pan-class I PI3K inhibitor, has antineoplastic effects, but its associated toxicities hinder its beneficial role in patients. Calcitriol, active vitamin D (Vit D), possesses anticancer functions by targeting both pathways. Therefore, Vit D could help achieve low buparlisib doses and boost its effects.

Patients with non-small cell lung cancer (NSCLC) deficient in SMARCA4 (SMARCA4-dNSCLC) are commonly diagnosed at advanced stages with a poor prognosis. Although immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy regimens are widely used, their efficacy in SMARCA4-dNSCLC patients remains suboptimal. Herein, we present the case of a SMARCA4 dNSCLC patient treated at Yijishan Hospital on January 18, 2023. Following our comprehensive treatment, our patient's general condition and quality of life (QOL) have remained satisfactory, and there has been no disease progression to date.

Osimertinib, an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), improves survival in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, a substantial proportion of patients do not proceed to subsequent therapy (ST). This study aimed to identify patient characteristics associated with ineligibility for post-osimertinib therapy.

Neurofibromatosis type-1 (NF1) patients rarely develop mucosal melanomas. We report a rare form of anorectal mucosal melanoma (ARMM) in an NF1 syndromic patient profiled for genomics and transcriptomics to assess the determinants of the response to nivolumab.

We describe the case of a NUT carcinoma of the thorax in a 27-year-old male, non-smoker, presenting a voluminous neoformation in the hilum and the left side of the mediastinum infiltrating heart and great vessels. The biopsy revealed a poorly differentiated cancer with focal crush artifact consisting of undifferentiated small to medium-size cells, with minimal indistinct to clear cytoplasm, round or oval nuclei, nuclear molding and brisk mitotic activity. Suggestive morphological features often associated with NUT carcinoma, for example abrupt foci of keratinization, were not seen. Moreover, immunohistochemical (IHC) analysis showed negativity for epithelial markers, such as Cytokeratin AE1/AE3, CK7, CK-CAM5.2, CK5/6, p40 and TTF1; therefore, further immunohistochemical markers were evaluated, and the conclusive diagnosis was based on a diffuse speckled nuclear positivity for NUT1 (clone C52B1). Considering the unusual morphological and IHC findings, a comprehensive genome profiling, by FoundationOne®CDx Next Generation Sequencing (NGS), was performed on DNA from the transbronchial needle aspiration formalin-fixed and paraffin-embedded cell block. Neither NUTM1 gene fusions nor other pathogenic gene variants were detected. However, focal and segmental copy number variations (CNV) were seen in chromosome 19, in the middle of the BRD4 gene, the most common NUTM1 fusion partner. In addition, an array CGH (aCGH) analysis was performed: this analysis revealed different CNV, including a 2.7Mb deletion and a 14.4Mb duplication in chromosome regions were NUTM1 and BRD4 are respectively located. Finally, an RNA-based NGS confirmed the presence of a BDR4-NUTM1 fusion transcript, supporting IHC findings. IHC and molecular results all together are suggestive for a likely non-canonical BRD4-NUTM1 fusion. Our case showed unusual features both from a morphological and a molecular point of view: the diagnosis was driven by NUT1 positive immunohistochemistry, thus underlining the crucial role of this test.

Hairy cell leukemia (HCL) is a rare, indolent B-cell neoplasm, typically involving bone marrow, spleen, and peripheral blood, with extranodal sites rarely affected. Herein, we present the unique case of a 52-year-old man with lung and lymph node involvement by HCL concurrently with atypical mycobacteriosis. Initial imaging showed mediastinal lymphadenopathy and a pulmonary nodule, which raised suspicion for lung neoplasia. A minimally invasive biopsy of the mediastinal nodes and hilar lesion revealed a lymphoid proliferation mixed with necrotizing granulomatous inflammation, with an immunophenotype consistent with HCL and BRAF V600E mutation, confirmed by digital PCR. Notably, molecular analyses detected atypical mycobacteria in lymph nodes. This unusual co-occurrence of HCL with atypical mycobacterial infection in the lung and lymph nodes poses a complex diagnostic and therapeutic challenge, highlighting the importance of recognizing such presentations to optimize patient management.

Ongoing discoveries in cancer research keep expanding the landscape of renal cell carcinoma classification, particularly for "molecularly-defined" tumors like TFE3-rearranged and TFEB-altered renal cell carcinoma. However, scientific updates often do not align with pathologists' daily practice and resources. Herein, we present the results from a national Italian survey assessing physicians' personal experience on TFE3-rearranged and TFEB-altered renal cell carcinomas.

The aim of this study is to assess the impact of Oncotype DX on treatment decisions and healthcare economy.

Primary neuroendocrine carcinoma of the breast (NEBC) is a rare entity among breast malignancies, and is usually associated with a more aggressive clinical course compared to other types of invasive breast cancer. Although some studies have characterized the molecular profile of NEBCs using targeted sequencing, these tumors are often treated similarly to other primary breast carcinomas despite their unique morpho-phenotypic characteristics. In this study, we present the case of a woman with HER2-positive primary large cell NEBC with homolateral axillary nodal metastases. After neoadjuvant therapy, the patient underwent surgical resection of the breast, showing a partial pathological response. Next-generation sequencing was performed on pre- and post-treatment samples using a 174-genes panel. Both samples exhibited a similar molecular profile, including a somatic mutation in GATA3 and amplifications of CCND1, FGF19, and IGF1R. ERBB2 amplification was identified in the pre-operative biopsy but was lacking in the post-treatment surgical specimen. This study represents the first report of CCND1, FGF19, and IGF1R gene amplification in a breast neuroendocrine carcinoma. These findings provide new insights into the molecular profile of this entity and may contribute to future studies on precision oncology.

Despite the promising introduction of anti-PD-L1 therapy for advanced stage of prostate cancer (PCa), recent studies have demonstrated limited success, suggesting the need to improve patient selection.

Spread through air spaces (STAS), a mode of lung cancer progression, is recognized as a poor prognostic factor, although its pathogenesis remains unclear. This study aimed to identify microRNAs (miRNAs) associated with STAS.

Aryl hydrocarbon receptor nuclear transporter-like 2 (ARNTL2) can bind to clock circadian regulator (CLOCK) to regulate gene expression and is abnormally expressed in various cancers. Nevertheless, its effects on esophageal cancer (ESCC) are unclear. This work can uncover the intriguing mechanism of ARNTL2 in ESCC.

5-hydroxymethylcytosine (5hmC), an epigenetic modification derived from the oxidation of 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of dioxygenases, plays a pivotal role in the regulation of gene expression, cellular differentiation, and developmental plasticity. Once considered an intermediate in DNA demethylation, 5hmC is now recognized as a stable and functionally significant epigenetic mark with distinct genomic distributions and significant regulatory implications. This review provides a comprehensive analysis of the biological functions of 5hmC in normal cellular processes, including its role in maintaining tissue-specific gene expression, lineage commitment, and genomic integrity. We also describe its role in cancer, the mechanistic underpinnings of its loss or redistribution in tumor cells, and how these changes contribute to oncogenic signaling pathways, epithelial-mesenchymal transition, and tumor heterogeneity. Furthermore, we explore the utility of 5hmC as a biomarker in cancer diagnostics and prognostics, supported by recent advances in sequencing technologies and cell-free DNA profiling. We also examine the intersection of 5hmC and chemotherapy, highlighting how aberrant 5hmC levels can influence drug resistance and sensitivity, and assess the therapeutic potential of targeting TET enzymes and associated pathways. By integrating insights from basic epigenetics, cancer biology, and therapeutic research, this review underscores the multifaceted role of 5hmC in human malignancies and outlines the translational opportunities for exploiting 5hmC-related mechanisms in precision oncology.

Astrocyte elevated gene-1 (AEG-1), also known as metadherin (MTDH), has emerged as a multifunctional oncogene implicated in cancer progression, metastasis, immune evasion, and notably, drug resistance across diverse malignancies. AEG-1 exerts its effects by modulating key signaling cascades, including PI3K/Akt, NF-κB, and Wnt/β-catenin, and by regulating genes associated with epithelial-mesenchymal transition, apoptosis suppression, cancer stemness, and multidrug resistance. Its interactions with molecular partners such as SND1, USP10, and nucleolin further amplify its oncogenic potential, especially in immune suppression and therapy resistance. This review provides a comprehensive overview of AEG-1-mediated drug resistance mechanisms across tumor types including breast, liver, lung, glioma, and gynecological cancers. Tumor-specific signaling contexts and immune microenvironmental interactions are examined to highlight how they shape AEG-1 function. Therapeutic challenges in targeting AEG-1-such as its non-enzymatic structure and intracellular localization-are critically discussed. We further explore emerging strategies to inhibit AEG-1, including RNA interference, long noncoding RNA modulation, partner interaction disruption, phytochemical inhibitors, and nanoparticle-based delivery systems. AEG-1 is also evaluated as a prognostic and predictive biomarker with translational relevance in precision oncology. Future studies should prioritize its integration into biomarker-guided clinical trials and the development of tumor-specific AEG-1-targeted therapies. This review underscores AEG-1 as a central mediator of drug resistance and a compelling target for next-generation cancer therapeutics.

Breast cancer remains the most frequently diagnosed cancer and a leading cause of cancer-related mortality in women globally. While genetic mutations are well-established contributors to breast cancer pathogenesis, accumulating evidence underscores the pivotal role of epigenetic dysregulation including DNA methylation, histone modifications, and non-coding RNAs in driving tumor initiation, progression, metastasis, and therapeutic resistance. These reversible modifications regulate gene expression and chromatin structure without altering the underlying DNA sequence, offering unique opportunities for biomarker discovery and targeted intervention. This review provides a comprehensive overview of the epigenetic landscape in breast cancer, highlighting key molecular players such as BRCA1, RASSF1A, CDH1, and SOX17, and detailing the roles of histone acetylation, methylation, and phosphorylation in chromatin remodeling and gene regulation. The contributions of microRNAs and long non-coding RNAs in modulating cancer phenotypes and therapy responses are also discussed. Furthermore, we explore emerging epigenetic therapies ("epidrugs"), their integration with standard chemotherapy and immunotherapy, and the potential of multi-omics approaches in precision oncology. By linking molecular insights to clinical applications, this review emphasizes the promise of epigenetic strategies in advancing personalized treatment for breast cancer patients.

Medulloblastoma (MB) stands out as the most prevalent, invasive, and biologically heterogeneous pediatric brain tumor. MB accounts for almost 1/4th of all intracranial neoplasms. The prime age of diagnosis is 5-9 years of age; however, the disease is also seen at a later age in approximately 25 % adults. The standard treatment for the disease is comprised of multimodal approaches incorporating surgery, radiation therapy, and adjuvant chemotherapy, which increases the survival to 70-80 %. Despite considerable progress in therapies and novel drug discoveries, 30 % of the survivors succumb to lifelong morbidities and chronic disabilities. A deeper understanding of the disease's molecular landscape has led to the identification of four distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4. This classification, coupled with clinical-pathological assessments of the disease, has enhanced the search for more targeted and effective therapies for MB. In this review, we present an overview of MB, with an emphasis on current treatment options and challenges, utilization of molecular subgroup-specific genetic alterations in development of targeted therapies, including immunotherapy. Additionally, emerging nanomedicine approaches aimed at overcoming the inefficient blood brain barrier (BBB) penetration of drugs used for the treatment of MB, are discussed.

To date, results on relationship between CYP3A4 gene polymorphism were limited and inconclusive, and no study focused on the influence of CYP3A4 gene-obesity interaction on breast cancer risk, especially in Chinese women. The purpose of this study was to evaluate the impact of four single nucleotide polymorphisms (SNPs) of CYP3A4 gene, the SNP-SNP and gene-environment interactions on the susceptibility to breast cancer in Chinese women.

Genome-wide association studies (GWASs) have highlighted the importance of pleiotropy in human diseases, where one gene can impact 2 or more unrelated traits. Examining shared genetic risk factors across multiple diseases can enhance our understanding of these conditions by pinpointing new genes and biological pathways involved. Furthermore, with an increasing wealth of GWAS summary statistics available to the scientific community, leveraging these findings across multiple phenotypes could unveil novel pleiotropic associations. Existing selection methods examine pleiotropic associations one by one at a scale of either the genetic variant or the gene, and thus cannot consider all the genetic information at the same time. To address this limitation, we propose a new approach called MPSG (Meta-analysis model adapted for Pleiotropy Selection with Group structure). This method performs a penalized multivariate meta-analysis method adapted for pleiotropy and takes into account the group structure information nested in the data to select relevant variants and genes (or pathways) from all the genetic information. To do so, we implemented an alternating direction method of multipliers algorithm. We compared the performance of the method with other benchmark meta-analysis approaches such as GCPBayes, PLACO, and ASSET by considering as inputs different kinds of summary statistics. We provide an application of our method to the identification of potential pleiotropic genes between breast and thyroid cancers.