Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC), yet radioresistance frequently develops and leads to the failure of treatment for NPC. NSUN2 acts as a potential oncogene in NPC, but its role in NPC radioresistance remains unclear. In this study, we revealed that NSUN2 was upregulated in radioresistant NPC tissues. Through a series of functional assays following radiotherapy, including CCK-8, colony formation, apoptosis analysis by flow cytometry, we demonstrated that NSUN2 promoted radioresistance and enhanced DNA damage repair in NPC cells. Mechanistically, NSUN2 negatively regulated TP53 expression and competitively enhanced the UCHL3-RAD51 interaction, thereby facilitating RAD51 deubiquitination and RAD51-mediated homologous recombination repair of DNA double-strand breaks. Moreover, the suppressive effect of NSUN2 knockdown on NPC radioresistance was reversed by TP53 knockdown. Furthermore, the small molecule GSK-F1 was found to directly bind to NSUN2 and promote its proteasomal degradation, consequently activating the downstream TP53/RAD51 signaling axis and increasing NPC cell cytotoxicity and radiosensitivity. In conclusion, our study elucidates that NSUN2 promotes NPC radioresistance by negatively regulating the TP53/RAD51 axis, and the NSUN2 inhibitor GSK-F1 functions as a radiosensitizer in NPC by disrupting the NSUN2/TP53/RAD51 signaling pathway, thereby providing a potential clinical strategy for the targeted therapy and radiosensitivity in NPC.

Glioblastoma (GBM) is a highly aggressive malignancy characterized by dysregulated cell proliferation and impaired stress-response control. Here, we identify the E3 ubiquitin ligase TRIM47 as a regulator of p53 proteostasis and proliferative signaling in GBM. Integrated bioinformatic analyses and immunohistochemistry revealed that TRIM47 is upregulated in GBM and associated with unfavorable survival. Functional assays demonstrated that TRIM47 depletion suppressed GBM cell proliferation and clonogenic growth, induced G1-phase arrest, and markedly inhibited intracranial tumor growth in vivo. Mechanistically, TRIM47 interacted with p53 through its RING-containing region and promoted K48-linked ubiquitination predominantly at lysine 319, leading to proteasome-dependent degradation of p53. Loss of TRIM47 results in stabilization of p53 protein, activation of p21, accumulation of DNA damage, and attenuation of cell-cycle progression. In GBM models exposed to temozolomide-induced genotoxic stress, TRIM47 expression was reduced whereas p53 signaling and DNA damage markers were elevated. Moreover, inhibition of PDK1 kinase activity impaired TRIM47-mediated p53 ubiquitination and enhanced p53-dependent stress responses. Collectively, these findings establish TRIM47 as a critical regulator of p53 proteostasis and cell-cycle progression in GBM, thereby maintaining proliferative fitness under genotoxic stress.

Epidermal growth factor receptor (EGFR) is a pivotal therapeutic target in pancreatic ductal adenocarcinoma (PDAC); however, the clinical efficacy of tyrosine kinase inhibitors (TKIs) such as erlotinib is frequently curtailed by acquired resistance. This study identifies histone deacetylase 1 (HDAC1) as a critical epigenetic driver of this resistance. HDAC1 is markedly upregulated in erlotinib-resistant PDAC cells, where it directly suppresses the transcriptional activity of TFCP2 through site-specific deacetylation at lysine 256 (K256). This modification attenuates TFCP2 function, leading to transcriptional repression of the metastasis suppressor NDRG1 and increased expression of EGFR, thereby activating EGFR-TKI resistance signaling pathways. Furthermore, EGFR-mediated tyrosine phosphorylation protects HDAC1 from ubiquitin-proteasome system (UPS)-dependent degradation, stabilizing HDAC1 and establishing a self-reinforcing feedback loop that sustains its elevated expression in the resistant state. To counter this mechanism, we designed a bioactive peptide derived from TFCP2 that competitively inhibits K256 deacetylation, thereby restoring TFCP2 transcriptional activity. In vitro and in vivo studies demonstrate that pharmacological inhibition of HDAC1 or restoration of TFCP2 acetylation reverses erlotinib resistance in PDAC. These findings unveil a previously unrecognized mechanism of EGFR-TKI resistance and suggest a promising strategy to enhance therapeutic efficacy in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with limited therapeutic options. Dysregulated transcriptional networks are key drivers of its aggressive biology. Here, by integrating clinical datasets with mechanistic studies, we performed a family wide systematic analysis of E2F transcription factors and identified E2F3 as a key oncogenic driver with prognostic significance comparable to E2F1. Functional studies showed that E2F3 accelerates PDAC proliferation and xenograft growth. Mechanistically, E2F3 transcriptionally activates the E3 ligase TRIM26, which binds TAB1, promotes K11-linked polyubiquitination, and facilitates TAB1-TAK1 complex formation to engage canonical NF-κB signaling. The SPRY and RING domains of TRIM26 mediate TAB1 interaction and ubiquitination, respectively. TRIM26 depletion attenuated E2F3 induced NF-κB activation and tumor growth, whereas its restoration rescued these effects. Clinically, E2F3, TRIM26, and phosphorylated p65 levels were positively correlated in PDAC tissues, and therapeutic delivery of siTRIM26 recapitulated NF-κB inhibition. These findings uncover an unrecognized E2F3-TRIM26-TAB1/TAK1-NF-κB signaling axis that links cell cycle regulation with inflammatory activation in PDAC and nominate TRIM26 as a druggable vulnerability to therapeutically decouple this oncogenic crosstalk.

Given the lack of effective targeted therapeutic options for triple-negative breast cancer (TNBC), there is an imperative demand for innovative treatment approaches, with ferroptosis standing out as a promising direction. This study identifies HSPA6 as a key ferroptosis sensitizer in TNBC. Mechanistically, HSPA6 binds to NF-κB p65, inhibits its nuclear translocation and Ser468 phosphorylation, thereby suppressing transcription of the lipogenic enzyme FASN and downregulating phospholipid-remodeling enzymes LPCAT1/cPLA2. This dual inhibition enriches membrane phospholipids with polyunsaturated fatty acids, heightening peroxidation susceptibility and triggering ferroptosis. Concurrently, HSPA6-mediated suppression of lipogenesis depletes palmitate, thereby attenuating ANKIB1 palmitoylation and inhibiting its E3 ligase activity. This impairs K48-linked ubiquitination and degradation of HSPA6, forming a stabilizing positive feedback loop. Our study uncovers a HSPA6-p65-FASN-ANKIB1 axis linking lipid metabolism to ferroptosis, offering a novel TNBC therapeutic target.

Cutaneous squamous cell carcinoma (cSCC) is a type of cancer that originates from the growth of skin cells. It represents the second most common form of non-melanoma skin cancer and primarily arises from the malignant proliferation of keratinocytes in the epidermis or skin appendages. The global incidence of cSCC is increasing, and its onset is primarily associated with prolonged exposure to ultraviolet radiation, genetic susceptibility, and immunosuppression. These factors severely impair patients' quality of life and skin health. Conventional therapeutic strategies for cSCC mainly rely on surgery, radiotherapy, or photodynamic therapy. Although these approaches are widely applied in clinical practice, they present several limitations, including high recurrence rates, poor suitability for special populations, and significant toxic side effects. To overcome these shortcomings, researchers worldwide have recently conducted extensive studies on novel therapeutic approaches. Among them, innovative drug delivery systems have emerged as a highly promising research direction. Unlike traditional treatments, these new drug delivery systems, including nanocarriers (liposomes, polymeric nanoparticles, inorganic nanoparticles), microneedle arrays, hyaluronic acid-based carriers, and DNA nanocomposites, can precisely deliver therapeutic agents to cSCC lesions, reduce systemic toxicity, and achieve sustained drug release at the tumor site. These advantages make them an optimal option for cSCC therapy. This study provides a comprehensive summary of recent advances in the design, functional performance, and translational prospects of these novel delivery technologies. It particularly elucidates how they overcome the limitations of conventional therapies and offer new possibilities for developing effective treatment strategies for cSCC.

BIRC5 (survivin), an inhibitor of apoptosis protein, is overexpressed in most tumors and is associated with drug resistance, proliferation, and metastasis, while being largely undetectable in normal differentiated tissues. This unique expression pattern makes BIRC5 an exceptionally selective therapeutic target, offering the potential to maximize anticancer efficacy while minimizing systemic toxicity to healthy tissues. However, few BIRC5-targeted agents have advanced to late-stage clinical trials.

We developed two nanodrug formulations using poly-L-lysine-modified NH₂-Fe₃O₄ magnetite nanoparticles (PL-MNPs) for selective targeting of BIRC5-positive cancer cells. We further evaluated their anti-cancer efficacy in vitro and in vivo (zebrafish xenograft model), using cancer cell models that expressed BIRC5 and exhibited ABCB1-mediated drug resistance and IDO1-induced immune therapy insensitivity.

The PL-MNPs delivered plasmids driven by the BIRC5 promoter (pBIRC5) encoding either antisense BIRC5 mRNA (As-BIRC5) or a dominant-negative BIRC5 protein (dN-BIRC5), for tumor-specific BIRC5 inhibition. These nanodrugs demonstrated robust in vitro and in vivo anti-cancer activity in multiple BIRC5-positive cell lines (MIA PaCa-2, NTUB1, NTU0.017, SK-OV-3, KB, and KB-TAX50). The activity was preserved across cancer types and independent of ABCB1-mediated drug resistance, while maintaining cancer cell specificity, and was not affected by IDO1 expression, a factor associated with poor responses to immune therapy. PL-MNP uptake was partially mediated by clathrin-dependent endocytosis, with acidic intracellular environments facilitating efficient plasmid release. Conjugation of nanoparticles with Herceptin^® (trastuzumab) significantly increased cellular uptake and anticancer activity, especially in clathrin-deficient SK-BR-3 cells that overexpress ERBB2.

These findings establish that the easily synthesized PL-MNP-pBIRC5/As-BIRC5 and PL-MNP-pBIRC5/dN-BIRC5 nanodrugs have strong potential to overcome BIRC5- and ABCB1-related drug resistance, representing a broadly applicable strategy against various malignancies. While the size of our nanodrug (~400 nm in hydrodynamic diameter) is compatible with reported effective nanoparticle sizes in some models, the extent to which the enhanced permeability and retention (EPR) effect contributes to tumor accumulation in human cancers remains uncertain and will require validation in more clinically relevant models and imaging modalities.

To investigate potential diagnostic approaches and therapeutic strategies for renal inflammatory myofibroblastic tumors (IMT).

Renal IMT is a rare mesenchymal neoplasm with intermediate malignant potential arising within the urinary system. Its clinical presentation and imaging characteristics are nonspecific; thus, histopathological examination remains the diagnostic gold standard. This article presents a retrospective analysis of the clinical course of a single patient diagnosed with renal IMT.

An elderly female presented with intermittent abdominal pain. Abdominal contrast-enhanced computed tomography (CT) revealed a solid mass located in the anterior lip of the right kidney. Following radical right nephrectomy, histopathological evaluation confirmed the diagnosis of renal IMT.

At the 3- and 6-month follow-up visits postoperatively, the patient showed no evidence of local recurrence or distant metastasis.

Definitive diagnosis of renal IMT relies exclusively on histopathological assessments. For localized disease, complete surgical resection, preferably radical nephrectomy, is the treatment of choice. In advanced or unresectable cases, tyrosine kinase inhibitors and other targeted agents may be considered as potential therapeutic options.

Bacteria-mediated cancer therapy leverages bacteria to modulate the tumor immune microenvironment and deliver therapeutics. However, its clinical application is limited by toxicity, off-target effects, and uncontrolled drug release. Improving tumor targeting and precise payload delivery through rational bacterial engineering is essential for increasing efficacy and safety.

An attenuated Salmonella ΔhtrA::luxI-VNP20009 strain expressing OmpA-SpyTag (AISI-ST) was constructed for the modular surface conjugation of SpyCatcherΔ (SC)-fused quadruple arginine-glycine-aspartic acid (RGD) peptides (named AISI-ST/SC-RGD×4) and for building biointerfaces for enhanced tumor adhesion via RGD-mediated integrin αvβ3 interactions. The tumor-bearing mice received intravenous injections of AISI-ST/SC-RGD×4, and their biodistribution was analyzed using bioluminescence imaging and colony-forming unit (CFU) counts. Quorum-sensing (QS)-regulated high-temperature requirement A (HtrA) and anti-programmed cell death protein 1 (anti-PD1) nanobody expression based on the LuxI promoter in strains was validated by Western blotting. Immune responses were assessed using flow cytometry.

The incubation of the fused proteins with the AISI-ST strain for 1 h was sufficient to form a stable biological interface. The quadruple RGD-modified bacteria (AISI-ST/SC-RGD×4) exhibited greater enrichment in various solid tumors and lung metastases with reduced off-target accumulation. QS induced the expression of the HtrA protein within tumors, resulting in enhanced extracellular polysaccharide-mediated immunogenicity to activate immune cells. Further expression of anti-PD1 nanobodies synergistically enhanced antitumor immunity, increasing the percentage of M1 macrophages (MACS) and CD8⁺ T cell proliferation while suppressing M2 MACS and regulatory T cells (Tregs). This approach achieves potent tumor suppression via targeted immune remodeling.

This study presents octopus-inspired engineered bacteria with a "plug-and-display" system and tumor-specific drug delivery that achieves enhanced tumor targeting and potent antitumor effects. This study describes a promising strategy for the precise and safe clinical translation of bacteria-mediated cancer immunotherapy.

Advanced gastric cancer (AGC) exhibits a high incidence in Northwest China, largely attributed to region-specific dietary patterns and environmental exposures. Its pathogenesis involves complex host-microbiota crosstalk, which has not yet been comprehensively elucidated through integrated multi-omics approaches. Herein, we employed trasncriptomic and shotgun metagenomic sequencing on paired tumoral and peritumoal mucosal tissues from 88 AGC patients in Northwest China. Our aim was to systematically characterize host gene expression profiles, the composition and functional potential of the gastric mucosal microbiota, and their intricate interrelationships.

Transcriptomic profiling clearly distinguished tumoral from peritumoral regions (PERMANOVA, R² = 0.24, P = 0.0001), with 8870 differentially expressed genes (DEGs) identified between the two tissue types. Tumor tissues harbored 8377 up-regulated DEG, which were enriched in extracellular matrix (ECM) organization, cell cycle regulation, signaling transduction, and inflammatory pathways (e.g., PI3K-Akt, IL-17 signaling). In contrast, peritumoral tissues showed 493 up-regulated DEGs primarily associated with metabolic processes. Host gene expression was significantly modulated by Lauren classification in tumoral mucosa (P = 0.025) and by Helicobacter pylori (Hp) infection in peritumoral tissues (P = 0.0424). Hp-infected tissues exhibited 65 up-regulated DEGs linked to transcriptional misregulation in cancer, inflammation, immune activation and mitochondrial pathways. Lauren subtypes displayed distinct transcriptomic signatures: intestinal-type AGC was enriched in metabolic processes, diffuse-type in immune and signal transduction pathways, and mixed-type in Ras/MAPK/ErbB and NF-κB signaling pathways. Correlation analysis between the 8870 DEGs and seven differentially abundant bacterial species (e.g., Serratia surfactantfaciens, Pseudomonas protegens, Prevotella jejuni, and Streptococcus infantis) revealed 13199 significant correlations. Among these, S. surfactantfaciens and P. protegens exhibited the strongest connectivity with host genes. Functionally, the correlated DEGs were involved in ECM structure, cell cycle progression, immune and inflammatory responses, cellular proliferation and differentiation, and metabolic processes.

Our findings demonstrated phenotype- and tissue-specific regulation of host gene expression in AGC and revealed extensive host-microbe interactions. This work fills a critical gap in multi-omics research on AGC in the Northwest Chinese population and suggests potential diagnostic and therapeutic targets for AGC.