Solid tumors create an acidic tumor microenvironment (TME) that drives cancer progression, therapy resistance, and immune evasion. Bicarbonate is crucial for maintaining acid-base balance, however, its role in non-small cell lung cancer (NSCLC) remains unclear. Through the analysis of single-cell RNA sequencing data and the TCGA and CPTAC databases, we identified solute carrier family 4 member 7 (SLC4A7) as the predominantly expressed bicarbonate transporter in NSCLC. Functionally, SLC4A7 knockdown impaired bicarbonate uptake, resulting in intracellular acidification and extracellular alkalinization. This phenomenon led to a decrease in glycolysis and subsequently suppressed the growth and metastasis of NSCLC. Both in vivo and in vitro data demonstrate that the alkalinization of the TME induced by Slc4a7 knockout enhances the infiltration and function of cytotoxic T cells, significantly inhibiting tumor growth. Additionally, Slc4a7 knockout exhibits synergistic antitumor efficacy in combination with PD-1/PD-L1 immune checkpoint inhibitors. Mechanistically, integrative analysis of RNA-seq and ATAC-seq data identified CTCF as a transcription factor regulating SLC4A7 expression. In summary, our study demonstrates that SLC4A7-mediated bicarbonate transport is crucial for maintaining acid-base homeostasis in NSCLC and represents a promising therapeutic target for this disease.

During metastasis, circulating tumor cells (CTCs) are subjected to fluidic shear stress (SS), which eliminates many of them but paradoxically enhances malignancy and metastatic success. Meanwhile, given the critical roles of reactive oxygen species (ROS) in stress response and cancer, we engineer a circulation-mimicking microfluidic system which generates pulsatile SS to investigate the interplay among SS, ROS and metastasis. A 3-hour SS treatment rapidly elevates ROS levels, boosting metastatic abilities in triple-negative breast cancer (TNBC) cells in vitro and in vivo. RNA-sequencing and subsequent investigation identify activator protein-1 (AP-1) transcription factor members FOS, ATF3 and FOSB, which undergo dramatic ROS-dependent increase and nuclear localization upon SS stimulation. All three genes exhibit metastasis-promoting potential, while FOS displays the strongest ability to trigger distant lung metastasis in an orthotopic tumor model and correlates with worse clinical outcomes. Mechanistically, calcium channel acts as the mechano-sensor to initiate the SS-ROS cascade, with calcium channel blockers Mibefradil and Nifedipine effectively weakening SS-ROS-induced invasiveness. Following ROS elevation, the downstream activation of p38-ELK1-cFOS and JNK-cJUN pathways subsequently increase the expression of malignancy-related genes. This metastasis-promoting SS-calcium channel-ROS-FOS axis provides new insights for combating metastatic progression in breast cancer.

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.