Cancer immunotherapy has emerged as a transformative therapeutic strategy that harnesses the immune system to combat malignant tumors, overcoming critical limitations such as the nonspecific cytotoxicity of conventional chemotherapy and radiotherapy and drug resistance arising from target mutations in targeted therapies. Growing evidence demonstrates that the human microbiome plays a pivotal role in modulating immune responses and influencing the efficacy of immunotherapeutic interventions. Although the impact is increasingly recognized, the molecular mechanisms and translational potential of microbiome-based strategies remain incompletely explored. This review systematically elucidates how microorganisms from distinct anatomical sites (including bacteria, fungi, and viruses residing in the gut, oral cavity, skin, respiratory tract, and urogenital tract) and intratumoral microbes modulate the tumor immune microenvironment through metabolites, immune cell priming, and antigen mimicry. Furthermore, we discuss how specific microbial signatures predict responses to immune checkpoint inhibitors (ICIs) and CAR-T cell therapy, and highlight emerging interventional strategies, including fecal microbiome transplantation (FMT), probiotics, and engineered bacteria, that demonstrate synergistic effects with immunotherapy in preclinical and clinical settings. By integrating mechanistic insights with translational advances, this review provides a comprehensive scientific foundation for microbiome-based precision immunotherapy, aimed at improving patient survival outcomes and reducing treatment-related adverse events.
The advent of neuroimmunology has dismantled the traditional doctrine of the brain's immune privilege, uncovering a sophisticated and dynamic bidirectional regulatory interplay between the nervous and immune systems. This review synthesizes pivotal advances in neuroimmunology, integrating recent anatomical and molecular discoveries to refine the understanding of neuro-immune communication. It highlights the pathological roles of neurotransmitters, cytokines, and their signaling networks in neurodegenerative, psychiatric, and neoplastic diseases, while critically examining contested regulatory mechanisms. The review further evaluates the clinical translational potential and challenges of innovative strategies such as vagus nerve stimulation, optogenetics, multiomics sequencing, and cytokine-targeted therapies. By integrating multidisciplinary perspectives, this review consolidates a theoretical framework for neuro-immune research and provides insights into precision medicine for related diseases. On the basis of synthesizing existing knowledge, it proposes promising research directions, identifies priorities and potential challenges for future investigations, and emphasizes the value of neuro-immune mechanisms in guiding therapeutic development—including target identification, design of individualized treatment strategies, and cross-disciplinary collaborative innovation to advance clinical interventions for neuro-immune diseases. Finally, the review delves into the recent advances and challenges in combined neuromodulation-immunotherapy strategies.
The interplay between diet, gut microbiota, and depressive symptoms is increasingly recognized, but underlying mechanisms remain unclear. We investigated whether adherence to several dietary patterns relates to gut microbial signatures and whether these profiles are associated with depressive symptoms in an elderly Mediterranean cohort. In 644 participants, 16S ribosomal RNA gene sequencing and dietary intake from a food-frequency questionnaire were obtained at baseline and 1-year follow-up. Adherence scores were computed for the Mediterranean diet adherence score (MEDAS), energy-reduced MEDAS (erMEDAS), Dietary Approaches to Stop Hypertension (DASH), Healthy Plant-Based Diet Index (HPDI), Unhealthy Plant-Based Diet Index (UPDI), and Western Diet Score (WESTDIET). Healthy patterns (erMEDAS, MEDAS, DASH, HPDI) were associated with 22, 28, 24, and 16 genera, of which 82%, 75%, 79%, and 88% showed a protective profile (more abundant with lower, or less abundant with higher, depressive symptoms). UPDI and WESTDIET were associated with 20 and 27 genera, but only 25% and 26% were protective. Mediation analyses indicated that gut microbiota mediated the associations of MEDAS (ACME = –0.066, p = 0.006) and erMEDAS (ACME = –0.029, p = 0.011) with depressive symptoms. This study is among the first to test whether diet shapes a microbiota signature that mediates the diet–depression relationship, adding mechanistic insight into diet–mental health research.
Radiogenomics is a rapidly developing field that links radiological image features (radiomics) to genomic-level data (genomics, transcriptomics, and epigenomics), addressing the limitations of single-omic approaches. Radiomics provides a noninvasive and cost-effective method to capture tissue-level characteristics, while genomics elucidates the underlying molecular mechanisms. The central hypothesis is that the formation of imaging phenotypes is associated with the genetic and molecular processes, and thus can reflect underlying biological activities. This review presents the fundamental principles of radiogenomic analysis, covering key concepts in image analysis and gene analysis, as well as advanced analytical techniques for linking imaging and genomic data. Moreover, we summarize recent research findings across various human diseases, including oncology and nononcology, to highlight the current understandings and achievements in this field. Radiogenomics shows potential in clinical applications for elucidating disease mechanisms, detecting genomic variations noninvasively, and improving prognosis predictions. However, its implementation in clinical practice is limited by data scarcity, analytical methods, and barriers in translational processes. Future research should focus on enhancing data quality and establishing guidelines, developing analytical platforms, and validating current findings through animal models and clinical trials.
Natural products, originating from diverse biological sources, serve as a critical reservoir of bioactive compounds for cancer intervention across prevention, treatment, and supportive care. Their mechanisms extend beyond direct cytotoxicity to include modulation of tumor metabolism—such as glucose, lipid, and glutamine pathways—and the tumor microenvironment (TME), highlighting their multifaceted role in oncology. However, a systematic synthesis of how natural products concurrently target metabolic reprogramming and immune–stromal components across different clinical phases remains lacking. This review delineates the therapeutic applications of natural products—such as flavonoids, alkaloids, and terpenoids—across the clinical continuum, including perioperative support, concurrent chemoradiotherapy, maintenance therapy, and metastasis suppression. We detail their actions in disrupting core metabolic pathways and elucidate their influence on TME components like cancer-associated fibroblasts, extracellular matrix, and immune cells including tumor-associated macrophages and T lymphocytes. Furthermore, we discuss innovative delivery strategies—including nanocarriers and codelivery systems—that enhance bioavailability and enable synergistic combination with chemotherapy or immunotherapy. By integrating mechanistic insights with clinical translation strategies, this work provides a comprehensive framework for employing natural products in biomarker-driven, precision oncology regimens, supporting their evolving role in multimodal cancer care.
Graft-versus-host disease (GVHD) are still key obstacles of haploidentical transplantation. Interleukin-2 (IL-2) could promote natural killer (NK) cells and T-regulatory cells (Tregs) cells expansion in vitro and in vivo. We explored whether low-dose IL-2 administration at an early stage could promote NK cells and Tregs reconstitution and reduce GVHD after haplo-HSCT. This cohort trial included 10 recipients of accepting IL-2 treatment and case-pairing 30 recipients without IL-2 treatment post haplo-HSCT. In contrast to the control group, the 5-year incidence of chronic GVHD (cGVHD) was lower (p = 0.018), and GVHD progression-free survival (GPFS) was better (p = 0.025) in the IL-2 group. Blood NK-cells, Treg cells, conventional T cells (Tcon) cells, and the expression of CD62L+ on Tregs and Tcon cells reconstitution were increased post-IL-2 treatment. NKG2A expression on NK cells increased significantly post-IL-2 treatment. Meanwhile, IL-2 administration shortly increased the plasma levels of IFN-Ƴ, TNF-a, IL-10, and IL-2 in subjects post haplo-HSCT. Relative to the control group, low-dose IL-2 increased NK cell counts and the expression of CD122, DNAM-1, and NKG2D on NK cells post transplantation. Administration of low-dose IL-2 after haplo-HSCT correlated with reduced cGVHD, which should be explored further with randomized trial.
While thrombolytic therapy can be effective for stroke, many patients are unable to benefit due to time restrictions. In an aging society, sarcopenia, a condition marked by reduced muscle volume, often worsens recovery after stroke. Our study explored how mitochondria, which are abundant in muscle, could aid in stroke recovery through exercise-induced migration. Using mouse models of chronic hypoperfusion and ischemia, alongside in vitro studies with rat primary cells under oxygen–glucose deprivation and CoCl2 exposure, we found that treadmill exercise protected against white matter injury, myelin loss, astroglial formation, and memory deficits observed 28 days post-hypoperfusion. In acute ischemia models, training reduced glial activation and post-stroke complications. Exercise increased mitochondrial levels in muscle and blood, facilitating their migration between tissues via platelets. In vitro, the addition of muscle-derived mitochondria enhanced the survival of neurons, astrocytes, and oligodendrocytes. Notably, platelets carrying mitochondria from treadmill-trained mice significantly improved ischemic white matter injury and mitigated post-stroke complications. This study highlights mitochondria as a critical part of the secretome, suggesting that muscle-derived mitochondria might play a role in the protective effects of remote ischemic preconditioning. Cell–cell mitochondrial migration, therefore, could offer a promising new approach to reducing post-stroke complications and vascular dementia.
Although BRAF is frequently mutated across multiple cancer types, its clinical utility as a prognostic biomarker has remained inconsistent in clinical practice, likely due to additional events modulating BRAF signaling pathways. This inconsistency has driven our investigation into the broader landscape of BRAF signaling and the development of a robust molecular signature to assess BRAF-driven oncogenic activity. To achieve this, we introduced BRAF25, a transcriptional signature designed to effectively capture BRAF oncogenic activity. Our findings reveal that 25.6% of TCGA colorectal cancer (CRC) tumors exhibit BRAF pathway activation, even in 19.4% of BRAF wild-type (WT) cases, suggesting alternative mechanisms driving pathway activation. The BRAF-active subtype, termed BAG-3 (BRAF Activity Group-3), demonstrated reduced responsiveness to chemotherapy and anti-BRAF therapy. Notably, BRAF25 subtyping addresses the limitations of using BRAF mutation alone to predict patient survival. We experimentally screened and validated DUSP6 as a sensitizing target for anti-BRAF therapy, enhancing BRAF inhibitor efficacy in CRC. Furthermore, pan-cancer analyses implicate the BRAF25 signature in poor prognosis across diverse BRAF-driven malignancies. In conclusion, stratifying patients by transcriptional BRAF oncogenic activity, instead of relying solely on BRAF mutation status, provides a more precise approach to guide clinical decision-making and improve therapeutic outcomes.
Conventional approaches for the detection and surveillance of non-muscle invasive bladder cancer (NMIBC) remain invasive, burdensome, and costly. The utLIFE-UC assay, designed to identify mutations and large copy number variations in urine, has demonstrated high accuracy in detecting urothelial carcinoma. Here, we assessed its efficacy in early detection of NMIBC, identifying minimal residual disease, and monitoring recurrence. Among 108 consecutive NMIBC patients evaluated, utLIFE-UC exhibited a sensitivity of 90.5% in diagnosing NMIBC, with comparable performance in detecting both de novo and recurrent NMIBC. For patients undergoing repeat transurethral resection of bladder tumor (Re-TURBT), the assay accurately identified all cases with residual tumor, achieving a 100% negative predictive value. Positive postoperative utLIFE-UC results before the first follow-up cystoscopy predicted a higher risk of future relapse. A positive test result at any time following TURBT was correlated with poorer recurrence-free survival, whereas sustained negative test results indicated recurrence-free status. Moreover, utLIFE-UC could predict recurrence with a median lead time of 73.5 days prior to clinical confirmation. As the first prospective, longitudinal analysis of urinary tumor DNA in NMIBC, this study highlights the potential of utLIFE-UC to enable earlier recurrence detection and improve risk stratification, potentially obviating unnecessary Re-TURBT and surveillance cystoscopies.
Glioblastoma (GBM) is the most lethal brain tumor, characterized by strong resistance to conventional therapies. Despite recent therapeutic advancements, overcoming chemoresistance remains a major challenge. Here, we identified FOS-like antigen 1 (FOSL1) as a novel therapeutic target in GBM, particularly in patients with resistance to conventional drugs, including temozolomide (TMZ). FOSL1 gene was identified from the DepMap database as a potential mediator of TMZ resistance in GBM and found to be associated with chemoresistance molecular signatures and poor clinical outcomes. Functional analyses in GBM cells revealed that FOSL1 suppression enhanced apoptosis, induced G0/G1 cell cycle arrest, and reduced both cell migration and stemness marker expression. Transcriptomic profiling, including single-cell RNA-seq and bulk RNA-seq, highlighted the pivotal role of the interleukin-6 (IL-6)/STAT3 signaling pathway in FOSL1-mediated stemness. Mechanistically, in vitro experiments demonstrated that FOSL1 induces GBM stemness through IL-6-pSTAT3Tyr705 signaling axis. Furthermore, vemurafenib, which targets FOSL1, was identified as a potential therapeutic agent against TMZ-resistant GBM in a mouse model. These findings suggest that FOSL1 promotes TMZ chemoresistance by regulating IL-6-pSTAT3Tyr705-mediated stemness in GBM cells, making it a promising therapeutic target to overcome chemoresistance in GBM.
Cancer neuroscience has emerged as a transformative frontier in oncology research, focusing on the interplay between cancer cells and the nervous system. Cancer cells establish tumorspecific neural networks within tumor tissues via neurotrophic hijacking. The nervous system regulates tumor initiation, progression, and metastasis either directly by regulating signal transduction in tumor cells or indirectly by modulating the tumor microenvironment (TME). The positive feedback loop between cancer cells and nerves promotes tumor progression. Deciphering the regulatory role of nerves in tumor progression may yield novel anticancer therapeutic options. In this review, the interaction between nerves and cancer cells is described, including how cancer cells hijack and remodel nervous system structure and function, and how neuron-signaling regulates cancer cell growth directly or indirectly through modulating the TME. This evidence of the critical role of nerves in the malignant phenotype of tumors indicates the potential of using neuron-signaling targeting strategies in cancer treatment. By summarizing these findings, this review aims to provide comprehensive insights into the interaction between nerves and cancer cells, paving the way for neuron-signaling-based anticancer therapies.
Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons (DNs). Currently, there is no treatment that can cure PD. Deep brain stimulation has been used to treat PD due to its good effectiveness, but there are safety issues. Therefore, noninvasive electrical stimulation (NES) may be an effective and safe strategy for the treatment of PD. Here, we performed NES treatment and NES combined with human adipose-derived stem cells-induced DN transplantation (NES-DN) on the PD monkey model to explore the therapeutic effect of NES on PD. The results show that NES or NES-DN can increase dopamine levels, improve mitochondrial dysfunction, reduce neuroinflammation, enhance synaptic function, and protect TH neurons, thereby improving the movement disorders of PD. Moreover, NES/NES-DN may exert immunomodulatory effects by regulating serpin family A member 3 in PD monkeys. Our results support the scientific basis and preclinical evidence for NES in the treatment of PD. Not only does NES alone improve PD, but NES combined with stem cell therapy can greatly enhance the therapeutic effect of PD.
Traditional Chinese medicine (TCM), consisting of a complete TCM diagnosis and treatment system, is a valuable treasure in the long river of Chinese clinical history. However, the subjective diagnosis, ambiguous mechanisms, and complex formulas make it slightly lag behind the development of modern medicine. With the emergence of novel technologies such as artificial intelligence (AI) and nanotechnology, TCM modernization has regained its promise of hope. In this review, we provide an overview of applications of AI and nanotechnology to assist TCM modernization. Firstly, we summarize the auxiliary TCM diagnosis approaches based on machine learning and deep learning, which facilitate “four diagnostic methods” (inspection, auscultation–olfaction, inquiry, and pulse palpation) with standard and quantifiable data collection, and objective syndrome differentiation and diagnostic decisions. Secondly, a comprehensive overview of the nanotechnology used to enhance the therapeutic effects of TCM is provided, including optimizing TCM formulas and enhancing active targeting. Finally, we summarize the current challenges, clinical translation, and future perspectives of AI, TCM diagnosis, and nanotechnology. Our review and insights aim to provide valuable guidance for the continued advancement of TCM modernization.
Mechanical ventilation (MV) serves as a critical intervention to maintain adequate gas exchange. Unfortunately, MV often leads to the development of ventilator-induced lung injury (VILI). VILI pathogenesis involves alveolar-capillary barrier disruption, dysregulated inflammation, and mechanotransduction-driven cellular dysfunction, but the interplay of these mechanisms remains incompletely understood. Here, we review the types of mechanical stress in VILI, key signaling pathways implicated in MV-induced lung injury, with particular emphasis on the impact of altered mechanical forces in VILI. Furthermore, we discuss the cell-specific mechanisms in VILI. We also delineate the intricate molecular mechanisms that orchestrate intercellular communication in VILI. In addition, we discuss the limitations of current clinical strategies, and the identification of novel drug targets with transformative potential for treatment of VILI. Moreover, we summarize the current and emerging therapeutic strategies and discuss the existing knowledge gaps and future directions for VILI prevention. By integrating mechanical mechanistic insights with translational perspectives, this review identifies novel biomarkers and potential therapeutics to mitigate VILI. Our synthesis not only advances the understanding of VILI pathophysiology but also provides a framework for precision medicine approaches in critical care, ultimately optimizing MV outcomes.
Tumor-associated macrophages (TAMs) represent the most abundant immune cell population within the tumor microenvironment and are central drivers of malignant progression and treatment resistance. High TAMs infiltration in solid tumors consistently correlates with poor clinical outcomes, largely due to their role in establishing an immunosuppressive milieu that supports tumor growth, metastasis, and undermines the efficacy of chemotherapy, radiotherapy (RT), and immune checkpoint inhibitors. Although TAMs are well-recognized promoters of tumor progression, the development of effective strategies to therapeutically target them remains an unmet clinical need. In this review, we examine the multifaceted mechanisms through which TAMs contribute to malignancy, including phagocytic signaling modulation, metabolic reprogramming, exosomal communication, and crosstalk with other immune cells. We also evaluate three key therapeutic strategies: blocking TAMs recruitment and survival, reprogramming TAMs toward antitumor phenotypes, and the emerging approach of chimeric antigen receptor macrophage therapy. Furthermore, we highlight the synergistic potential of integrating TAMs-targeted strategies with conventional chemotherapy, RT, and immunotherapeutic approaches. By synthesizing current clinical evidence, this review aims to inform the rational design of next-generation TAMs-targeted interventions and to propose novel strategies for overcoming treatment resistance.
Although the physiological level of reactive oxygen species (ROS) is crucial for governing life processes through redox signaling, the excessive accumulation of ROS can contribute to biomolecular damage and pathological state, namely, oxidative stress. This review systematically summarizes the molecular mechanisms underlying the dynamic equilibrium of cellular redox state, including the intracellular sources of ROS and the multilayered antioxidant defense network. When ROS production exceeds the regulatory limits of the antioxidant system, excessive ROS will act on a series of molecular targets and participate in the pathogenesis of diseases. Therapeutic targeting of the redox balance is regarded as an effective strategy for treating oxidative stress-related diseases, such as supplementation of direct antioxidants and enhancement of endogenous antioxidant defense network. Nevertheless, clinical trials that attempt to delay the onset or progression of such diseases are mostly negative. This review discusses the challenges encountered in the clinical application of antioxidant therapy and highlights the opportunities brought by novel technologies such as intelligent drug delivery system and personalized medicine. By adopting these new technologies, it is expected to overcome the limitations of traditional antioxidant therapy.
Hydrogels, with excellent hydrophilicity and high-water content, have emerged as highly versatile biomaterials for tissue engineering and regenerative medicine. On account of the natural mimicry of extracellular matrix (ECM), moisture retention, porosity, biocompatibility, biodegradability, and tunable functionality, they provide crucial structural and biochemical support for tissue repair. As chronic wounds, aging, and degenerative diseases continue to increase, hydrogels offer great potential to overcome the limitations of traditional therapies. Despite these developments, there remains a crucial need for hydrogels that can effectively address the complex, multiphase nature of tissue repair while being cost-effective and easily applicable in various clinical settings. This review begins by taking wound healing as a representative example, particularly elaborating on the process of wound healing and therapeutic strategies to illustrate the importance of hydrogel design by tissue engineering technology. We then comprehensively evaluate the emerging hydrogel systems that integrate multiple therapeutic functions, including drug delivery, infection prevention, stimulus responsiveness, and clinical translation for wound dressings. Additionally, this review further extends to the application scope and incorporates the latest research advancements of multifunctional hydrogels in other biomedical applications. Finally, we summarize the shortcomings of existing studies and propose future research directions, with a view to providing a valuable reference basis for the development of multifunctional hydrogels within the realm of tissue engineering and regenerative medicine.
Biomedical research models are undergoing continuous evolution, while conventional models (two-dimensional/ three-dimensional cultures and animal studies) face limitations in physiological relevance and ethical constraints. Against this backdrop, the integration of organ-on-a-chip (OoC) technology with multi-omics methodologies is driving a profound paradigm shift in the field. OoC platforms utilize microfluidic technology to construct biomimetic three-dimensional microenvironments capable of highly simulating human physiological and pathological states, while multi-omics technologies (e.g., proteomics, transcriptomics, and metabolomics) provide systematic molecular profiling capabilities. The integration of these two approaches enables multi-scale mechanistic analysis from molecular networks to the tissue level, significantly enhancing their potential in drug development and personalized medicine strategies. This article systematically reviews the research progress and existing challenges in this interdisciplinary field, with a focus on: (1) The developmental trajectory of OoC platforms from two-dimensional to biomimetic three-dimensional systems; (2) mechanistic insights revealed by the integration of multi-omics and OoC technology in modeling disease processes; and (3) key issues in the standardization and clinical translation of OoC technology. Finally, the paper proposes a development roadmap for constructing next-generation disease models, aiming to provide a theoretical framework and strategic guidance for the establishment of standardized systems and clinical translation pathways in this field.
Bone metastasis (BoMet) is a common complication in various cancers. Approximately 20–30% of patients with cancer develop BoMet, which is most frequently associated with solid tumors, such as breast, prostate, and lung cancers. BoMet can lead to skeletal-related events such as fractures, bone pain, and hypercalcemia, negatively affecting the patient's quality of life and markedly shortening overall survival. The development of BoMet is a complex, multistep process driven by dynamic interactions between tumor cells and the bone microenvironment. The bone microenvironment provides a supportive niche for disseminated tumor cells, where intricate signaling networks and stromal interactions regulate the initiation, dormancy, reactivation, and progression of BoMet. Although current bone-targeted therapies can reduce the incidence of these complications, the clinical outcomes for patients with BoMet remain poor. Therefore, elucidating the molecular mechanisms governing these interactions is essential for identifying new therapeutic strategies. This review systematically explores the molecular drivers of BoMet progression, dynamic interactions within the metastatic niche, available preclinical models, established treatment modalities, and emerging therapeutic approaches. As fundamental research continues to advance toward clinical translation, the outlook for patients with BoMet is expected to improve significantly.
Inflammation is a core pathological factor regulating tumor initiation, progression, and therapeutic resistance, and elucidating its molecular crosstalk with tumors is crucial for developing effective clinical therapies. Internal drivers of inflammation–tumor transformation include genomic disorder, epigenetic memory, mitochondrial stress, and metabolic reprogramming, which synergistically initiate carcinogenesis. External factors amplifying tumor progression cover immune dysfunction, stromal fibrosis, microbial dysbiosis, vascular neoplasia, and neurotoxicity, collectively accelerating tumor development. Notably, current therapies such as immunotherapy and chemoradiotherapy often induce inflammatory accumulation, exacerbating chemoresistance and recurrence. However, cell-specific inflammatory signal regulation and the precise balance between anti-inflammatory effects and antitumor efficacy remain understudied, hindering clinical translation of potential strategies. This review systematically organizes the “internal driving force–external attractive force” regulatory network of inflammation-induced tumors, summarizes preclinical validation of inflammatory targets and combined therapy efficacy, and proposes future focus on cell-specific inflammatory signal regulation. It fills the gap in systematically integrating inflammation–tumor interaction mechanisms and provides important theoretical/practical guidance for developing precision anti-inflammatory–antitumor therapies.
RNA-targeted therapy is reshaping molecular medicine by shifting the traditional “protein-centric” view toward an “RNA-regulatory network” paradigm. Beyond carrying genetic information, RNA plays essential roles in posttranscriptional regulation, signaling pathways, and epigenetic modulation. Advances in high-throughput sequencing, structural biology, and delivery technologies have accelerated the development of diverse RNA therapeutics, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNA (miRNA) modulators, messenger RNA (mRNA) therapeutics, aptamers, short hairpin RNA, and CRISPR/Cas-guided single-guide RNAs. However, a concise comparison of these major RNA modalities and the translational barriers that limit their broader clinical application is still lacking. This review outlines the mechanisms and representative applications of these RNA-based strategies in gene silencing, editing, protein replacement, immune activation, and targeted drug delivery. Special emphasis is placed on ASOs and siRNAs for neurological, metabolic, and infectious diseases, as well as mRNA therapeutics that are transforming vaccine development. Common challenges-such as in vivo stability, delivery efficiency, and immune activation-are also discussed. Finally, we highlight how chemical modification, nanotechnology, and artificial intelligence-assisted design are enhancing the specificity, stability, and safety of RNA therapeutics, providing a framework for advancing next-generation precision RNA medicine.
Pulmonary hypertension (PH) is a fatal condition that affects individuals with systemic sclerosis (SSc), a multiorgan fibrotic disease with limited treatment options. A central feature of PH is vascular remodeling, defined by the narrowing of the arteriole lumen due to cell proliferation and extracellular matrix deposition. Herein, we identify a central mechanism that can regulate multiple transcripts important for vascular remodeling. The highlight of our study is the demonstration that reduced pulmonary artery smooth muscle (PASMC) Nudt21, which codes for the RNA binding protein Cleavage and Polyadenylation Specificity Factor Subunit 5 (CPSF5) The, known to regulate alternative polyadenylation, results in heightened right ventricle systolic pressures in mice exposed to hypoxia–sugen. We also report that increased PASMC proliferation is present in mice with reduced PASMC Nudt21 under normoxic conditions, recapitulating features of hypoxia–sugen exposure. Our studies reveal that reduced CPSF5 leads to 3′ untranslated region shortening of PTGER3 and CBFB, the latter contributing to increased levels of proliferative transcription factor RUNX1. We also identify miR-3163 as novel negative regulator of NUDT21 expression in PH. These observations are validated in remodeled vessels from patients with SSc associated with PH and in and point to common mechanisms of RNA processing deficits that contribute to vascular remodeling in PH.
This study aimed to evaluate the efficacy and safety of triple human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab, pertuzumab, and pyrotinib (TPPy) versus dual HER2 blockade with trastuzumab and pertuzumab (TP) in the neoadjuvant treatment of HER2-positive breast cancer. Patients with stage II–III HER2-positive breast cancer were randomized (1:1) to receive TPPy or TP alongside weekly nab-paclitaxel for 12 weeks. The primary endpoint was total pathological complete response (tpCR; ypT0/isN0). Exploratory biomarker and pathway analysis was done to identify patients benefiting from pyrotinib. A total of 109 patients were enrolled, and 108 received treatment: 55 in the TPPy group and 53 in the TP group. The tpCR rate was 65.5% (95% confidence interval [CI]: 51.4%–77.8%) in the TPPy group, and 60.4% (95% CI: 46.0%–73.5%) in the TP group (p = 0.585). In the TPPy group, 52 (94.5%) and 23 (41.8%) patients experienced dose interruption and discontinuation, respectively. The most common grade ≥3 adverse events in the TPPy and TP groups were diarrhea (58.1% vs. 0%) and neutropenia (23.6% vs. 15.1%). In conclusion, triple HER2 blockade did not improve tpCR rates compared with dual blockade but was associated with greater toxicity, particularly diarrhea.
The integration of artificial intelligence (AI) into surgical practices is advancing towards greater intelligence and precision. This study assesses the potential of AI in video-assisted thoracoscopic surgery (VATS) lobectomy for lung cancer by developing an AI system named LungSurg. LungSurg comprises two interconnected networks: a segmentation network for identifying intrathoracic anatomy and surgical instruments, and a classification network for recognizing surgical phases. We prospectively collected 222 VATS lobectomy videos from eight centers, generating over 32,000 annotations and more than one million frames with phase information. In external validation, the segmentation network achieved mean Average precision scores of 0.745 for the left lung and 0.726 for the right lung across various instruments and anatomical structures. The classification network demonstrated Top-1 and Top-3 accuracies of 71.5% and 88.0%, respectively, in identifying 14 surgical phases. Comparative experiments revealed that LungSurg performed comparably to senior surgeons in anatomical identification and surpassed them in sensitivity. In addition, an educational study showed that surgical residents trained with LungSurg significantly improved their anatomical identification and phase classification skills compared to those using conventional methods. These results indicate that LungSurg accurately analyzes VATS lobectomy procedures, highlighting the feasibility and potential of AI-driven tools in enhancing thoracic surgical practices.
The 2022 global mpox outbreak caused by the monkeypox virus (MPXV) has underscored the urgent need for improved vaccine development. To address this need, we developed four candidate vaccine antigens based on conserved sequences of the MPXV A35R and M1R proteins utilizing a lipid nanoparticle (LNP) delivery system. All four vaccine candidates elicited varying degrees of humoral and cellular immune responses and conferred differential protection against MPXV and vaccinia virus (VACV) in BALB/c mice; notably, the dual-antigen vaccines MV1 and MV2 induced more potent immunogenicity, including higher neutralizing antibody titers and cytokine secretion levels. However, among the four candidates, only the dual-antigen vaccines MV1 and MV2 conferred protective efficacy in AGB6 mice and reduced infection-induced pox lesion formation, indicating that antigens containing both intracellular mature virus (IMV) and extracellular enveloped virus (EEV) targets may be key to exerting robust protection. Notably, MV2—which was designed via structural truncation and recombination based on poxvirus-broad-spectrum antibodies using the AlphaFold3 prediction platform and adopts a single-chain “dimer-like” configuration—exhibited not only optimal protective efficacy but also sustained durable immune responses and protection. These findings indicate that MV2 induces favorable immunogenicity and has potential for preventing MPXV and VACV infections, supporting its promise as a clinical vaccine candidate for MPXV.
Cancer is a complex disease characterized by systemic dysfunction, necessitating a balance between therapeutic efficacy and safety. Immunotherapy is a core treatment approach for activating the antitumor immune response in the human body. The development of intelligent hydrogels has provided an innovative platform for tumor immunotherapy, owing to their adjustable properties for controlled drug delivery and immune modulation. Tumor immunotherapy has achieved remarkable success in recent years. However, it continues to face critical challenges such as targeting and delivery barriers, suppression by the TME, and immune evasion and drug resistance. In response, as injectable or implantable biomaterials, hydrogels are emerging as a promising platform to address these limitations by enabling localized, controllable drug delivery and immunomodulation. This review systematically categorizes contemporary hydrogel construction strategies tailored for immunotherapy, highlighting the distinct advantages of specific architectures in diverse clinical contexts. By classifying hydrogel applications according to immune-based strategies, the work underscores their multifunctional utility as precision delivery platforms and modulators of the immune microenvironment. This comprehensive overview elucidates the progress and design principles of hydrogel-based immunotherapeutic platforms, providing valuable insights to guide future research and development in this evolving field.
Inflammatory diseases, encompassing conditions like inflammatory bowel disease and rheumatoid arthritis, present a significant clinical challenge with substantial treatment-refractory patient populations despite biologic therapy advances. Stem cell therapeutics have emerged as a transformative approach, leveraging multifaceted regenerative mechanisms to address the complex pathophysiology of these conditions, which involves genetic, microbial, immunological, and epithelial dysregulation. This review focuses on comparing the clinical efficacy of contemporary stem cell strategies. We analyze outcomes across diverse cell sources, with a detailed examination of delivery methodologies. Our systematic analysis demonstrates superior efficacy with targeted delivery systems, particularly in managing localized inflammatory lesions (e.g., fistulas) and tissue restoration. Notably, minimally processed cellular interventions, such as autologous fat grafting and stromal vascular fraction therapy, show unexpected therapeutic promise. Critical translational barriers include suboptimal cell homing, limited engraftment persistence, and uncharacterized long-term safety profiles. We propose strategic solutions through induced pluripotent stem cell platforms, precision genetic modifications, and advanced delivery technologies. By integrating mechanistic insights with robust clinical evidence, this review establishes an evidence-based framework for optimizing stem cell therapeutics in inflammatory disease management. The analysis addresses fundamental scalability and safety considerations while identifying promising avenues for personalized regenerative medicine approaches in treatment-refractory inflammatory conditions.
Mycoplasma pneumoniae infections resurged globally in 2023–2024 following a significant decline during the coronavirus disease 2019 (COVID-19) pandemic. To understand the genomic epidemiology of this resurgence in China, a nationwide 1-year genomic surveillance identified 9907 patients infected with M. pneumoniae, resulting in an overall positive rate of 10.05%. We developed a hybrid capture-based targeted next-generation sequencing (hc-tNGS) assay, obtaining 271 high-quality genomes directly from clinical samples. Phylogenetic analysis of a global collection of 562 M. pneumoniae genomes identified six distinct lineages, including three newly emerged main Chinese clades (MCCs) that co-circulated across various regions of China. Among these MCCs, one clade, comprising P1-1, ST17, and L4, was localized in Taiwan, while two others—P1-1, ST3, and L6 clade, and P1-2, ST14 and L2 clade—co-circulated in different regions of China during the 2023–2024 epidemic season. Notably, 96.31% of the isolates identified in this study exhibited a point mutation, primarily A2063G (95.94%). This study offers a comprehensive genomic characterization of the post-pandemic M. pneumoniae resurgence in China, highlighting the emergence and spread of resistant clades. These findings emphasize the importance of adopting a One Health approach to address the potential global public health threats posed by this resurgent pathogen.
Vacuole membrane Protein 1 (VMP1) is widely known to be an important mediator in the formation of autophagosomes, playing a crucial role in macroautophagic processes. Emerging evidence suggests that VMP1 may have context-dependent functions across diverse cancer types and different tumor microenvironments, both within the context of autophagy and beyond. Here, using glioblastoma as a cancer model, we found that VMP1 can promote tumor growth independent of its autophagic functions. We observed significant upregulation of VMP1 in glioblastoma, which was correlated with poorer prognosis, and its ability to promote tumor growth without altering autophagic flux. Bulk, single-cell, and spatial transcriptomics analyses revealed that the pro-angiogenic markers were enriched in glioblastomas with high VMP1 expression. We further validated that overexpression of VMP1 would enhance angiogenesis through VEGFA-VEGFR2 signaling-mediated activation in endothelial cells. Treatment with bevacizumab, a monoclonal antibody against VEGFA, significantly inhibited VMP1-driven tumor growth and prolonged survival in mice. Our study thus uncovered non-autophagic functions of VMP1 as an important mediator in glioblastoma angiogenesis with the potential for therapeutic targeting.
Research on bedtime procrastination and depression has primarily used traditional psychometric approaches, limiting the ability to capture symptom-level temporal dynamics. This study aimed to examine within- and between-person associations between symptoms of depression and bedtime procrastination, considering sex differences. Data from 3296 adolescents followed over 18 months were used to explore symptom associations and their centrality in cross-sectional networks, as well as cross-lagged effects to clarify temporal relationships. In the within-person temporal network, not going to bed on time and trouble concentrating were the most influential symptoms for males and females, respectively. In the contemporaneous network, feeling worried and not going to bed on time were most central for males, while feeling tired and feeling worried were central for females. No significant sex differences were found in overall network strength (S = 0.10, p = 0.75) or structure (M = 0.48, p = 0.09). Positive associations were consistent at the between-person level. Overall, this study characterizes the symptom-to-symptom associations between depression and bedtime procrastination at both the within- and between-person levels, with notable sex differences. For males, sleep difficulties and worries were key factors, while for females, concentration issues and fatigue played a more significant role.
Polycystic ovary syndrome (PCOS) is a well-documented endocrine disorder associated with metabolic abnormalities. Research has indicated potential links between PCOS and the gut microbiome, and the presence of microbial communities in follicular fluid (FF) has been demonstrated; however, their functional interplay with metabolites has not been elucidated. This case–control study involved 40 patients with PCOS and 40 controls matched for age. A comprehensive analysis of FF metabolites and microbial communities by means of metabolomics analysis and 16S rDNA sequencing was performed. Twelve metabolites and 15 microbial communities were significantly different between the PCOS and control groups. AMH and AFC were significantly associated with the majority of the differentially abundant metabolites and bacteria, suggesting a potential association between FF components and ovarian function. In this study, we found that D-glucose and Alicyclobacillus were the most important variables in the metabolite model and microbial model, respectively. Mechanistically, Alicyclobacillus acidoterrestris, Terrimonas ferruginea, or Terrimonas pekingense can efficiently utilize glucose thereby reducing FF glucose levels, which provides insights into the microbiome–metabolite connection. These findings suggest a potential link among bacteria–metabolite–ovarian function, which could have implications for understanding the pathophysiology of PCOS and developing novel diagnostic and therapeutic strategies targeting metabolic and microbial aspects.
Estrogen receptor (ER) α is a central regulator of osteoclasts in osteoporosis induced by estrogen deficiency. ERα is regulated through interactions with various coactivators; however, the precise mechanisms of these interactions are not yet fully understood. We screened for proteins that bind to ERα using LC–MS/MS and identified a physical interaction between HSD17B7 and ERα, specifically ERα binding to the 119–172 domain of HSD17B7. This interaction blocked ubiquitin–proteasomal degradation of ERα and increased ERE activity. Estrogen-deficient mice lacking HSD17B7 in their preosteoclasts showed more severe bone loss than control mice. This was attributed to increased mitochondrial biogenesis through the activation of PLD1–mTOR signaling. Additionally, in preosteoclasts derived from patients with severe osteoporosis, the expression of HSD17B7 and ERα was significantly reduced compared to the control subjects. Finally, raloxifene, which boosts ERα, did not inhibit bone loss without HSD17B7, confirming the modulation of ERα through HSD17B7. Therefore, HSD17B7 regulation is a novel therapeutic approach for alleviating estrogen-deficient osteoporosis.
Gastric mucosal integrity is essential for maintaining systemic homeostasis, serving as the primary defense against external insults. Ethanol ingestion is a major clinical cause of gastric mucosal injury, yet effective prevention or treatment remains limited. This study investigates the protective role of nitrate against ethanol-induced gastric ulcers and its underlying mechanisms. In vivo, nitrate significantly ameliorated ethanol-induced gastric bleeding, edema, inflammation, and mucus layer thinning in rats, while strengthening the vascular endothelial barrier. Transcriptomic analyses and trefoil factor 2 (Tff2)-knockdown rats experiment identified Tff2 as the key gene responsible for mediating nitrate's protective effects against ethanol. In vitro, TFF2 was found to be a crucial target for nitrates, which enhance the migratory reparative capacities of human gastric epithelial cells. Further assays revealed that RBPJ regulates the TFF2 promoter, and NICD–RBPJ complex formation is critical for TFF2 transcriptional repression. We demonstrate for the first time that TFF2 is a central effector in nitrate-mediated gastric mucosal defense and repair and implicate the Notch signaling pathway in TFF2 regulation. These findings suggest nitrate exerts a protective effect on the gastric mucosa through multiple ways. TFF2 modulation as a potential preventive strategy for ethanol-induced gastric ulcers.
Significant residual cardiovascular risk persists in patients diagnosed with coronary artery disease despite intensive lipid-lowering therapy. Although insulin resistance (IR) is an established epidemiological risk factor, the biological mechanisms by which it promotes plaque destabilization remain poorly understood. This single-center retrospective study, involving 1271 patients, investigated the relationships between four validated IR indices—triglyceride-glucose (TyG), TyG–body mass index (TyG–BMI), metabolic score for insulin resistance (METS-IR), and atherogenic index of plasma (AIP)—and high-risk coronary plaque characteristics quantified by coronary computed-tomography angiography. Patients with coronary atherosclerosis demonstrated significantly higher IR indices than plaque-free controls, with all indices exhibiting strong correlations with a high-risk plaque burden. During follow-up, 41 patients experienced major adverse cardiovascular events (MACEs), and higher TyG index, AIP, and METS–IR independently predicted MACE after multivariable adjustment, whereas TyG–BMI exhibited a similar but non-significant trend. A composite model integrating high-risk plaque burden, pericoronary fat attenuation index, and the four IR indices achieved superior prognostic accuracy, substantially outperforming individual biomarkers. These findings provide novel mechanistic insights into how metabolic dysfunction promotes coronary plaque vulnerability and identify a promising integrated approach for residual risk stratification in patients with coronary artery disease. In this study, IR indices (TyG, TyG-BMI, AIP, and METS-IR) correlated high-risk coronary plaque features in 1271 patients. During 48-month follow-up, all indices independently predicted MACEs. Combined with coronary imaging markers, the composite model achieved AUC 0.82, revealing metabolic dysfunction drives plaque destabilization in coronary disease.