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.

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.

In this study, we used Mendelian randomization analysis to explore the causal relationships between drug targets and cutaneous melanoma (CM) and subsequently screened for new drug targets for CM. In addition, we verified whether targeted drugs could inhibit the development of CM in CM cells by suppressing the expression of target genes.

This study aims to elucidate the mechanism through which prostate cancer-associated transcript 6 (PCAT6) modulates immune escape in triple-negative breast cancer (TNBC), focusing on its interaction with IGF2BP1 and PD-L1.

The 2021 WHO classification reclassified "IDH-mutant glioblastoma (GBM)" as "Astrocytoma, IDH-mutant, grade 4." This study aims to provide real-world validation of this reclassification using the specific ICD-O-3 code (9445/3) from the Surveillance, Epidemiology, and End Results (SEER) "Transition Era" (2018-2022) and develop a machine learning (ML)-based prognostic model.

Skin cutaneous melanoma (SKCM) is a highly aggressive malignancy with a poor prognosis, necessitating the exploration of novel molecular mechanisms driving its progression. CircRNA, which have emerged as critical regulators in cancer biology, have been implicated in various tumorigenic processes. However, their specific roles in SKCM remain inadequately understood.

Few studies have evaluated the impact of organ-specific tumor microenvironments (TMEs) on clinical outcomes in diffuse large B-cell lymphoma (DLBCL). This study investigated potential molecular markers, the immune cell composition within the TME, and their associations with clinical outcomes in patients with primary intestinal DLBCL (PI-DLBCL). We initially analyzed RNA expression in tumor cells from 19 patients with PI-DLBCL in the experimental cohort. Candidate biomarkers were then assessed in lymphoma tissue from a total of 48 patients in the same cohort, including the 19 with RNA-expression data, and validated in an independent cohort of 29 patients with PI-DLBCL. Associations between these markers and clinicopathological features, event-free survival (EFS), and overall survival (OS) in the two cohorts were analyzed. In the RNA expression panel, CCL5 expression was higher in patients with advanced-stage PI-DLBCL and was associated with inferior EFS and OS. Its principal receptor, CCR5, expressed in approximately one-third of patients, was associated with lower complete response rates to first-line immunochemotherapy: 50% in the experimental cohort and 10% in the validation cohort and correlated with the 7-year worse OS rate in both the experimental (49.8% versus 71.4%, p = 0.082) and validation (0% versus 76.2%, p < 0.001) cohorts. In both the experimental and validation cohorts, CCR5-positive tumors exhibited decreased CD86-positive (M1-like) and increased CD206-positive (M2-like) macrophage infiltration, consistent with an immunosuppressive TME. Multivariate analyses revealed that CCR5 expression was independently associated with worse EFS (p < 0.001) and OS (p = 0.004) in patients with PI-DLBCL (combined experimental and validation cohorts). CCR5 expression indicates a biologically aggressive subtype of PI-DLBCL with poor clinical outcomes and M2 macrophage-dominant immunosuppression.

Innate immunity constitutes the body's first line of defense, deploying evolutionarily conserved mechanisms to detect and respond to pathogenic threats and tissue injury. In contrast to the adaptive immune system's specificity and memory, innate immunity relies on germline-encoded pattern recognition receptors (PRRs) to sense pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). This review outlines the major PRR families and their downstream signaling pathways, culminating in the production of cytokines and inflammasome activation. Additionally, this review explores the functional integration of cellular responses and examines the sophisticated regulatory circuits, including transcriptional, posttranscriptional, epigenetic, and metabolic mechanisms, that calibrate innate immune responses. Importantly, we highlight how dysregulated innate immunity underlies a wide spectrum of diseases, from autoinflammatory and autoimmune disorders to chronic inflammatory states and cancer. Recent insights into trained immunity and innate immune memory further redefine the scope of innate defenses, revealing that metabolic and epigenetic remodeling can prime innate cells for enhanced secondary responses. Finally, we discuss the therapeutic potential of modulating innate pathways, including PRR agonists as vaccine adjuvants or anticancer agents, and PRR inhibitors in autoimmune and inflammatory diseases. By integrating current mechanistic knowledge with emerging therapeutic strategies, this review underscores the central role of innate immunity in health and disease while pointing toward promising avenues for future research and clinical translation.

Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.

Tumor-specific targeting remains a major obstacle for the development of precision cancer therapies. For several tumors and specifically glioblastoma (GBM), an aggressive brain tumor with poor prognosis, more effective treatments are urgently needed. Recombinant adeno-associated viruses (rAAVs), with their established clinical utility and mutational capsid plasticity, offer a promising platform for targeted delivery. We engineered and evaluated modified AAV capsids derived from the established AAV2 with HSPG-tropism knockdown and two less-characterized, tropism-reduced AAV9 variants. The epidermal growth factor receptor (EGFR), a tumor marker often overexpressed in GBM, was targeted by inserting an affibody (ZEGFR:1907). Also chlorotoxin (CLTX) was inserted, a peptide from scorpion venom reported to bind GBM. Transduction efficiencies were initially assessed with established cell lines (A431, HeLa, U251MG, MCF7). Affibody-displaying capsids exhibited EGFR-dependent transduction, with AAV9-affibody variants surpassing AAV9 wild-type. Several affibody-displaying capsids also transduced patient-derived GBM explants, as confirmed by fluorescence microscopy. These findings highlight the potential of retargeting AAV9 variants and the use of human surgical tissue samples for the initial evaluation of newly designed AAV capsids.

Transarterial chemoembolization (TACE) remains a cornerstone therapy for intermediate-to-advanced hepatocellular carcinoma (HCC); however, the optimal embolic platform remains uncertain. This multicenter, retrospective, real-world study (Clinical trial registration number: ChiCTR2500113198) conducted across China compared a novel temperature-sensitive liquid embolic agent, TempSLE-TACE (T-TACE), with conventional drug-eluting bead TACE (D-TACE) in 328 patients with Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Following inverse probability of treatment weighting (IPTW), T-TACE achieved significantly superior objective response rates (ORRs) compared with D-TACE according to both RECIST 1.1 criteria (54.11% vs. 27.78%, P < 0.001) and mRECIST criteria (73.56% vs. 54.93%, P = 0.002). T-TACE was additionally associated with significantly prolonged progression-free survival (median PFS: 12.0 vs. 9.0 months; HR = 0.67, P = 0.001) and overall survival (median OS, 24.0 vs. 15.0 months; HR = 0.49, P < 0.001). Moreover, T-TACE demonstrated a favorable safety profile, with lower incidences of hepatic and gastrointestinal toxicities, including any-grade alanine aminotransferase elevation and hyperbilirubinemia. Subgroup analyses further demonstrated consistent OS, PFS, and ORR benefits across major clinical subgroups, with effect sizes remaining significantly favorable in high-risk populations, including advanced portal vein tumor thrombosis type Vp4, baseline AFP > 1000 ng/mL, and PIVKA-II > 2000 mAU/mL. Exploratory histo-molecular and spatial transcriptomic analyses suggested that T-TACE may promote immune microenvironment remodeling through enhanced Th17-cell infiltration and CD8⁺ T-cell activation, whereas incomplete embolization after D-TACE was more frequently associated with residual intermediate-state tumor cells and an immunosuppressive microenvironment. Collectively, these findings provide preliminary evidence supporting T-TACE as a promising real-world therapeutic strategy for intermediate-to-advanced HCC.