Cancer remains a major cause of global mortality, necessitating the identification of novel biomarkers to improve prognosis and guide therapy. ABCA1, an ATP-binding cassette transporter involved in cholesterol efflux, has been implicated in tumorigenesis, yet its pan-cancer roles and clinical relevance are not fully understood. We conducted a comprehensive multi-omics analysis of ABCA1 across diverse cancers, evaluating its expression, prognostic significance, genomic alterations, tumor immune microenvironment interactions, and regulatory mechanisms. ABCA1 expression was dysregulated in multiple malignancies and associated with poor prognosis in STAD, STES, and LGG, though favorable outcomes were observed in KIRC. It correlated with genomic instability markers (TMB, MSI, HRD), immune cell infiltration, and cancer stemness. Pathway analyses revealed enrichment in cholesterol metabolism and efferocytosis-related pathways. Among the cancer types examined, esophageal squamous cell carcinoma (ESCC) was selected for exploratory functional validation due to its prognostic relevance. In vitro, ABCA1 knockdown inhibited proliferation, invasion, and migration in ESCC cell lines. In silico drug sensitivity analysis suggested potential associations with dasatinib response and panobinostat resistance, warranting further experimental validation. Collectively, these findings highlight the context-dependent associations of ABCA1 with cancer progression, immune modulation, and genomic integrity, suggesting its potential utility as a prognostic biomarker that warrants further investigation for therapeutic targeting.

Extracellular vesicles (EVs) mediate intercellular communication within the tumour microenvironment by carrying cargoes from paracrine parent cells. EVs have attracted great research interest for their ability to carry nucleic acids into recipient cells and modulate cellular functions. However, previous studies have largely focused on RNA sequence information rather than RNA structure features. Here, we observed that EVs derived from colorectal cancer cells are enriched with endogenous double‑stranded RNA (dsRNA), a danger‑associated molecular pattern (DAMP) that leads to the activation of dsRNA‑sensing pathways in recipient cells. Crucially, we investigated the specific crosstalk between tumour-derived EVs and circulating platelets. As anucleate cells, platelets are uniquely suited models for isolating the effects of exogenous nucleic acids. Our analysis reveals that endogenous dsRNA from tumour EVs activates the platelet OAS-RNASEL innate immune ribonuclease cascade and the RNASEL/ABCE1/PELO axis, resulting in the decay of ribosomal protein mRNAs. This study, spanning from clinical observation to mechanistic validation, uncovers a novel pathway of tumour-platelet communication. We identify EV-enriched endogenous dsRNA as a functional mediator that enables tumour cells to directly reprogram platelet transcriptomes, revealing a new dimension of tumour-immune modulation.

PD-1 blockade has yet to achieve broad clinical success in colorectal cancer (CRC), with microsatellite-stable tumors proving especially resistant. At the same time, ferroptosis has emerged as a mechanistic link between redox control in tumor cells and the antitumor immune response. GPR39 is overexpressed in CRC, but its functional role in ferroptosis and immunotherapy resistance is currently unclear.

S-palmitoylation is a crucial post-translational modification that regulates diverse cellular processes, particularly signalling pathways. The ZDHHC family of enzymes catalyzes this modification, however, the role of ZDHHC16 in cancer warrants in-depth investigation. This study presents a comprehensive pan-cancer analysis of ZDHHC16, examining its expression patterns, clinical relevance, associations with immune responses, genomic characteristics, and potential as a therapeutic target. We further analysed single-cell and spatial transcriptomic data to identify specific cell populations associated with ZDHHC16 dysregulation. Our findings reveal that ZDHHC16 dysregulation is tissue-specific and promotes tumor progression and modulates immune responses, highlighting its potential as a therapeutic target in several cancers, including ACC and BRCA. In ACC and BRCA, high ZDHHC16 expression correlates with shorter overall survival (p < 0.001) and regulates PD-L1 expression.

Ovarian cancer (OC) remains a lethal gynecological malignancy with challenges in early diagnosis, treatment monitoring, and overcoming drug resistance. Liquid biopsy, a noninvasive approach analyzing tumor-derived components in bodily fluids, has emerged as a promising tool in OC management. This review summarizes advances in liquid biopsy technologies, focusing on circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). ctDNA enables minimally invasive assessment for diagnosis, prognosis, treatment guidance (e.g., BRCA1/2-targeted therapy), minimal residual disease (MRD) detection, and monitoring of tumor evolution. CTCs, particularly clusters, provide insights into metastasis and therapeutic response. Emerging modalities such as tumor-educated platelets (TEPs), circular RNAs (circRNAs), and exosomes and protease activity-based liquid biopsy also show diagnostic and prognostic potential. Despite technical challenges like standardization and sensitivity, liquid biopsy holds significant promise for personalized OC care, with ongoing efforts to translate these technologies into clinical practice.

The incidence of breast cancer shows its largest peak around the age of 65 but also a peak around 45 indicating a bimodal distribution. While some potential explanations, such as age-related enrichment in specific breast cancer sub-types and BRCA1/2 mutations were proposed, they do not explain why the peaks are at 45 and 65, raising the possibility that the way the breast ages may play a role. Here using two mouse models, we show two distinct aging patterns of the mammary gland; one being progressive, the other bimodal. In the bimodal model, waves of overlapping genes and proteins associated with breast cancer pathways are observed at 11 and 19 months but are absent at 3 and 14 months. Further, in the bimodal model, the mammary glands at 11 and 19 months are more permissive to the growth of cancer cells but not at 14 or > 22 months, while in the progressive model, the growth of cancer cells increases starting at 14 months of age. Using scRNAseq, we established a bimodal aging signature. Since 11 and 19 months in mice correlate with 45 and 65 in humans, we tested the mammary gland-derived bimodal signature in two breast cancer databases and found that the signature is enriched in women diagnosed at 45 and 65. Therefore, our study raises the possibility that distinct patterns of aging of the breast exist and that they may contribute to the bimodal distribution of breast cancer. Further, our study adds to the growing evidence of non-linear aging.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Identifying novel molecular mechanisms underlying its progression and treatment resistance is crucial. MAGEA1, a cancer-testis antigen, exhibits oncogenic functions in multiple solid tumors; however, its expression profile and precise role in NSCLC remain poorly defined. MAGEA1 expression in NSCLC versus normal tissue was analyzed via TCGA bioinformatics, and differential expression was orthogonally validated by RT-qPCR and Western blot in normal lung epithelial and lung adenocarcinoma cell lines. Cellular proliferation, migration, and invasion were assessed by CCK-8 and Transwell assays. Apoptosis and radiosensitivity were evaluated using flow cytometry, colony formation, immunofluorescence, and comet assays. In vivo tumor growth and metastasis was examined in subcutaneous and lung metastasis mouse models. Downstream pathways were explored via RNA-seq. MAGEA1 was significantly upregulated in NSCLC tissues. Its overexpression promoted lung adenocarcinoma cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and in vivo tumor growth and metastasis, whereas MAGEA1 knockdown reversed these effects. Moreover, MAGEA1 overexpression increased irradiation-induced DNA damage and apoptosis and decreased clonogenic survival, indicating increased radiosensitivity. Mechanistically, MAGEA1 exerted its oncogenic effects primarily through activation of the AKT pathway. This study demonstrates that MAGEA1 drives lung adenocarcinoma progression by activating the PI3K/AKT pathway and correlates with elevated radiosensitivity, highlighting its potential as a therapeutic target in lung adenocarcinoma.

miR-210-3p is a well-established hypoxia-induced microRNA that is commonly upregulated in a wide range of solid tumors, traditionally linked to mitochondrial repression and hypoxia-inducible factor (HIF) signaling. However, its functional role in cancer remains complex and highly context dependent. Here we perform a comprehensive pan-cancer transcriptomic analysis together with functional assays, revealing that miR-210-3p not only mediates classical hypoxic responses but also amplifies mitotic gene expression through activation of FOXM1. Mechanistically, this effect is shown to be dependent on HIF1α but not on HIF2α and, importantly, it has not been recapitulated by hypoxia alone. Notably, activation of the mitotic program is observed in breast cancer cells but not in head and neck squamous carcinoma models, highlighting a strong degree of context dependency across tumor types. In breast cancer cells, miR-210-3p overexpression enhances FOXM1 phosphorylation, upregulates kinetochore regulators, and induces mitotic defects, correlating with poor prognosis in aggressive tumors. Together, these findings position miR-210-3p as a molecular integrator linking pseudohypoxia to mitotic dysregulation, contributing to tumor aggressiveness by sustaining HIF activity and promoting mitotic stress. This dual functionality reconciles its paradoxical effects on proliferation and highlights its potential as a therapeutic target in cancers characterized by pseudohypoxia and mitotic abnormalities.

Glucuronide prodrug strategies may enhance target specificity and reduce the toxicity of PARP inhibitors, but no clinical evaluation has been performed. We evaluated TSL-1502, a novel glucuronide prodrug of a PARP inhibitor, in a randomized, open-label, phase 2 study at 28 sites in China (NCT05420779). Eligible patients were women aged 18-75 years with HER2-negative locally advanced or metastatic breast cancer and germline BRCA mutations. Patients were assigned randomly (2:2:1) to receive TSL-1502 at 350 mg or 500 mg once daily or the investigator's choice of chemotherapy (eribulin, capecitabine, or vinorelbine) in 3-week cycles. Sixty-three patients were enrolled between August 18, 2022, and March 5, 2024. According to the Independent Review Committee assessment, the objective response rates were 36.0% (95% CI, 18.0-57.5) in the 350 mg group, 55.6% (95% CI, 35.3-74.5) in the 500 mg group, and 40.0% (95% CI, 12.2-73.8) in the chemotherapy group. The median progression-free survival times were 5.6 (95% CI, 4.0-8.2), 8.8 (95% CI, 5.7-not assessable [NA]), and 9.2 (95% CI, 1.38-NA) months, respectively, and the overall survival times were 17.4 months (95% CI, 9.1-NA), not reached (95% CI, 16.9-NA), and 19.8 months (95% CI, 9.2-NA), respectively. Grade ≥3 treatment-related adverse events occurred in 60.0%, 59.3%, and 80.0% of patients, with anemia most common in the TSL-1502 group and neutropenia most common with chemotherapy. No treatment-related deaths occurred. TSL-1502 at 500 mg showed promising antitumor activity and a manageable safety profile, supporting further clinical development.

miRNAs are short RNA transcripts that modulate gene expression after transcription and have emerged as pivotal regulators of cancer biology. A subset, termed oncomiRNAs, functions as oncogenes or tumor suppressors, influencing key cellular events such as cell growth, programmed cell death, neovascularization, tissue invasion, and metastatic spread. Dysregulation of these miRNAs drives tumor initiation and progression, underscoring their role in cancer evolution. Traditionally, studies have relied on bulk tissue analyses, overlooking the profound spatiotemporal heterogeneity of oncomiRNA expression, including variations across tumor regions, metastatic sites, disease stages, and during treatment.

Glycolipid transfer protein (GLTP) is a key regulator of glycosphingolipid distribution between intracellular membranes. Although aberrant GLTP expression has been implicated in various cancers, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear.

Lung cancer in never-smokers represents a distinct clinical and biologic entity. However, its epidemiologic characteristics remain incompletely described in the Middle East.

Survival in metastatic pancreatic ductal adenocarcinoma (mPDAC) has long been limited by a dismal second-line therapeutic ceiling dictated by conventional chemotherapy. However, breakthrough data from the ASCO 2026 Annual Meeting and the publication of the phase III RASolute-302 trial mark a definitive shift toward targeted KRAS inhibition. This correspondence highlights how the first-in-class pan-RAS (ON) inhibitor daraxonrasib (RMC-6236) virtually doubled median overall survival (13.2 vs. 6.6 months) and progression-free survival compared to chemotherapy in second-line mPDAC, establishing a new standard of care. Concurrently, we evaluate emerging allele-specific strategies from ASCO 2026 designed to optimize target engagement and safety. These include the selective KRAS G12D inhibitor DN022150 and promising horizontal combinations pairing the G12D inhibitor HRS-4642 with either the anti-PD-L1 antibody adebrelimab or a Nectin-4-targeted antibody-drug conjugate (ADC). Furthermore, we address the KRAS G12C cohort where farnesyl transferase co-inhibition (darlifarnib plus adagrasib) successfully bypasses adaptive resistance. Ultimately, the therapeutic landscape of mPDAC is transitioning toward tailored genomic frameworks. Future success will rely on optimizing the clinical sequencing or combination of pan-RAS and allele-specific agents, guided by real-time liquid biopsies, to permanently dismantle resistance and transform mPDAC into a manageable molecular entity.

In humans, about 5-10% of all cancers are caused by germline pathogenic variants (PVs) in cancer-predisposing genes, and their identification enables precision oncology approaches, such as surveillance for early detection, preventive medicine, and targeted therapy. Although cancer is a leading cause of death in cats, PVs have not been investigated for precision oncology. We developed a feline-specific multiplex targeted sequencing method to analyze 813 cats for putative PVs in 27 candidate feline cancer-predisposing genes. A total of 784 variants were identified, 13 of which were classified as putative PVs based on predicted truncating impact of amino acid sequence, clinical interpretation of corresponding variants in human, and in silico prediction on amino acid functions. Among 18 cats with one of the 13 putative PVs, seven (38.9%) had various types of confirmed or suspected tumor. Although PV carriers do not always develop cancer even in humans, putative PV carriers without tumors tended to be younger (1.83-16.58, years old, 9.16 years old on average) than the median age of tumor-bearing putative PV carriers (11.83 years old), suggesting that the proportion of affected cats may increase over time. Moreover, five cats with putative PVs in homologous recombination repair genes (BRCA2, RAD51C, or ATM) and two cats with those in mismatch repair genes (MSH2 and MSH6) may be candidates for targeted therapy with PARP inhibitors and immunotherapy with immune checkpoint inhibitors, respectively. These findings provide the first characterization of putative PVs in feline candidate cancer-predisposing genes, representing an important step toward genomics-informed oncology and risk stratification in cats.

Tumor protein p53 (TP53) alterations are frequently reported in canine cancers but remain incompletely characterized due to differences in reference genomes and sequencing cost.

Recent advances in pathology foundation models have markedly improved the accuracy and generalizability of histopathological image analysis in breast cancer. However, the mechanisms of resistance to CDK4/6 inhibitors in hormone receptor-positive, HER2-negative advanced breast cancer remain incompletely understood. This article outlines a strategy to identify therapeutic targets by integrating pathology AI with spatial transcriptomics. We developed AI-directed spatial transcriptomics (AID-ST), a framework that compares gene expression profiles between drug-sensitive and drug-resistant regions identified by pathology AI. In a preliminary analysis of clinical breast cancer specimens, this approach suggested that KRAS pathway activation is a major driver of resistance, accompanied in part by Polycomb dysregulation, RB loss, PI3K pathway alteration, and acquisition of stem-like features. Additional spatial analyses of paired pre- and post-treatment specimens supported these findings and further suggested a role for the tumor microenvironment, including EMT- and IL6/JAK/STAT3-related changes, in promoting resistant phenotypes. These results indicate that integrating pathology AI with spatial transcriptomics may enable systematic classification of resistance subtypes and prioritization of actionable therapeutic targets in breast cancer.

KRAS mutations represent one of the most prevalent oncogenic alterations, occurring in approximately 20% of human cancers. Although KRAS had long been regarded as"undruggable,"the identification of a druggable pocket has catalyzed rapid progress in the development of targeted therapeutics. To date, the only approved KRAS-directed agent in Japan is sotorasib, a GDP-state inhibitor specific for the KRAS G12C mutation. However, a diverse array of next-generation strategies-including pan-KRAS inhibitors, pan-RAS inhibitors, tri-complex inhibitors, and targeted protein degradation modalities-are currently under active investigation. These advances have drawn increasing attention to the functional heterogeneity and differential druggability among distinct KRAS mutation subtypes, as well as organ-specific biological differences that had previously received limited consideration. Moreover, as with other molecularly targeted therapies, multiple resistance mechanisms to KRAS inhibition have been reported, underscoring the need for therapeutic strategies capable of overcoming or preventing treatment resistance.

Sotorasib and adagrasib, which are KRAS G12C inhibitors, have shown favorable clinical results mainly in non-small cell lung cancer (NSCLC) and have already been introduced into clinical practice. However, for patients with non-G12C mutations that account for the majority, such as G12D, G12V, and G13D, effective targeted therapies have still not been established. Setidegrasib (ASP3082) is a first-in-class proteolysis-targeting chimera molecule (PROTAC) that targets the KRAS G12D mutation. Phase Ⅰ trial targeting previously treated patients with advanced solid tumors harboring KRAS G12D mutations has been initiated, and the latest results were reported in the N Engl J Med in March 2026. Daraxonrasib (RMC-6236) is a pan-RAS inhibitor that targets all ON-state RAS (KRAS, NRAS, HRAS) by forming a specific pocket spanning the Switch Ⅰand Switch Ⅱ regions of KRAS through a mechanism called tri-complex/molecular glue. Currently, multiple international collaborative phase Ⅲ trials on RMC-6236, mainly focusing on PDAC and NSCLC, are underway. The development of new drugs targeting molecules other than KRAS G12C is progressing rapidly, and in KRAS mutation-positive solid cancers where prognosis was difficult to improve with conventional chemotherapy, there is a high possibility that the existing standard treatments will be significantly revised.

KRAS G12C has emerged as a clinically important therapeutic target in non-small cell lung cancer (NSCLC), representing a major advance in the treatment of KRAS-driven malignancies. The development of covalent inhibitors targeting the switch-Ⅱ pocket of inactive, GDP-bound KRAS has transformed a previously undruggable oncogene into a molecularly actionable target. First-generation KRAS G12C inhibitors, including sotorasib and adagrasib, have demonstrated clinically meaningful activity in previously treated NSCLC; however, their benefit is limited by acquired resistance, which arises through secondary KRAS alterations, bypass pathway activation, and adaptive reactivation of downstream MAPK signaling. In addition, treatment-related hepatotoxicity, particularly in the setting of prior or closely sequenced immune checkpoint inhibitor exposure, has emerged as an important clinical concern. Multiple next-generation KRAS G12C inhibitors, such as divarasib, glecirasib, and olomorasib, are currently under clinical development, with early evidence suggesting improved potency, selectivity, and tolerability. Furthermore, combination strategies incorporating immune checkpoint inhibitors and upstream or downstream pathway-targeted agents, including SHP2, SOS1, and MEK inhibitors, are being actively investigated to enhance the depth and durability of response. More recently, the advent of RAS (ON) inhibitors, exemplified by daraxonrasib (RMC-6236), has introduced a distinct therapeutic paradigm by directly targeting active RAS through a tri-complex mechanism. As the therapeutic landscape continues to evolve, optimal treatment selection will require integrated consideration of molecular heterogeneity, resistance mechanisms, toxicity profiles, and patient-centered shared decision-making.

The analysis of cell-free DNA (cfDNA) in blood is expected to serve as a new diagnostic method for early cancer detection and treatment monitoring by examining trace amounts of ctDNA derived from cancer cells. In cancer patients, ctDNA circulates in the bloodstream, and thanks to technological innovations in next-generation sequencing (NGS) and the analysis of fragmented DNA at low levels, it is now possible to non-invasively detect the presence and type of cancer. Multi-cancer early detection (MCED) is a method for detecting cancer early and identifying its specific type by analyzing cfDNA fragment characteristics, ctDNA somatic variants, and DNA methylation status; some MCED tests are already commercially available. However, when used as a standalone test, MCED faces challenges in early detection reliability and the risk of overdiagnosis, necessitating improvements in sensitivity and specificity, as well as clinical efficacy evidence. For this reason, MCED is currently positioned to complement existing screening methods. Furthermore, in addition to analyzing DNA fragment characteristics and methylation, machine learning is expected to enable more accurate detection. However, challenges remain, such as improving sensitivity in clinical stage Ⅰ and reducing false positives, making further research progress essential. Nevertheless, MCED holds great potential for personalized cancer prevention. This review discusses early cancer diagnosis using cfDNA analysis and the technological advancements in this field.