Theranostics最新文献

Rationale: Evidence accumulating across experimental studies and clinical settings supports a central role for the C5a-C5aR signaling axis in promoting tumor progression and immune evasion. Nevertheless, whether a vaccination approach targeting C5a can elicit robust anti-tumor immune responses and suppress tumor growth has not yet been investigated. This research aimed to develop an efficient B-cell peptide epitope vaccine targeting the C5a-C5aR pathway for cancer therapy. Methods: Chimeric C5a B-cell peptide epitope vaccines were synthesized using high-performance liquid chromatography (HPLC), and C5a antibodies titers were determined using enzyme-linked immunosorbent assay (ELISA). Multiple mouse tumor models were employed to evaluate the vaccine's efficacy. The mechanisms of MAX449 were assessed through in vitro and in vivo approaches, incorporating single-cell RNA sequencing (scRNA-seq), flow cytometry, western blotting, real-time quantitative PCR, transwell migration assays and ELISA. Results: The vaccine MAX449 could induce high titer of C5a antibodies and effectively suppress tumor growth in multiple mouse models. Furthermore, MAX449 significantly boosted the effectiveness of anti-PD1 therapy. It not only inhibited the migration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment through downregulating CCRL2 expression via the NF-κB signaling pathway but also reduced the immunosuppressive function of PMN-MDSCs by decreasing IL-1β production through the same pathway. Following vaccine administration, a significant expansion of anti-tumor CD8⁺ T cells was observed. Most importantly, the vaccine proved to augment the antitumor efficacy of programmed death-1 (PD-1) antibodies in cold and hot tumor mouse models. Conclusions: This research demonstrated that MAX449 induced C5a antibodies, which block C5a-C5aR pathway in PMN-MDSCs, suppression of their migratory and immunosuppressive functions, and consequent antitumor activity. Meanwhile, MAX449 boosted the therapeutic efficacy of PD-1 antibody in hot and cold tumor model mice. This study provides compelling evidence supporting the clinical evaluation of MAX449 as an innovative therapeutic approach for cancer.

Glioblastoma (GBM) is an aggressive brain tumor characterized by limited therapeutic efficacy and challenges in accurate imaging, largely due to its invasive growth, drug resistance, and the restrictive blood-brain barrier (BBB) hindering the delivery of both therapeutic and diagnostic agents. Current GBM treatments and imaging approaches often suffer from insufficient agent penetration into the tumor. Additionally, they frequently exhibit toxicity or poor signal-to-noise ratios. Polysaccharide (PSC)-based polymers, with their inherent biocompatibility, biodegradability, and versatile chemical modifiability, offer a promising platform to overcome these limitations. These natural polymers can be engineered into sophisticated nanocarriers that enhance BBB traversal, enable targeted tumor accumulation of therapeutic payloads and imaging agents Furthermore, they facilitate controlled drug release and improve diagnostic signal generation. Consequently, PSC-based systems can improve therapeutic efficacy and enhance diagnostic accuracy for tumor visualization. Furthermore, they reduce systemic side effects and support multimodal strategies, ranging from single-modality interventions to integrated theranostic systems. This review aims to comprehensively discuss recent advancements, current challenges, and future perspectives of PSC-based nanomedicines in GBM therapy and imaging.

Rationale: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy. The metastasis and poor prognosis of ESCC are closely associated with tumor microenvironment (TME) heterogeneity, which is driven by epithelial-mesenchymal transition (EMT). Clinically, how to diagnose and target EMT progression remains a key challenge for ESCC. Methods: Integration of pathological images and bulk RNA sequencing profiles identified a high-risk subtype exhibiting EMT enrichment and immunosuppression. Single-cell and spatial transcriptomics revealed EMT macrostates and their spatial distribution. The role of CACNA1C in programming malignant phenotype was tested in vitro. A pathological image-based deep learning model successfully predicted the spatial expression distribution of CACNA1C, indicating possible clinical utility. Results: EMT progression comprised three macrostates: the early state (high epithelial and metastatic potential), the stable state (hybrid E/M phenotype and high stemness), and the late state (high mesenchymal and invasive propensity). ITGA3 and ITGB4 antagonistically regulate malignant phenotype in the early state. Notably, suppression of CACNA1C induced transdifferentiation from stable/late-state cells to normal epithelium-like cells. Conclusions: This study provides novel insights into the EMT mechanism in ESCC, proposes an intervention strategy, and emphasizes the promising clinical application of pathological images in EMT assessment.

Rationale: The anatomical complexity and restricted regenerative potential of alveolar bone defects create a significant clinical challenge and highlight the need for spatially biomimetic and biologically supportive biomaterials. Methods: We developed a bone-mimicking matrix hydrogel scaffold inspired by the features of a "flowerbed," utilizing machine learning-guided three-dimensional bioprinting. Gelatin methacrylate (GelMA), decellularized bone matrix (DBM), and urine-derived stem cell exosomes (USC-Exos) were co-integrated during the printing process to deliver crucial biophysical and biochemical signals for bone regeneration. Results: The GelMA/DBM/USC-Exos scaffold exhibited high printing fidelity, enabling precise fabrication of defect-specific geometries while preserving exosome bioactivity and achieving sustained release (> 16 days). Functionally, the scaffold promoted M2 macrophage polarization and markedly upregulated osteogenic and angiogenic gene expression, which was approximately 2-fold higher than that of the control (p < 0.01). Mechanistically, the scaffold enhanced oxidative phosphorylation by activating the AMP-activated protein kinase pathway, resulting in a nearly 2-fold increase in adenosine triphosphate content and promoting the osteogenic differentiation of jawbone marrow-derived mesenchymal stem cells. In vivo implantation in mandibular defect models induced robust neovascularization and bone formation, resulting in a nearly 3-fold increase in vessel density and 65.6 ± 3.0% new bone volume after 4 and 8 weeks, respectively, effectively promoting coordinated and functional alveolar bone regeneration. Conclusions: This study establishes a biomimetic approach that integrates structural biomimicry, exosome-mediated bioactivity, and energy metabolism regulation, offering a promising and targeted strategy for personalized alveolar bone regeneration.

THz technology is expected to provide breakthroughs for precision oncology due to its physical nature, such as non-ionizing radiation nature, sensitivity to water and fingerprint recognition. Yet, its clinical application is severely limited due to their drawbacks: shallow penetration depth, difficult interpretation and sensitivity. This review examines recent interdisciplinary advances that integrate THz technology with materials science, nanotechnology, artificial intelligence (AI), computational modeling, gene editing, and microfluidics to develop intelligent diagnostic and therapeutic systems capable of supporting the full oncology continuum-from tumor imaging and biomarker detection to treatment monitoring and drug delivery assessment. For example, combining THz with metamaterials or nanostructures enhances sensitivity for trace-level biomarker detection; AI algorithms enable rapid, accurate interpretation of complex spectral data for automated diagnosis; and convergence with microfluidics and CRISPR-based systems has led to ultra-sensitive liquid biopsy platforms. These integrated approaches not only address existing technical barriers but also open pathways toward multifunctional theranostic systems with practical clinical utility. By fostering cross-disciplinary collaboration, THz technology can be further optimized to enable more accurate, effective, and personalized cancer care, transforming its potential from foundational research into real-world clinical impact.

Rationale: Non-target lesions (NTLs) progression is common in patients with coronary artery disease (CAD). However, its predictors remain obscure. Methods: An angiographic study was conducted in patients with CAD who underwent coronary angiography twice at an interval of 6 to 30 months. NTLs were defined as lesions not treated with percutaneous coronary intervention (PCI) during the first hospitalization. A stenosis index (SI) was calculated from all NTLs in each patient. NTLs progression was defined as an increase in SI (ΔSI > 0) at follow-up. Results: Among 1658 patients recruited, 1061 (64.0%) exhibited NTL progression, with a ΔSI of 0.75 (0.40, 1.30) over a mean follow-up period of 13 months. The NTLs progression group had more males, diabetics, higher neutrophil ratio, creatinine, fasting blood glucose (FBG), uric acid, more PCI therapy and higher SI on the first admission, and higher systolic blood pressure, heart rate, serum levels of low-density lipoprotein cholesterol and FBG at readmission. Multiple logistic regression analysis identified male sex, PCI therapy, and SI on the first admission, and FBG on the second admission were independent predictors of NTLs progression, with the odds ratio of 1.390 (95%CI 1.034~1.869), 1.375 (95%CI 1.087~1.740), 1.003 (95%CI 1.002~1.004) and 1.184 (95% CI 1.086~1.291), respectively. Conclusions: Over 60% of CAD patients developed NTL progression within 30 months. Male sex, PCI therapy and SI on the first admission, and FBG on the second admission were independent predictors of NTLs progression.

Recent breakthroughs in radiopharmaceutical (RP) therapy have emerged interest in employing Auger electron (AE)-emitting radionuclides as potential agents for precise theranostics. AE provides energy with exceptional localization due to their short tissue penetration range (TPR, < 10 nm), rendering them particularly effective for targeting nuclear DNA in tumor cells. In this context, AE-emitting radionuclide therapy (AE-emitting RLT) enables the targeted destruction of tumor cells while reducing harm to adjacent healthy tissue, a significant challenge in this field. Preclinical and early clinical investigations reveal the efficacy of AE-emitting RLTs in the theranostics of diverse malignancies, such as glioblastoma, prostate cancer, and neuroendocrine tumors. Notwithstanding these developments, challenges and limitations persist regarding dosimetry, delivery efficiency, and the treatment of radiotoxicity. A new paradigm is being developed to tackle the obstacles encountered by integrating molecular target markers (e.g., PARP) that function near the nucleus to improve the intranuclear delivery efficiency of AE-emitting radionuclides. Novel radiochemical methods such as these have facilitated the more stable and efficient labeling of biomolecules with AE-emitting radionuclides. Also, recent advances in DNA-molecular targeting, nanoparticles, nucleic acid/protein engineering, click- or bioorthogonal conjugation chemistry, and artificial intelligence (AI)-based structure modeling present concrete opportunities to overcome these limitations. Moreover, the integration of diagnostic imaging companion platforms employing theranostic radioisotope pairings facilitates real-time assessment of therapeutic efficacy and biodistribution, resulting in the formulation of enhanced treatment regimens. This review summarizes the prior development, recent advancements, barriers in clinical implementation, and future perspective of AE-emitting RLTs.

Efferocytosis, phagocytic clearance of apoptotic cells (ACs), is an essential biological process that resolves inflammation and regulates tissue regeneration in various organ systems. Through removal of apoptotic cell debris, efferocytosis attenuates secondary necrosis and dampens the release of damage-associated molecular patterns (DAMPs). More importantly, it can reprogram phagocytes towards a pro-reparative phenotype via the secretion of anti-inflammatory mediators, metabolic rewiring, and the production of growth factors. There are four closely regulated stages in the entire process: "find-me" signal-mediated phagocyte recruitment, recognition of ACs via "eat-me" signals, AC internalization via Rho GTPase-dependent actin remodeling, and phagolysosomal degradation of ACs by either canonical or light chain 3 (LC3)-associated phagocytosis (LAP). In a repair context, efferocytosis may refer to the clearance of dying cells during various tissue repair processes, such as wound healing, liver injury, myocardial infarction, intestinal damage, kidney injury and muscle injury. Efferocytosis regulates inflammation resolution, stem/progenitor cell activation, extracellular matrix remodeling, and angiogenesis to coordinate tissue repair. Chronic pathology (e.g., diabetic ulcers, fibrosis) induced by dysfunctional efferocytosis results from accumulation of non-phagocytosed ACs that maintain inflammation and impair regeneration. Therapeutic strategies targeting dysfunctional efferocytosis have been developed, encompassing active pharmaceutical ingredients, biologics, and biomaterials-assisted therapeutic modalities. Despite promising outcomes from preclinical studies, challenges still exist in the spatiotemporal control and clinical translation of these therapeutic strategies. Future research could focus on the multi-omics integration and smart biomaterial development to dynamically modulate efferocytosis during different disease phases.

Rationale: Loss of histone deacetylase 5 (HDAC5) is frequently observed in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC), and is associated with poor patient survival. Although HDAC5 has been implicated in DNA damage repair, the molecular mechanisms by which it regulates DNA double-strand break (DSB) repair pathway choice remain unclear. Methods: Using PDAC cell lines, genetically engineered mouse models, patient-derived organoids, and biochemical assays, we investigated the role of HDAC5 in DNA end resection and homologous recombination (HR). Protein interactions, post-translational modifications, DNA repair pathway activity, and cellular responses to DNA damage and PARP inhibition were systematically analyzed. Results: We identify HDAC5 as a critical regulator of DNA end resection and HR through deacetylation of Ku70. DNA damage induces casein kinase 2 (CK2)-mediated phosphorylation of HDAC5, promoting its nuclear translocation. Nuclear HDAC5 directly deacetylates Ku70 at lysine 287, facilitating Ku70 dissociation from DSB sites, thereby enabling DNA end resection and HR repair. In contrast, HDAC5 loss or CK2 inhibition results in Ku70 K287 hyperacetylation, prolonged retention of the Ku heterodimer at DSBs, impaired DNA end resection, and suppression of HR. Consequently, HDAC5-deficient PDAC cells exhibit increased sensitivity to PARP inhibitors, while pharmacological CK2 inhibition sensitizes HDAC5-proficient tumors to PARP inhibition. Conclusions: These findings uncover a previously unrecognized CK2-HDAC5-Ku70 signaling axis that governs DNA repair pathway choice by regulating DNA end resection. Targeting this axis provides a mechanistic rationale for enhancing PARP inhibitor sensitivity in PDAC, including tumors without classical homologous recombination deficiency.

Background and Aim: Magnesium ion (Mg²⁺)-mediated metallo-immunotherapy effectively promotes the activation of memory T cells, thereby helping to mitigate tumor recurrence following traditional treatments such as radiotherapy (RT). However, factors such as the acidity of the tumor microenvironment, along with the upregulated expression of immune checkpoints induced by RT and Mg²⁺, may compromise its therapeutic efficacy. Material and Methods: In this work, we developed a T cell membrane-coated, hemin-loaded magnesium carbonate nanomedicine (designated as THM). Following intravenous injection, THM catalyzes the hydrogen peroxide generated during RT to induce a burst of reactive oxygen species (ROS), thereby producing a tumor vaccine that promotes dendritic cell maturation and T cell activation. Simultaneously, THM reacts with H⁺ to mitigate the acidic tumor microenvironment while releasing Mg²⁺, which further enhances the generation and activation of central memory T cells (Tcm) to confer long-term anti-tumor immunity following RT. Results: RT combined with Mg²⁺ treatment upregulates PD-L1 expression in tumor cells. Notably, the PD-1 protein on THM can competitively bind to PD-L1, thereby mitigating the side effects associated with the combined therapy. In vitro and in vivo data confirm that this combinatorial therapy boosts Tcm-mediated antitumor activity, mitigates treatment-induced immune suppression, and potently prevents tumor recurrence. Conclusions: This work provides critical insights for the clinical translation of antitumor immunotherapy.