Although immune checkpoint inhibition has proven highly effective in patients with metastatic or advanced squamous cell carcinomas, such as oral cancer, the role of innate immune responses in regulating oral cancer progression remains poorly understood. In this study, we examined the impact of innate immune responses in an orthotopic oral squamous cell carcinoma model (NR-S1-Luc cells) using bioluminescence imaging. In severe combined immunodeficiency mice lacking adaptive immune cells, CD11b+ Ly6Ghi Ly6Chi (Ly-6G+) myeloid cells accumulated more prominently than CD11b+ Ly6Gint Ly6Chi (Ly-6C+) cells within NR-S1-Luc tumors. Although Ly-6G+ myeloid cells were predominant in orthotopic NR-S1 tumors, in vivo depletion of Ly-6G+ cells did not alter tumor growth. Treatment with a Toll-like receptor 3 (TLR3) agonist (poly I:C) significantly inhibited tumor growth, accompanied by enhanced inflammation and upregulation of Ly-6C expression on Ly-6G+ myeloid cells. Moreover, depletion of Ly-6G+ cells partially impaired this TLR3-mediated effect. Transcriptomic analysis of Ly-6G+ myeloid cells from NR-S1-Luc tumor-bearing mice revealed that poly I:C treatment induced functional reprogramming of these cells, accompanied by broad alterations in immune-related and metabolic pathways within the orthotopic oral tumor microenvironment. Collectively, these findings suggest that tumor-infiltrating Ly-6G+ myeloid cells are functionally plastic and can be reprogrammed by TLR3 stimulation, thereby contributing to the regulation of tumor progression.

Acquired resistance limits the durability of programmed cell death protein-1 (PD-1) blockade in lung adenocarcinoma, yet the tumor-intrinsic programs and immune circuits that drive acquired resistance relapse remain poorly defined. The purpose of this study was to identify tumor-intrinsic mediators of acquired resistance and determine how they remodel antitumor immunity.

BackgroundPathological fractures (PFs) are clinically important skeletal-related events in patients with bone metastases from solid tumors and may negatively affect survival. This meta-analysis aimed to quantify the association between PFs and overall survival (OS) in patients with metastatic solid cancers.MethodsThis systematic review and meta-analysis was conducted in accordance with PRISMA 2020 using a PICOS-defined protocol. PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 2025 without language restrictions. Eligible studies included adults with metastatic solid tumors, compared patients with and without PFs, and reported OS using hazard ratios (HRs). Tumor types were pooled a priori because the included studies evaluated the same exposure-comparator-outcome framework across metastatic solid tumors. Random-effects models were used, and heterogeneity was explored through moderator analyses and meta-regression. Two reviewers independently screened records, extracted data, and assessed risk of bias using MINORS for observational studies and the Cochrane tool for randomized trials.ResultsFrom 198 records, four studies comprising seven cohorts and 3,607 participants met the inclusion criteria. Random-effects pooling showed that PFs were significantly associated with poorer OS compared with no PFs (pooled HR 1.40, 95% CI 1.08-1.81; p = 0.010). However, heterogeneity was substantial (I2 = 92.6%), indicating that the pooled estimate should be interpreted cautiously. Meta-regression suggested a positive association between publication year and effect size (β = 0.041; p = 0.041), whereas primary cancer subgrouping was not a significant moderator. Funnel-plot asymmetry and Egger's test suggested possible small-study effects.ConclusionsPFs appear to be associated with worse OS in patients with metastatic solid tumors, highlighting the importance of fracture prevention, early identification of impending fractures, and multidisciplinary care. Nevertheless, the small evidence base, substantial heterogeneity, and possible publication bias warrant cautious interpretation. Prospective studies with standardized PF definitions and adjusted survival analyses are needed.

The response to neoadjuvant therapy in patients with locally advanced rectal cancer varies considerably among individuals. While some patients achieve a complete pathological response, others may even experience disease progression during treatment. The aim of the study was to investigate the predictive value of serum adipokines in determining the response to neoadjuvant therapy.

The prognostic value of tumor-infiltrating lymphocytes has been studied in several cancers, but in gastric cancer, their evaluation by standard hematoxylin-eosin staining remains controversial.

Isthmin-1, a recently discovered adipokine, was first characterized for its role in early brain development. Subsequent studies have demonstrated that isthmin-1 is involved in a broad range of biological processes, including metabolism, immunity, tumorigenesis, cellular proliferation, endothelial permeability, and organ development.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare yet highly aggressive subtype of non-small cell lung carcinoma (NSCLC) with limited therapeutic options. We conduct a comprehensive proteogenomic analysis of LCNEC using tumors and paired normal adjacent tissues from 107 patients (81 pure LCNEC and 26 combined LCNEC). APOBEC mutational signatures strongly correlate processes of tumor initiation and immune suppression, and KEAP1 mutations correlate with metabolic reprogramming in LCNEC combined with NSCLC. A conflicting relationship is observed between neuroendocrine and immune phenotypes. We identify three LCNEC subtypes with unique prognosis features, microenvironment dysregulation, genetic alterations, and potential therapeutic targets. Interleukin-33 (IL-33) emerges as a critical therapeutic biomarker associated with enhanced T cell infiltration and antitumor activity. We further optimize recombinant IL-33 (rIL33) with site-directed mutagenesis and develop PEGylated rIL33, demonstrating its prolonged circulation time in cynomolgus monkeys and superior immune agonist activity in mouse models. Overall, this study offers insights into LCNEC biology and provides promising innovative immunoagonist therapy strategies for lung cancer.

Myasthenia gravis (MG) presents a clinical challenge where autoantibody titers poorly predict disease severity, and thymectomy provides inconsistent benefits. We hypothesized that thymic B cells acquire survival mechanisms that bypass canonical tolerance checkpoints, enabling persistence independent of antigen-specific selection. Using single-cell RNA sequencing, V(D)J repertoire analysis, and spatial transcriptomics to generate the largest MG atlas to date (237,661 cells), we identified a tolerance checkpoint swap in MG pathogenesis. Pathological class-switched B cells within thymic germinal centers exhibited reduced antigen presentation (CD74 and CD1C) and diminished CD40 costimulation while up-regulating TNFRSF17 to engage BAFF-driven survival. This shift allows polyclonal autoreactive B cells to evade stringent selection and seed peripheral sites. T follicular helper cells supported this reprogramming via increased TNFSF13B and CHGB expression, with the latter facilitating dopamine-mediated synaptic acceleration. These findings offer insight into clinical paradoxes in MG and point to the BAFF-BCMA axis as a potential therapeutic target and biomarkers for disease activity.

Remodeling of fatty acid metabolism is increasingly recognized as a critical feature of tumor progression, yet the contribution of very long-chain fatty acid (VLCFA) remains incompletely understood. The elongation of VLCFAs, which is mediated by four consecutive enzymes in the endoplasmic reticulum (ER), has been implicated in tumor progression. However, the molecular mechanisms underlying VLCFA elongation enzymes and their specific contributions to tumorigenesis remain largely elusive. Here, we demonstrate that trans-2-enoyl-CoA reductase (TECR) is upregulated in colorectal cancer (CRC). Structural and biochemical analyses revealed a conserved catalytic mechanism for TECR-mediated trans-2-enoyl-CoA reduction. Moreover, we show that TECR forms a stable complex with 3-hydroxyacyl-CoA dehydratase (HACD), to cooperatively drive VLCFA elongation. A unique U-shaped loop in HACD is critical for recognizing TECR. Disruption of the HACD-TECR interaction interface significantly suppresses CRC cell growth. Collectively, these findings elucidate the molecular mechanism of HACD-TECR-mediated VLCFA elongation and suggest a potential therapeutic strategy for CRC treatment by modulating VLCFA metabolism.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Current treatments often fail to eradicate AML; therefore, new therapeutic strategies are essential. Here, we reveal that RNA terminal uridylyl transferase enzymes 4 and 7 (TUT4/7) are druggable therapeutic targets, whose genetic deletion suppresses AML growth, induces apoptosis, and improves the survival in leukemic mouse models. Notably, a preclinical TUT4/7 inhibitor promotes cell death in samples from patients with AML and synergizes with venetoclax. Mechanistically, TUT4/7 inactivation suppresses mevalonate pathway gene expression, compromising the cholesterol synthesis pathway. Current AML therapies often cause severe hematopoietic toxicity. Although Tut4/7 deletion results in inflammatory activation throughout the hematopoietic system, this is permissive to a normal life span and Tut4/7 deficiency does not compromise HSPC function. Together, these findings identify TUT4/7 as druggable targets, whose inactivation suppresses AML while sparing normal hematopoiesis. In combination with venetoclax, this represents a promising therapeutic strategy.

Glioblastoma (GBM) remains a lethal primary brain tumor, in part because therapeutic efficacy is limited by the blood-brain barrier (BBB) and the complex tumor microenvironment (TME). Sonodynamic therapy (SDT), i.e., use of ultrasound to activate chemical sensitizers and generate cytotoxic stress, offers a non-invasive strategy for treating deep-seated intracranial disease, but progress is constrained by the scarcity of validated sonosensitizers and the inefficiency of conventional in vitro screening methods. Here, we introduce a New Approach Methodology (NAM) that couples a neural network-based positive-unlabeled (PU) learning framework with a high-throughput, magnetic field-guided 3D bioprinting platform to accelerate identification and experimental validation of SDT-sensitizing agents. Using curated drug and small-molecule data and RDKit-derived molecular descriptors, the PU classifier identifies candidate ultrasound-responsive compounds without requiring reliable negative labels. We then validate the AI-based predictions in physiologically relevant U-87 MG glioblastoma spheroids that reproduce key TME features, including spatial heterogeneity and a hypoxic core. The NAM identifies two FDA-approved drugs, carboplatin (advanced ovarian cancer) and memantine hydrochloride (Alzheimer's disease), as effective ultrasound-responsive agents. In 3D spheroids, combining low-intensity pulsed ultrasound with either drug significantly reduces viability compared with drug-only controls, and both combinations outperform temozolomide (TMZ), the current standard chemotherapeutic. Time-resolved responses reveal distinct kinetics: memantine produces strong early cytotoxicity (24 h) enhanced by ultrasound, whereas carboplatin shows delayed but pronounced cytotoxicity (72 h), also improved by ultrasound. Together, these results establish an integrated computational-experimental NAM that enables rapid repurposing of approved drugs as SDT sensitizers and provides a scalable framework for advancing GBM therapeutic discovery while reducing reliance on animal studies.

Gastric cancer remains a major cause of cancer-related mortality worldwide, with tumor recurrence and distant metastasis being primary contributors to poor prognosis; however, the underlying molecular mechanisms are not fully understood. CD93, a type I transmembrane glycoprotein, has been implicated in tumor angiogenesis and metastasis in various solid cancers, yet its role in gastric adenocarcinoma (STAD) requires further elucidation.

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.

Merkel cell carcinoma (MCC)is a rare but aggressive cutaneous malignancy with increasing incidence and poor prognosis. Host immune status is a key determinant of MCCmerkel cell carcinoma development and outcome. While the AEIOU criteria are widely used to facilitate clinical recognition, their value for prognostic assessment remains unclear. To evaluate the association between individual AEIOU presentation features and disease progression in patients with merkel cell carcinoma, with particular emphasis on immunosuppression. We performed a retrospective single-centre cohort study including 400 patients diagnosed with merkel cell carcinoma. Disease progression, defined as local recurrence, nodal involvement or distant metastasis, served as the primary endpoint. AEIOU criteria were assessed at diagnosis and analysed using logistic regression. Complete follow-up data were available for 241 patients, of whom 81 (33.6%) experienced disease progression. Patients with progression were significantly older and more frequently male. Among the AEIOU components, immunosuppression was the only criterion significantly associated with disease progression, conferring an increased risk compared with immunocompetent patients (p<0.001). Other AEIOU features showed no consistent prognostic association. Complete follow-up data were available for 241 patients, of whom 81 (33.6%) experienced disease progression. Patients with progression were significantly older and more frequently male. Among the AEIOU components, immunosuppression was the only criterion significantly associated with disease progression, conferring an increased risk compared with immunocompetent patients (p<0.001). Other AEIOU features showed no consistent prognostic association.

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).

Diethylnitrosamine (DEN) is a potent environmental carcinogen commonly found in cigarette smoke and polluted air, which is strongly associated with the initiation and progression of lung cancer through oxidative stress, inflammation, and dysregulated cell signaling. Alloimperatorin, a bioactive furanocoumarin compound isolated from Angelica dahurica, has demonstrated anti-inflammatory, antioxidant, and anticancer potential. The current study was designed to explore the chemoprotective effect of alloimperatorin against DEN-induced lung cancer in rats and explore the underlying signaling pathways.

To evaluate the cytotoxic efficacy and interaction dynamics of curcumin, morin, and phyllanthin - individually and in dual (C + M) and triple (C + M + P) combinations - in estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with frequent recurrence and strong immune evasion. Programmed death ligand-1 (PD-L1) facilitates immune evasion by suppressing T-cell activity. Andrographolide (AD), a natural diterpenoid with anti-inflammatory, antiviral, and immunomodulatory properties, has demonstrated antitumor potential.

Early diagnosis and effective treatment of pancreatic cancer remain major clinical challenges, one of the most aggressive and lethal tumors. The tumor microenvironment (TME) in pancreatic cancer exhibits unique features, including high interstitial fluid pressure (IFP), abnormal blood vessels, hypoxia, acidosis, and excess reactive oxygen species (ROS), all favoring tumor progression and immunosuppression, meanwhile offsetting diagnostic efficiency and treatment efficacy. Thus, the TME of pancreatic cancer is considered as a target of profound theranostic significance. Nanoparticles (NPs) have shown a high profile in bio-imaging and targeted drug delivery. Here, we depicted the TME of pancreatic cancer and reviewed the designs and performances of TME-transforming NPs in the diagnosis and treatment of pancreatic cancer, as well as the obstacles to be overcome before their clinical translation. This review is expected to provide sparks for the early diagnosis and personalized treatment for pancreatic cancer.

The ubiquitin-proteasome system (UPS) plays a central role in regulating protein homeostasis and degradation. Its dysregulation is closely associated with various diseases, including cancer. S-phase kinase-associated protein 2 (SKP2) is a key E3 ubiquitin ligase component of the UPS. It induces proteasome-mediated protein degradation or modulates substrate function by conjugating K48-linked or K63-linked ubiquitin chains to diverse target proteins. Recent studies have shown that the overexpression of SKP2 in several cancer types is correlated with poor clinical outcomes, underscoring its potential as a therapeutic target. Notably, emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment (TME) and immunotherapy response, positioning it as an increasingly attractive target for intervention. In this review, the oncogenic properties of SKP2 and its underlying mechanisms were elucidated in multiple cancer types. Moreover, we systematically summarized future directions for SKP2-targeted therapy.