CUSABIO Monthly Citation Review: 200 New Product Citations in February, Total Citations Hit 25,000!

This study reveals a novel mechanism by which γδ T cells recognize ectopically expressed intracellular proteins on the cell membrane to activate immune responses. The researchers found that γδ T cell receptors (TCRs) can specifically recognize certain intracellular proteins, such as nucleolin (NCL) and transglutaminase 1 (TGM1), which are ectopically expressed on the cell membrane under stress conditions. These proteins can be recognized as “non-self” antigens by γδ T cells, triggering cytotoxic responses. Additionally, radiation therapy was shown to enhance the expression of stress-induced proteins on tumor cells, thereby increasing the antitumor efficacy of γδ T cells. This finding not only expands the understanding of γδ T cell recognition patterns but also provides new strategies for cancer immunotherapy, such as targeting these stress-induced proteins with CAR-T or TCR-T cell therapies.

This study reveals the role of S100A12 in acute myocardial infarction (AMI), showing that it exacerbates myocardial injury by triggering NETosis via the ANXA5-calcium axis. Using a transgenic mouse model, researchers found that elevated S100A12 worsens cardiac function and ventricular remodeling. Mechanistically, S100A12 interacts with ANXA5 to enhance calcium influx, promoting NETs formation and cardiomyocyte apoptosis. Inhibiting ANXA5 or blocking NETs formation mitigates myocardial damage and improves cardiac function. Additionally, plasma S100A12 levels correlate with dsDNA concentration in AMI patients, predicting increased 1-year mortality risk. This study identifies the S100A12-ANXA5-calcium axis as a potential therapeutic target and biomarker for AMI.

This study investigates the role of WNT11 in liver metastasis and reveals that WNT11 promotes CD8+ T-cell exclusion and immunosuppression via the CAMKII-mediated signaling pathway, leading to poor prognosis. WNT11-overexpressing tumor cells reduce CD8+ T-cell recruitment and activity by downregulating CXCL10 and CCL4, and induce immunosuppressive macrophage polarization by upregulating IL17D. The study also shows that CAMKII inhibition with KN93 enhances the efficacy of anti-PD-1 therapy in a mouse model of liver metastasis. Serum WNT11 levels are identified as a potential biomarker for predicting immunotherapy response. The findings highlight the WNT11/CAMKII axis as a critical regulator in the tumor microenvironment and a promising target for immunotherapy in liver metastasis.

This study investigates a silk fibroin nanoparticle hydrogel loaded with an NK1R antagonist (SF@CP@Gel) for treating dry eye disease (DED). DED is a multifactorial condition characterized by chronic ocular surface inflammation and tissue damage. The study shows that SF@CP@Gel can regulate the Th17/Treg balance by inhibiting the SP/NK1R signaling pathway, thereby exerting anti-inflammatory and reparative effects. The hydrogel exhibits excellent biocompatibility and sustained drug release, maintaining effective drug concentrations for up to 25 hours on the ocular surface. In vitro tests reveal that SF@CP@Gel is non-toxic to human corneal epithelial cells, reduces reactive oxygen species levels in oxidatively damaged cells, and promotes cell migration and proliferation. In vivo experiments further demonstrate that SF@CP@Gel significantly alleviates clinical symptoms in a DED mouse model by reducing pathological Th17 cells and restoring Treg activity, while repairing damaged ocular surface tissues. This study provides a novel and potentially translatable approach for treating DED.

This study introduces PRIZE, a virus-mimicking nanosystem designed to repair p53 abnormalities in tumor cells and enhance the immunogenicity of in situ cancer vaccines (ISCVs). PRIZE delivers p53 mRNA and Zn(II) to restore intracellular p53 levels, transforming tumor cells into antigen reservoirs. It effectively repairs p53 defects in 4T1 (p53-deficient) and MC38 (p53-mutant) cells, upregulating MHC I and CD80 expression to boost antigen presentation. Additionally, the co-delivered photothermal agent ICG triggers immunogenic cell death under laser irradiation, releasing tumor antigens and inducing ISCV formation. In p53 abnormal tumor mouse models, PRIZE-activated ISCVs initiate the cancer immune cycle, demonstrating remarkable antitumor efficacy and inhibiting tumor metastasis and recurrence. This work provides valuable insights for advancing personalized cancer immunotherapy.

This study investigates the role of GPR37 activation in alleviating bone cancer pain. It was found that activating GPR37 (using neuroprotectin D1 or artesunate) significantly reduces acute and persistent pain in multiple mouse models of bone cancer and protects against cancer-induced bone destruction. Mechanistically, GPR37 activation promotes IL-10 release from macrophages, inhibiting osteoclastogenesis, and directly activates GPR37 in dorsal root ganglion neurons and the spinal dorsal horn, reducing neuronal hyperexcitability. The activation is dependent on β-arrestin 2. In patients with bone metastases, endogenous NPD1 levels are negatively correlated with pain intensity and the bone resorption marker CTX-I. This study highlights GPR37 activation as a potential therapeutic strategy for bone cancer pain, acting through direct and synergistic inhibition of osteoclastogenesis and neuronal hyperexcitability.

This study investigates the role of 3-hydroxyacyl-CoA dehydratase 2 (HACD2) in pancreatic cancer (PC) progression. HACD2 is highly expressed in PC and associated with poor prognosis. Mechanistically, HACD2 promotes PC cell proliferation by binding to parkin (PRKN) and enhancing the dissociation of pyruvate kinase PKM2 from PRKN, reducing PKM2 ubiquitination and increasing its dimerization, which subsequently promotes c-Myc expression and tumor growth. HACD2 overexpression-induced PC growth is mitigated by PKM2 knockdown or PRKN overexpression. Additionally, the weight loss drug orlistat, which binds to HACD2, disrupts the interaction between HACD2 and PRKN, increasing PKM2 ubiquitination and inhibiting PC cell proliferation. This study identifies the HACD2/PRKN/PKM2 signaling axis as a potential new target for personalized PC treatment.

This article investigates how the gut microbiota, particularly Lactobacillus reuteri (L. reuteri), alleviates bile acid disorder-induced diarrhea by regulating bile acid metabolism. The study finds that L. reuteri produces I3C (indole-3-carbinol), which inhibits the host enzyme UGT1A4, reducing the production of CDCA-3β-glucuronide and mitigating diarrhea. Additionally, it reveals the crucial role of LKB1 in gut epithelial cells, which binds to P53 to inhibit apoptosis and alleviate diarrhea. The research highlights the intricate interplay between gut microbes and host metabolism, proposing I3C as a potential therapeutic strategy for bile acid disorder-induced diarrhea.

This study investigates the role of CX3CR1+ macrophages in the progression of thoracic aortic aneurysms (TAA) in Marfan syndrome (MFS). It reveals that these macrophages accumulate in the aortic intima and exacerbate TAA by inducing vascular smooth muscle cell (VSMC) inflammation through the secretion of TNF-α and IGF1. The study demonstrates that specifically eliminating CX3CR1+ cells or inhibiting monocyte recruitment significantly mitigates TAA progression. Additionally, it identifies that CX3CR1+ macrophages originate from bone marrow monocytes recruited via CCR2 signaling. These findings highlight the pathogenic role of immune cells in MFS-related TAA and suggest potential therapeutic strategies targeting CX3CR1+ macrophages.

This study presents a novel cancer treatment strategy integrating sonodynamic therapy (SDT) and ferroptosis via engineered exosomes (EXO@CAT) for enhanced efficacy. Catalase (Cat) and ACSL4-overexpressing 4T1 cells were constructed via lentivirus transfection, and exosomes enriched with Cat and ACSL4 (EXO@CA) were extracted. The sonosensitizer TCPP was then loaded into EXO@CA to create EXO@CAT. The engineered exosomes demonstrated significant oxygen generation in a hydrogen peroxide environment, enhancing SDT efficiency by increasing singlet oxygen (^1O₂) production. ACSL4 further promoted lipid peroxidation (LPO) accumulation, sensitizing cells to ferroptosis. EXO@CAT exhibited homologous targeting ability, allowing efficient accumulation in tumor tissues, alleviating hypoxia, and improving SDT penetration. In vivo experiments in breast tumor-bearing mice confirmed that EXO@CAT significantly inhibited tumor growth and reduced lung metastasis. This study offers a promising synergistic cancer treatment approach combining SDT and ferroptosis.