Metabolic reprogramming is a hallmark of cancer, while tricarboxylic acid cycle is increasingly recognized as a multifaceted hub driving tumor metabolism and progression. Integrated analysis of solute carrier (SLC) transporters revealed consistent down-regulation of SLC13A2 in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and mouse models. Adeno-associated virus-mediated liver-specific knockout or overexpression of SLC13A2 (SLC13A2-OE) promoted or ameliorated HCC progression, indicating its protective role. SLC13A2 inhibited HCC proliferation by decreasing mitochondrial function via suppressed glycolysis, respiration, and adenosine 5'-triphosphate production. Flux analysis showed that SLC13A2 imported citrate to generate acetyl-coenzyme A for pyruvate kinase isozyme type M2 acetylation, triggering its degradation. Reduced pyruvate kinase activity limited pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. Moreover, SLC13A2-imported citrate induced intracellular protein acetylation, particularly histone proteins, which provided an epigenetic basis for transcriptional regulation and contributed to tumor suppression. Thus, SLC13A2 perturbs metabolic and transcriptional programs to suppress tumor growth, highlighting potential drug targets for HCC therapy.

Both primary and metastatic brain malignancies are fatal and highly infiltrated with tumor-associated macrophages (TAMs). Enhancing the phagocytosis of neoplastic cells by TAMs is pivotal for slowing tumor growth. Great endeavors have been made to develop tyrosine kinase inhibitors (TKIs) for brain malignancies, yet whether tumor-targeting TKIs affect the phagocytic capacity of TAMs remains largely unknown. In this preclinical study, we report that repurposing ibrutinib, a blood-brain barrier-penetrable TKI, effectively suppresses the growth of several primary and metastatic brain tumors highly expressing Bruton's tyrosine kinase (BTK) or bone marrow X-linked nonreceptor tyrosine kinase (BMX) but concurrently dampens the TAM phagocytic function. Mechanistically, BTK, which is activated in TAMs, interacts with and phosphorylates Wiskott-Aldrich syndrome protein (WASp) to organize the actin cytoskeleton, which is imperative for phagocytosis. Ibrutinib treatment disrupts BTK-mediated WASp activation, thereby compromising TAM phagocytic efficacy. Pharmacological activation of WASp by its selective small-molecular activator EG-011 restores the ibrutinib-impaired TAM engulfment of tumor cells and effectively improves ibrutinib efficacy in mice bearing glioblastomas, primary central nervous system lymphomas, and lung carcinoma brain metastases. Furthermore, elevated expression of phosphorylated BTK or phosphorylated WASp in TAMs correlates with an increased phagocytic TAM subset identified by single-cell RNA sequencing and correlates with prolonged patient survival in a cohort with glioblastoma. Our preclinical study highlights the necessity of evaluating the on-target, off-tumor attack of TAMs during TKI administration and provides a proof of concept for reinvigorating the TAM phagocytic function to achieve additional clinical benefit.

In this article, we propose a deep reinforcement learning based chemotherapy regulation framework to realize personalized and dynamic optimization of cancer treatment. We use a nonlinear dynamic system to model the dynamic evolution of the tumor microenvironment including tumor cell, normal cell and immune cell interactions, with drug concentration serving as the control input variable. The Deep Deterministic Policy Gradient (DDPG) algorithm makes agents can study optimal dosing strategy in a continuous space of movement to inhibit tumor growth effectively and minimize damage to normal tissues. To make the strategy more stable, Gauss noise is added to the model to simulate physiological oscillations and uncertainties in the treatment reaction. Experimental results show that it can control the growth of tumor in various initial scenarios and the accumulation of the drug concentration with high flexibility and safety. Our technique provides a feasible technical way for precision, low toxicity adaptive chemotherapy.

Tumor-derived exosomes play critical roles in pancreatic ductal adenocarcinoma (PDAC) progression by mediating intercellular communication within the tumor microenvironment. This study identifies the long non-coding RNA PLBD1-AS1 as a functional oncogenic lncRNA enriched in PDAC exosomes. We demonstrate that PLBD1-AS1 promotes tumor cell proliferation, migration, and invasion by interacting with the glycolytic enzyme ALDOA and enhancing glycolytic flux. Furthermore, tumor exosomes deliver PLBD1-AS1 to pancreatic stellate cells (PSC), augmenting their glycolysis and facilitating their activation into cancer-associated fibroblasts, thereby shaping a pro-tumorigenic microenvironment. To target it, we developed an engineered exosome system modified with the tumor-penetrating peptide iRGD for specific delivery of siPLBD1-AS1 to both tumor and stromal cells. The resulting iRGD-exo-siPLBD1-AS1 construct demonstrated enhanced cellular uptake and effectively suppressed PLBD1-AS1 expression, inhibited glycolysis, impaired PSC activation, and significantly attenuated tumor growth. Our findings reveal a novel mechanism of exosome-mediated metabolic crosstalk in PDAC and establish a promising RNAi-based therapeutic strategy targeting this lethal malignancy.

Bladder cancer remains a significant therapeutic challenge due to its marked heterogeneity and capacity for immune evasion. Here, we employ spatial metabolomics and spatial transcriptomics to systematically characterize and visualize the metabolic and transcriptional landscapes of bladder cancer. Our findings identify distinct metabolic and transcriptional profiles across different tumor regions, highlighting heterogeneity and immune-associated metabolic reprogramming in BLCA. Further investigation identifies zinc finger protein 36 (ZFP36) as a potential immunotherapeutic target. Utilizing Zfp36 whole-body knockout and T cell-specific Zfp36 conditional knockout mice, we validated that Zfp36 knockout decreases the activation threshold for T cells and increases T cell infiltration in tumors. Moreover, we found that elevated ZFP36 expression is dramatically linked to worse patient outcomes. Mechanistically, ZFP36 facilitates mRNA degradation of key immune regulators, including C1QBP, thereby inhibiting T cell activation and cytotoxicity. Notably, combining Zfp36 knockout with anti-PD-1 therapy produced synergistic antitumor effects, suggesting that ZFP36 inhibition could be a promising therapeutic strategy. This integrated multiomics approach collectively uncovers immune-metabolic regulatory pathways in BLCA and points to critical molecular targets for immunotherapy.

Ewing sarcoma is driven by chromosomal translocations that fuse a FET RNA-binding protein to an ETS transcription factor, most commonly generating the EWS-FLI1 fusion oncoprotein. EWS-FLI1 engages GGAA microsatellite repeats to form de novo enhancers that activate oncogenic transcriptional programs essential for tumorigenesis. In addition to this truncal driver, recurrent loss-of-function alterations in the cohesin subunit STAG2 occur in approximately 10 to 15% of Ewing sarcomas and are associated with adverse clinical outcomes. However, how STAG2 loss reshapes EWS-FLI1 chromatin engagement and transcriptional output remains poorly understood. Here, using genetic STAG2 loss-of-function models combined with integrative multiomic profiling, we demonstrate that STAG2-cohesin deficiency reprograms the EWS-FLI1 chromatin landscape by altering its binding at GGAA-microsatellite enhancers. Despite increased EWS-FLI1 protein abundance, STAG2 loss eliminates over 40% of EWS-FLI1 binding sites, predominantly at enhancers containing short (1-4) GGAA repeats, while concurrently increasing binding at multimeric enhancers with ≥5 GGAA-repeat motifs. These reprogrammed sites show changes in both chromatin accessibility and H3K27ac, leading to selective amplification of EWS-FLI1 activity at multimeric microsatellite enhancers. By integrating Hi-C chromatin interaction maps with altered EWS-FLI1 occupancy, we define distinct monomeric and multimeric GGAA enhancer-driven transcriptional gene signatures and demonstrate that STAG2 loss selectively augments the multimeric transcriptional program. Consistently, the long GGAA microsatellite-activated gene signature is enriched in patient tumors with aggressive clinical features and deleterious STAG2 alterations. Together, these findings reveal that STAG2 loss reprograms, rather than globally attenuates, EWS-FLI1 function, amplifying a high-risk oncogenic transcriptional state in Ewing sarcoma.

Despite the availability of several chemotherapeutic regimens for early-stage breast cancer (BC), the ideal combination and dosing strategy remain to be defined. Thus, we conducted a network meta-analysis (NMA) comparing the current chemotherapeutic regimens used in the treatment of women with early-stage BC.

Progastrin, is over-expressed in human colorectal tumor cells and also directly targets the ß-catenin/Tcf4 oncogenic pathway, The association between Wnt/ß-catenin pathway and cancer is not merely restricted to colorectal cancer as disruption of this pathway results in epithelial mesenchymal transition in oral carcinogenesis. As therole of progastrin in subjects with Oral cancer(OC) is less explored, this study was contemplated to assess the role of plasma progastrin levels in subjects with various stages of oral squamous cell carcinoma.

In Algeria, breast cancer accounts for 37.8% of new cancer cases in women. It is an epithelial cell tumor in most cases. CA15-3 (carbohydrate antigen) is the marker of choice for therapeutic monitoring, although ASCO (the American Society of Clinical Oncology) does not recommend its routine use, preferring CYFRA21.1 (cytokeratin19 fragment) to assess response to treatment. The aim of this study was to estimate the degree of correlation between these two biological markers as a function of tumour histological type and the presence or absence of metastases. In a prospective descriptive study, sera from 110 breast cancer patients (mean age 49 ± 7.23 years) were measured using the electrochemiluminescence (ECL) technique to assess CYFRA 21.1 and CA 15.3 levels. Comparison of CA15.3 and CYFRA21.1 levels between patients and controls (79 controls) showed a highly significant association (p<0.0001) between these two markers and breast cancer. The significant correlation between CA15.3 and CYFRA21.1 (r=0.245; P< 0.0001) suggests that reliance on CYF 21.1 for monitoring breast cancer patients undergoing chemotherapy is possible. The results show a good correlation between the two markers, especially for the two histological types luminal a and luminal b+HER2 (r=0.602 ; p<0.0001, r=0.505 ;p< 0.0001 respectively). This study also assessed the correlation between CA15.3 and CYFRA21.1 levels in patients with and without metastases. A significant correlation was also found between CA15.3 and CYFRA 21.1 in the presence of metastases (r=0.472, p<0.0001). A multi-marker approach could provide a more comprehensive assessment of tumor burden and response to treatment.

Accurately estimating physiological fitness and life expectancy is challenging in older patients with early-stage non-small cell lung cancer (NSCLC) considered for stereotactic body radiotherapy (SBRT). Noninvasive biological age metrics may improve assessment beyond chronological age.

Real-world evidence (RWE) is increasingly used in health technology assessment (HTA) to address uncertainties surrounding the generalizability of randomized clinical trial (RCT) data. Pembrolizumab plus platinum-based chemotherapy improves survival in metastatic, non-small cell cancer (mNSCLC); however, existing economic evaluations primarily rely on RCT inputs. This study aimed to provide a within-model comparison of cost-effectiveness estimates derived from RCT and population-based RWE for pembrolizumab plus platinum therapy versus platinum therapy alone.

Real-world evidence on the treatment of early triple-negative breast cancer (TNBC) remains limited. This study provides an overview of neoadjuvant chemotherapy (NACT) regimens used in the 2010s of the 21st century, analyzing patient outcomes and treatment patterns based on real-world data from a large population-based cancer registry.

IntroductionThe prognosis differences of gastrointestinal stromal tumors (GISTs) between the jejunum and ileum have rarely been studied. This study aimed to evaluate the long-term survival outcomes in patients with jejunal and ileal GISTs.MethodsThis population-based retrospective cohort study utilized data from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2019. Kaplan-Meier analyses and Cox proportional hazards models were employed to assess overall survival (OS) and cancer-specific survival (CSS). A 1:1 propensity score matching (PSM) approach was implemented to address confounding factors, and subgroup analyses were performed for various variables.ResultsA total of 1237 patients were analyzed, with 848 in the jejunum and 389 in the ileum. Ileal GISTs patients were older, exhibited higher T stages, larger tumor sizes, elevated mitotic rates, and were more susceptible to distant metastasis (P<0.05). After PSM, the jejunal GISTs group and the ileal GISTs group demonstrated comparable OS (hazard ratio [HR]: 1.25, 95% confidence interval [CI]: 0.97-1.60, P=0.082) and CSS (HR: 1.13, 95% CI: 0.81-1.59, P=0.461). Additionally, jejunal GISTs and ileal GISTs exhibited similar OS and CSS across various subgroups. Multivariate Cox regression analysis revealed age, TNM stage, and mitotic rate as independent risk factors influencing OS, whereas race, N stage, and M stage were identified as independent risk factors affecting CSS.ConclusionsJejunal GISTs and ileal GISTs have comparable OS and CSS, with the occurrence of lymph node metastasis and distant metastasis being important factors affecting their prognosis.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, yet its genetic etiology remains poorly understood. In this study, we described a family from the Shanghai General Hospital Osteosarcoma (SGH-OS) cohort in which two siblings developed osteosarcoma as their first primary malignancy, and we investigated the germline and somatic genetic basis underlying this familial presentation.

Diabetes mellitus and cancer are growing global health concerns with a rising prevalence and substantial associated mortality. The study aims to find impact of diabetes mellitus in cancer. A narrative review was conducted by analysing evidence from various sources, including meta-analyses, systematic reviews, retrospective studies, database analyses, and cohort studies. The review explored the complex interplay between Diabetes Mellitus and cancer, like cancer incidence, oncology outcome i.e., acute and late toxicities, treatment compliance, overall survival (OS), and quality of life (QoL). Diabetes mellitus increases the risk of developing cancer by 10%. Diabetic patients had higher infection rates [2.6%-52%, odds ratio (OR) 1.38-1.57], increased haematologic toxicity (13%-65.7%, P=0.004), and greater hospital admissions (17.2%-74.5%, OR 2.1, P< 0.001). They received significantly lower cisplatin doses (18%-33% reduction), experienced more surgical delays [adjusted OR 1.16, 95% confidence interval (CI) 1.05-1.27], higher risk of flap failure (RR=1.83, 95% CI 1.18-2.85, P=0.007) and were less likely to undergo breast reconstruction (adjusted OR 0.48-0.54, 95% CI 0.24-1.00). Diabetes mellitus decreases local control by 10-20%, increases mortality by 27-98%, and decreases OS by 18-50% across various cancers. It increases late toxicity and negatively impacts QOL with a 1.3-2.7 times higher risk of grade ≥2 genitourinary and gastrointestinal toxicity in prostate cancer, a twofold increase in grade ≥3 radiation pneumonitis in lung cancer, and a 50% higher incidence of severe peripheral neuropathy in breast cancer, leading to delayed recovery and long-term morbidity. In patients receiving cancer directed therapy, diabetes mellitus increases acute and late toxicities, decreased local control and overall survival, and have poor quality of life.

Background and objectives The relationship between sarcopenia and prognosis in patients undergoing chemotherapy for testicular germ cell tumours remains underexplored. We aimed to evaluate the impact of sarcopenia on disease progression and overall survival in these patients. Methods This retrospective multicentre study included patients who received chemotherapy for testicular germ cell tumours between January 2010 and December 2023. The psoas muscle index was calculated by measuring the cross-sectional area of the psoas muscle at the third lumbar vertebral level and was divided by the square of the height. Patients were divided into two groups based on changes in PMI (before and after chemotherapy): Group 1 (<10% change) and Group 2 (≥10% change). Results A total of 159 patients were analysed. Of these, 113 (71.1%) were in Group 1 and 46 (28.9%) in Group 2. Group 2 showed higher rates of disease progression (26.1% vs. 10.6%) and mortality (8.7% vs. 1.8%) (P=0.023 and P=0.038, respectively). In multivariable analysis, ≥10 % decrease in psoas muscle index [Hazard Ratio (HR)=6.499, P<0.001], rete testis invasion (HR=3.459, P=0.007), and non-seminomatous/mixed histology (HR=5.777, P=0.020) were identified as independent predictors of disease progression. For mortality, only a ≥10 % decrease in psoas muscle index was found to be a significant predictor (HR=5.994, P=0.049). Interpretation and conclusions A reduction in PMI is an independent prognostic factor for both disease progression and mortality in patients undergoing systemic chemotherapy for testicular germ cell tumours.

Telomerase is active in the majority of high-risk neuroblastomas, a pediatric tumor associated with poor patient outcomes. In other cancer types, resistance to immune checkpoint blockade was overcome by induction of telomere dysfunction using the telomerase substrate precursor 6-thio-2'-deoxyguanosine (6-thio-dG). Here, we explored whether induction of telomere dysfunction improves the anti-tumor efficacy of immune checkpoint inhibition in neuroblastoma. 6-thio-dG treatment induced the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and programmed cell death ligand-1 (PD-L1) expression in murine neuroblastoma cells in vitro. In a MYCN;ALKF1174L-driven transgenic neuroblastoma mouse model, 6-thio-dG treatment delayed tumor growth and prolonged survival. Treatment with anti-PD-L1 also led to growth delay and improved survival, which occurred; however, only after an initial lag phase. Combination with anti-PD-L1 improved the anti-tumor effects of 6-thio-dG and overcame the initial lag phase of anti-PD-L1 treatment. Mechanistically, 6-thio-dG combined with anti-PD-L1 treatment induced cGAS and PD-L1 expression and promoted immune cell infiltration in the tumors. Our findings suggest that 6-thio-dG treatment activates the cGAS-STING pathway in neuroblastoma and that induction of telomere dysfunction in combination with immune checkpoint blockade boosts intratumoral immune cell infiltration and improves survival in a high-risk neuroblastoma mouse model.

Cancer therapy imposes sustained mechanical and biochemical stress on lymphatic tissues, reshaping the signaling environments in which endothelial and contractile programs operate via molecular signals, cell-cell interactions, and mechanical forces. We propose that cancer-associated lymphedema arises from destabilized receptor crosstalk within integrated lymphatic signaling units rather than solely from anatomical insufficiency. Lymphatic vessels function as multicellular signal-processing systems in which receptor activity is context dependent and continuously modulated by ligand availability, tissue stiffness, inflammatory tone, and metabolic state. Under therapeutic stress, receptor systems that are secondary under homeostatic conditions, including mechanosensitive ion channels, purinergic receptors, and stress-responsive G protein-coupled receptors, can exert disproportionate influence over endothelial transcription, barrier function, contractile coordination, and immune-vascular feedback loops. Sustained activation of these networks may reinforce inflammatory and remodeling programs, providing a mechanistic explanation for delayed onset, nonlinear progression, and interindividual variability. This signaling-centered framework positions lymphatic failure after cancer therapy as a disorder of network integration and identifies stress-responsive receptor systems as tractable points for early intervention.

Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.

Cancer is a leading cause of mortality worldwide, yet access to specialized pathology services remains limited in many low- and middle-income countries, including Tanzania. Telepathology offers a practical means to expand diagnostic capacity and improve timely cancer care. Through a partnership with the American Society for Clinical Pathology (ASCP) and Duke University, Kilimanjaro Christian Medical Centre (KCMC) implemented a telepathology consultation platform to provide expert review for diagnostically challenging cases.