Neutrophil extracellular traps (NETs) are reticular structures composed of neutrophil elastase (NE), cathepsin G (CG) and DNA-histone enzyme complexes. Accumulating evidence has revealed that NETs play important roles in tumor progression, metastasis, and thrombosis. However, our understanding of its clinical value and mechanism of action in oral squamous cell carcinoma (OSCC) is limited and has not yet been systematically described. Here, we aimed to investigate the clinical significance of NETs in OSCC and the mechanisms by which they affect its invasive and metastatic capacity. Our results demonstrated that high enrichment of NETs is associated with poor prognosis in OSCC, and mechanistic studies have shown that NE in NETs promotes invasion and metastasis via NLRP3-mediated inhibition of pyroptosis in OSCC. These findings may provide a new therapeutic approach for OSCC.

Tumor invasion and metastasis are the underlying causes of high mortality rate due to oral squamous cell carcinoma (OSCC). Energy metabolism reprogramming has been identified as a crucial process mediating tumor metastasis, thus indicating an urgent need for an in-depth investigation of the specific mechanisms of tumor energy metabolism. Here, we identified an RNA-binding protein, DAZ-associated protein 1 (DAZAP1), as a tumor-promoting factor with an important role in OSCC progression. DAZAP1 was significantly upregulated in OSCC, which enhanced the migration and invasion of OSCC cells and induced the epithelial–mesenchymal transition (EMT). RNA sequencing analysis and experimental validation demonstrated that DAZAP1 regulates mitochondrial energy metabolism in OSCC. Mechanistically, DAZAP1 underwent liquid–liquid phase separation to accumulate in the nucleus where it enhanced cytochrome c oxidase 16 (COX16) expression by regulating pre-mRNA alternative splicing, thereby promoting OSCC invasion and mitochondrial respiration. In mouse OSCC models, loss of DAZAP1 suppressed EMT, downregulated COX16, and reduced tumor growth and metastasis. In samples from patients with OSCC, expression of DAZAP1 positively correlated with COX16 and a high expression of both proteins was associated with poor patient prognosis. Together, these findings revealed a mechanism by which DAZAP1 supports mitochondrial metabolism and tumor development of OSCC, suggesting the potential of therapeutic strategies targeting DAZAP1 to block OSCC invasion and metastasis. Significance: The RNA-binding protein DAZAP1 undergoes phase separation to enhance COX16 expression and mediate metabolic reprogramming that enables tumor metastasis, highlighting DAZAP1 as a potential metabolic target for cancer therapy.

Bisphosphonate-related (BP-related) osteonecrosis of the jaw (BRONJ) is one of the severe side effects of administration of BPs, such as zoledronic acid (ZA), which can disrupt the patient’s quality of life. Although the direct target of skeletal vasculature and bone resorption activity by BPs has been phenomenally observed, the underlying mechanism in BRONJ remains largely elusive. Thus, it is urgently necessary to discover effective therapeutic targets based on the multifaceted underlying mechanisms in the development of BRONJ. Here, we determined the inhibitory role of ZA-treated macrophages on osteoclast differentiation and type H vessel formation during tooth extraction socket (TES) healing. Mechanistically, ZA activated the NF-κB signaling pathway and then induced p65 nuclear translocation in macrophages to promote miR-149-5p transcription, resulting in impaired osteoclast differentiation via directly binding to the Traf6 3′-UTR region. Moreover, we identified that miR-149-5p–loaded extracellular vesicles derived from ZA-treated bone marrow–derived macrophages could regulate biological functions of endothelial cells via the Rap1a/Rap1b/VEGFR2 pathway. Furthermore, local administration of chemically modified antagomiR-149-5p was proven to be therapeutically effective in BRONJ mice. In conclusion, our findings illuminate the dual effects of miR-149-5p on skeletal angiogenesis and bone remolding, suggesting it as a promising preventive and therapeutic target for BRONJ.

Cell cycle pathway, especially via cyclin D1‐CDK4/6 signaling, is enriched in immunotherapy‐resistant and immune‐excluded tumors. CDK4/6 inhibitor (CDK4/6i) induces antitumor immune phenotypes by targeting both tumor and immune cells, enhancing immune checkpoint blockade (ICB), but optimal combination modalities and the corresponding cellular mechanisms remain unclear. Here, it is shown that activation of tumor cell‐intrinsic cyclin D1‐CDK4/6 signaling is associated with low tumor‐infiltrating lymphocyte populations and immunotherapy resistance in head and neck squamous cell carcinoma (HNSCC). Comparison of sequential versus combinatorial regimens in subcutaneous or orthotopic HNSCC mice revealed that CDK4/6i priming before anti‐PD‐1 enhances response durability by promoting CD8 ⁺ and CD4 ⁺ T cell infiltration and decreasing overall neutrophil abundance. Mechanistically, IL15‐secreted Sell(hi) neutrophils induced Stat5a+ progenitor exhausted CD8 ⁺ T cells contributed to the antitumor effect of CDK4/6i priming modalities. Together with corroborating evidence from a clinically relevant patient‐derived‐organoid‐TIL (PDO‐TIL) co‐culture model, these findings support further clinical testing of brief CDK4/6i dosing before anti‐PD‐1 to improve ICB efficacy.

This study aimed to add two functional components—antibacterial 45S5BGs particles and AIE nanoparticles (TPE-NIM⁺) with bioprobe characteristics—to the guided tissue regeneration (GTR) membrane, to optimize the performance. The PLGA/BG/TPE-NIM⁺ membrane was synthesized. The static water contact angle, morphologies, and surface element analysis of the membrane were then characterized. In vitro biocompatibility was tested with MC3T3-E1 cells using CCK-8 assay, and antibacterial property was evaluated with Streptococcus mutans and Porphyromonas gingivalis by the LIVE/DEAD bacterial staining and dilution plating procedure. The fluorescence staining of bacteria was observed by Laser Scanning Confocal Microscope. The results showed that the average water contact angle was 46°. In the cytotoxicity test, except for the positive control group, there was no significant difference among the groups (p > 0.05). The antibacterial effect in the PLGA/BG/TPE-NIM⁺ group was significantly (p < 0.01), while the sterilization rate was 99.99%, better than that in the PLGA/BG group (98.62%) (p < 0.01). Confocal images showed that the membrane efficiently distinguished G⁺ bacteria from G⁻ bacteria. This study demonstrated that the PLGA/BG/TPE-NIM⁺ membrane showed good biocompatibility, efficient sterilization performance, and surface mineralization ability and could be used to detect pathogens in a simple, fast, and wash-free protocol.