Therapeutic genome editing has advanced rapidly with the development of diverse programmable nucleases, from zinc-finger nucleases and transcription activator-like effector nucleases to clustered regularly interspaced short palindromic repeats (CRISPR)-based systems such as base and prime editors. Despite these breakthroughs, clinical translation remains constrained by the challenge of achieving safe, efficient, and tissue-specific delivery. Viral vectors, particularly adeno-associated viruses, have enabled durable editing in selected organs but are limited by their restricted cargo capacity, immunogenicity, and complex manufacturing. Nonviral platforms, most notably ionizable lipid nanoparticles, have demonstrated remarkable efficacy for hepatic targets, with clinical trials reporting up to 93% protein knockdown after a single dose. An expanding set of emerging modalities, including virus-mimicking nanosystems, cell-derived extracellular vesicles, cell-penetrating peptides, and intelligent-responsive multifunctional scaffolds, further enriches the delivery toolbox by supporting transient expression and programmable targeting across diverse editors and tissues. Parallel advances in high-throughput barcoded screening and machine learning are accelerating vector optimization, while rational chemical modification of payloads improves in vivo stability and specificity. This review provides a comprehensive overview of current and emerging delivery systems for genome editing, highlighting key innovations, unresolved challenges, and interdisciplinary strategies poised to unlock broader therapeutic potential.

Hypoxia is a hallmark of solid tumors, and hypoxia-inducible factors (HIFs) are the master transcription factors that allow cancer cells to sense and cope with a hypoxic microenvironment. However, the mechanism by which the HIF-mediated transcription process is precisely regulated remains poorly understood. Here, we demonstrate that the RNA helicase DDX21 facilitates breast tumor growth and metastasis by triggering HIF-mediated transcription elongation. Mechanistically, DDX21 induces the release of CDK9 from the 7SK complex, enhancing the interaction between CDK9 and HIF-1α. This interaction stimulates the transcription elongation of HIF target genes by elevating the enrichment of phosphorylated RNA Polymerase II at serine 2 on the hypoxia-response element of HIF target genes. These target genes, including IGFBP1, WNT1, WNT10B, TGFB1, PCK1, and SLC2A3, are critical for cancer cell proliferation and metastasis. Consequently, DDX21 enhances breast cancer cell proliferation, survival, migration, and invasion in vitro, and promotes breast tumor growth and metastasis in vivo. Importantly, DDX21 is highly expressed in breast tumors and correlates negatively with clinical outcomes in breast cancer patients. Our study reveals a novel mechanism of HIF regulation and positions DDX21 as a potential therapeutic target for disrupting the hypoxic adaptation machinery in breast cancer.

This phase II trial investigated perioperative camrelizumab plus neoadjuvant chemotherapy for patients with stage IIB–IIIB lung squamous cell carcinoma (LUSC) and explored predictive biomarkers of treatment response. Patients received neoadjuvant camrelizumab (200 mg, Day 1) in combination with nab-paclitaxel (130 mg/m², Days 1 and 8) and carboplatin (area under the curve = 5, Day 1) every 3 weeks for two cycles, followed by surgery and adjuvant camrelizumab for 1 year. The primary endpoint was major pathological response (MPR) rate. Forty-five patients were treated, of whom 41 underwent surgery. Twenty-seven of 45 patients (60.0%) achieved MPR and 20 (44.4%) achieved pathological complete response (pCR). With a median follow-up of 37.5 months, the 3-year disease-free survival and overall survival rates were 65.9% and 68.7%, respectively. Among eight patients with stage IIIB disease, three (37.5%) achieved pCR. Baseline neutrophil percentage and smoking history were associated with MPR. T-cell receptor (TCR) sequencing revealed that three V-J gene pairs in TCR beta clones differed between the pCR and non-pCR groups. This study supports the application of perioperative immunotherapy combined with neoadjuvant chemotherapy in patients with resectable locally advanced LUSC. The identification of blood biomarkers for precise patient selection warrants further in-depth investigation.

The recent resurgence of the mpox virus (MPXV) has raised global health concerns due to its potential to cause severe illness in vulnerable populations. Targeting the extracellular enveloped virus (EEV) protein A35R is a promising strategy to restrict viral dissemination within the host. In this study, we combined mRNA-LNP immunization with the Beacon Optofluidic system to rapidly screen and isolate high-affinity monoclonal antibodies. One of these antibodies, 17H1, exhibited exceptional neutralization against authentic MPXV. Cryo-electron microscopy (Cryo-EM) analysis revealed that 17H1 binds to a specific epitope at the distal ends of the A35R dimer. The interaction is stabilized by a unique network of hydrogen bonds and salt bridges, particularly involving residue E120, distinguishing its binding mode from previously reported A35R antibodies. Furthermore, 17H1 exhibited complete protective efficacy against MPXV infection in vivo and significantly reduced pulmonary viral load and lung pathogenesis. These findings highlight 17H1 as a promising therapeutic candidate for novel mpox interventions.

This prospective phase II multicenter study evaluated a novel sandwich total neoadjuvant treatment (TNT) strategy for patients with relatively low-risk distal locally advanced rectal cancer (LARC). The regimen consisted of two cycles of capecitabine and oxaliplatin (CapeOx) administrated before, during, and after radiotherapy, followed by surgery or a watch-and-wait strategy, and two cycles of adjuvant capecitabine chemotherapy. The primary endpoint was the clinical complete response (cCR) rate. All 98 patients completed radiotherapy, and 88.8% received six cycles of neoadjuvant chemotherapy. In the intention-to-treat analysis, 46.9% of patients achieved cCR, 7.1% achieved near-clinical complete response (near-cCR), and 45.9% had non-clinical complete response (non-cCR). In the observed population, the complete response (CR), pathological complete response (pCR), and sphincter-preservation (SP) rates were 61.2%, 46.4%, and 79.6%, respectively. The local regrowth-free survival, local recurrence-free survival, distant metastases-free survival, and overall survival rates were 89.5%, 100%, 92.9%, and 96.9%, respectively. Overall, this sandwich TNT strategy achieved high rates of cCR, pCR, CR, and SP, with favorable survival outcomes and acceptable toxicity, suggesting a promising organ-preserving treatment approach for selected patients with distal LARC.

Trial Registration: ClinicalTrials.gov identifier: NCT03840239

Bispecific antibodies (BsAbs) represent a growing class of cancer immunotherapeutics, yet their wider adoption remains limited by complex recombinant production and limited manufacturing efficiency. Here, we report a chemically assembled macrophage-engaging glypican-3 × signal regulatory protein-α (SIRP-α) bispecific antibody for the treatment of liver cancer. Using our bifunctional linker, glypican-3-binding peptide dimers were conjugated to a native anti-SIRP-α IgG via a rapid one-pot, two-step process, yielding a novel dendritic bispecific antibody (dBsAb). Such a construct simultaneously targets glypican-3-positive hepatocellular carcinoma cells and blocks the CD47–SIRP-α axis, thereby promoting macrophage engagement and phagocytosis. In vitro studies showed substantially enhanced macrophage adhesion and tumor cell clearance compared with the monoclonal antibody. In an in vivo experiment, dBsAb demonstrated a 68% reduction in tumor growth, with increased macrophage infiltration, M1 polarization, and elevated antigen presentation without observable systemic toxicity. This chemical assembly approach offers a practical alternative to recombinant methods for constructing bispecific antibodies and may facilitate the development of macrophage-directed immunotherapies.

Respiratory syncytial virus (RSV) is a major cause of severe lung injury, particularly in infants. Most previous studies have relied on single-omics or single-model systems, limiting a comprehensive understanding of the dynamic and coordinated host response. To overcome this, we employed an integrated multiomics approach across complementary in vivo (murine) and physiologically relevant ex vivo (human bronchial organoid) models, combining longitudinal transcriptomic and proteomic profiling to systematically delineate the spatiotemporal dynamics of RSV-induced lung injury and repair. Our analysis revealed a stage-specific progression from early inflammatory injury to late repair, in which extracellular matrix (ECM)–receptor interaction and PI3K–Akt signaling play central roles. Moreover, a core set of hub genes including Itgb3, Itga2b, and Fn1 were positively correlated with RSV-induced lung injury and clinical disease severity. Pharmacological inhibition of αIIbβ3 (encoded by Itga2b and Itgb3) or fibronectin (Fn1) in vivo significantly attenuated immunopathology and lung injury without affecting viral clearance, directly establishing their causal role in disease pathogenesis. Collectively, our study not only provides novel insights into the integrin-centric network driving RSV immunopathology but also identifies a potential biomarker panel for clinical severity stratification and therapeutic targets for intervention.

Tumor heterogeneity creates selective pressures and ecological niches that enable cancer cell plasticity; conversely, plasticity continuously generates and reshapes heterogeneity. Together, these processes drive tumor progression, therapeutic resistance, recurrence, and divergent clinical outcomes, thereby limiting the durability of precision oncology. In this Review, we synthesize recent advances in our understanding tumor heterogeneity and cancer cell plasticity across spatial, temporal, and molecular scales, and discuss how the tumor microenvironment regulates plasticity through physical, chemical, and biological cues. We further outline three fundamental challenges for precision therapy, namely, target loss, bypass pathway activation, and adaptive cell-state transitions, and argue that drug resistance is critically shaped by cancer cell plasticity, which varies widely among patients and contributes to heterogeneous therapeutic efficacy. Building on this framework, we propose a next-generation precision-oncology paradigm integrating stratified diagnosis, rational combination intervention, and adaptive monitoring. Finally, we discuss how the integration of single-cell and spatial multiomics, together with artificial intelligence, could enable the development of “digital twin” tumor models to guide individualized therapeutic decision-making. Collectively, this review provides an integrated conceptual foundation and practical roadmap for overcoming key bottlenecks in precision oncology driven by tumor heterogeneity and cancer cell plasticity.

Diabetes encompasses a range of diseases characterized by chronic hyperglycemia and serious health complications. However, predicting therapeutic response in latent autoimmune diabetes in adults (LADA) remains a major challenge, limiting the development of personalized treatment strategies. LADA is a relatively newly defined diabetes type that shares features of Type 1 diabetes (T1D) and Type 2 diabetes and is estimated to be more prevalent than T1D. We developed a LADA model in NOD mice and assessed combination treatment (CT) comprising GABA, sitagliptin, and omeprazole. Surprisingly, ∼30% of the CT-treated mice completely recovered, exhibiting normoglycemia and insulin independence. We identified two cell-free RNA markers, Adgrb1 and Chd5, that distinguish responders from nonresponders, indicating promising predictive ability. These discoveries offer a potential diagnostic tool for identifying LADA patients who could benefit from CT, representing an advance in personalized diabetes treatment. CT-induced β-cell neogenesis involved replication, providing valuable insights into β-cell regeneration mechanisms. Furthermore, the cured mice exhibited insulitis primarily populated by T regulatory Type 1 cells, potentially suppressing autoimmunity and facilitating β-cell survival and regeneration. This study opens new avenues for targeted LADA therapies and paves the way for precision medicine in diabetes management.

Posttranslational modification (PTM) is pivotal in cancer progression. However, the mechanisms, biological function, and clinical significance underlying PTM crosstalk are unclear. Here, we performed systematic analyses of 2-hydroxyisobutyrylation (Khib), phosphoproteomic, proteomic, and transcriptomic profiles from 60 esophageal squamous cell carcinoma (ESCC) samples, comprising matched normal, primary tumor, and metastatic lymph node tissues. The integrative analysis identified 4499 proteins co-modified by Khib and phosphorylation on distinct residues. Interestingly, while the two PTMs target distinct motifs across proteins, they engage common motifs within individual proteins. Functionally, Khib and phosphorylation show prevalent positive crosstalk linked to metastatic progression. Mechanistically, Khib mediates this intra-protein crosstalk by recruiting kinases and potentiating phosphorylation events. Machine learning-based artificial intelligence (AI) analysis of secreted proteins with PTM crosstalk revealed an independent and highly effective plasma signature predicting lymph node metastasis. Moreover, molecular subtyping stratified ESCC into three groups, with immunotherapy-resistant Subtype 3 associated with the worst survival. While combined treatment of integrin inhibitor cilengitide and immunotherapy exhibited targeted efficacy. By deciphering the mechanistic basis of Khib-phosphorylation crosstalk, identifying a novel plasma biomarker for lymph node metastasis, and providing a therapeutic strategy to sensitize tumors to immunotherapy, this work collectively advances the precision diagnosis and treatment of ESCC.

RNA modifications are pivotal posttranscriptional gene expression regulators with profound functions in both physiological and pathological states, particularly during cancer initiation and progression. Within the complex tumor microenvironment (TME), these modifications orchestrate diverse mechanisms that significantly impact tumor growth, facilitate immune evasion, and drive therapeutic resistance. Recent advances have demonstrated their critical roles in shaping RNA metabolism and maintaining genome integrity, as well as modulating key stromal pathways such as immune responses, extracellular matrix remodeling, and vascular supply. Emerging evidence further suggests that RNA modifications dynamically regulate intercellular communication between tumor cells and surrounding stromal and immune cells within the TME. In this review, we provide a comprehensive overview of the mechanisms and functional roles of major RNA modifications, including adenosine, guanosine, and pseudouridine modifications. We discuss their regulatory roles in RNA metabolism and genome integrity, and examine their diverse functions within the TME, including immune regulation, tumor proliferation, extracellular matrix remodeling, and DNA damage response (DDR) pathways. Additionally, we highlight recent advances in therapeutic strategies targeting RNA-modifying enzyme and discuss their potential for improving cancer treatment. Collectively, targeting RNA modification represents a promising strategy for overcoming cancer resistance and improving clinical treatment outcomes.

A comprehensive understanding of age-related changes in the human immune system is critical for deciphering the mechanisms of immunosenescence. Although transcriptomic studies have described immune alterations during aging, investigations into the proteomic layer and integrated multi-omics approaches remain scarce. Here, we performed multi-omics sequencing on peripheral blood samples from 69 individuals aged 23–75 years. We identified widespread dysregulation of RNA splicing in aging immune cells, with exon skipping being the most prevalent splicing event, which was mainly enriched in protein regulation-related processes. Notably, lncRNAs such as SNHG1 and RP1-3J17.3 modulated the expression of splicing-regulatory mRNAs and proteins in aging immune cells, thereby influencing the RNA splicing of downstream genes. Splicing dysregulation of genes including EIF4G1, a translation initiation factor, led to alterations in protein translation, modification, and degradation, ultimately reshaping protein profiles in aging leukocytes. These proteomic alterations in our data reflect a gradual weakening of T-cell function during aging. Together, unlike previous studies that focused only on single molecular layers, our study elucidates the interconnected nature of molecular regulation within leukocytes during aging, uncovers cross-level interactions and regulatory networks, and provides a comprehensive multi-omics resource for understanding immune aging and identifying potential strategies to delay immunosenescence.

The heterogeneity of acute respiratory failure (ARF) in non-intubated patients remains poorly defined. This study aimed to identify novel phenotypes in non-intubated ARF patients and evaluate their prognostic and predictive ability. We analyzed data from three cohorts: a training cohort from the Chinese Database in Intensive Care, validation cohort A from a randomized controlled trial, and validation cohort B from a multicenter dataset. Latent class analysis and k-means clustering were applied independently across cohorts to identify phenotypes. A two-class model demonstrated the optimal fit in the training cohort (n = 706). Compared to Phenotype 1, Phenotype 2 exhibited worse oxygenation, higher lactate concentrations, and more severe coagulation dysfunction, along with significantly higher intubation (56.7 vs. 28.7%, p < 0.001) and mortality rates within 28 days (22.0 vs. 9.7%, p < 0.001). Similar phenotypes were verified in validation cohorts A (n = 409) and B (n = 609). Notably, Phenotype 1 patients benefited most from prolonged awake prone positioning (APP), with a significant interaction observed (p = 0.035; adjusted p = 0.048). Two parsimonious models were further developed for phenotype assignment prediction. The two novel phenotypes with both prognostic and predictive ability may help tailor APP to individual non-intubated ARF patients.

Hepatic ischemia reperfusion injury (IRI) is a frequent complication of liver surgery and is strongly associated with poorer recipient survival. Sorafenib, a multi-kinase inhibitor, has been implicated in hepatic metabolic and redox regulation, yet its role in hepatic IRI remains unclear. Our study finds that middle-dose sorafenib protects the liver from IRI by reducing hepatic necrosis, inflammation, and apoptosis. Mechanistically, transcriptomic and metabolomics analyses confirm that middle-dose sorafenib enhances pentose phosphate pathway-mediated antioxidant activity through the c-rapidly accelerated fibrosarcoma (c-Raf)/heat shock protein 90 (HSP90)/glucose-6-phosphate dehydrogenase (G6PD) axis. Co-immunoprecipitation, Western blot, and confocal immunofluorescence analyses demonstrate the direct binding interaction between HA-c-Raf and Myc-HSP90, as well as between Flag-G6PD and Myc-HSP90. Meanwhile, the overexpression of HSP90 disrupts the benefits of sorafenib on hepatic IRI, and inhibition of G6PD also rescues its protective effect. Notably, in human liver transplant recipients, elevated HSP90 levels correlated with poor graft function and survival, supporting its clinical relevance. Furthermore, a novel oral nanoparticle delivery system, targeting the liver tissue, enhances the therapeutic efficacy of sorafenib, restoring liver enzyme levels by up to 76%. Collectively, these findings identify middle-dose sorafenib, particularly when delivered via the novel oral nanoplatform, as an effective strategy to mitigate hepatic IRI.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) employs sophisticated strategies to subvert host innate immunity, a critical determinant of viral establishment and dissemination. Nevertheless, the immunomodulatory functions of coronavirus structural proteins remain incompletely understood. Here, we identify the evolutionarily conserved membrane (M) protein of SARS-CoV-2 as an innate immune antagonist that suppresses nuclear factor kappa-B (NF-κB) activation. Functional assays revealed that the M protein markedly inhibited NF-κB activation and reduced proinflammatory cytokine production in vitro. In lung epithelial M-expressing mouse, M significantly attenuated LPS-induced inflammation. Mechanistically, M protein from diverse coronaviruses directly interacts with host Toll-interacting protein (TOLLIP), stabilizing TOLLIP-IRAK1 complex, preventing IRAK1 activation, thereby suppressing downstream NF-κB signaling and creating a permissive cellular microenvironment for viral replication. We mapped a conserved linker region within the M protein as the core motif mediating this interaction. This binding is highly conserved across coronaviruses, highlighting the fundamental role of the M–TOLLIP axis in viral immune evasion. Our findings reveal a conserved pan-coronavirus immune evasion strategy by which coronaviruses target TOLLIP to subvert Toll-like receptor (TLR)–NF-κB signaling. The conserved M-linker region thus represents a potential broad-spectrum antiviral target, providing a structural framework for developing next-generation antivirals against current and emerging coronavirus threats.

Ischemia–reperfusion injury (IRI) is a common pathological process underlying cardiovascular events, organ transplantation, and shock resuscitation. Its paradox is that restoration of blood flow, while essential for tissue survival, can itself intensify cellular stress and amplify tissue damage. This review delineates the cross-organ mechanistic cascade of IRI, beginning with metabolic collapse, adenosine triphosphate (ATP) depletion, and ionic dysregulation during ischemia, and progressing to reperfusion-driven mitochondrial dysfunction, oxidative and nitrosative stress, and activation of regulated cell death programs. We further highlight how sterile inflammation evolves into a coordinated endothelial–immune–coagulation interaction network centered on neutrophil extracellular traps (NETs), which couple microvascular obstruction with inflammatory signaling to promote immunothrombosis and propagate injury locally and to distant organs. Despite major advances in mechanistic insight, translation into effective therapies remains inconsistent, largely due to phenotypic heterogeneity, narrow therapeutic windows, and the lack of real-time biomarkers that capture pathway activity. Future progress will require a systems-level, cross-organ framework for immune remodeling, with particular emphasis on targetable NET-driven immunothrombotic phenotypes. Biomarker-guided precision stratification, multimodal data integration, ex vivo machine perfusion platforms, and organoid-based human models may enable mechanism-aligned trials and shift therapy from macroscopic reperfusion toward microvascular stabilization and cellular repair.

Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with epidermal growth factor receptor (EGFR) mutations being one of the most common actionable genetic alterations. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), has significantly improved the prognosis of patients with EGFR-mutated NSCLC, but acquired resistance remains a major clinical obstacle limiting its long-term efficacy. This review summarizes key mechanisms of osimertinib resistance, including both EGFR-dependent and EGFR-independent resistance pathways. A major focus is placed on the chromatin remodeler Switch/Sucrose nonfermentable (SWI/SNF) related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), which mediates resistance through its interplay with EGFR signaling. Epigenetically, SMARCA4 loss modulates the tumor microenvironment and therapeutic response by triggering a stress-induced yet functionally impaired nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway and activating phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling. This cascade not only promotes tumor proliferation and survival but also directly confers resistance to osimertinib. Beyond SMARCA4, this review also discusses bypass pathway activation and further summarizes recent advances in novel targeted agents and combination therapies against osimertinib resistance. Overall, it provides an integrated overview of resistance mechanisms and supports the development of improved precision therapies for EGFR-mutant NSCLC.

Despite being a common complication of Crohn's disease (CD), evidence regarding the use of ustekinumab (UST) for treating symptomatic strictures in China remains limited. This study evaluated the effectiveness of UST in this population and identified the predictors of successful therapy. This cohort study enrolled adults with CD initiating UST therapy for symptomatic strictures confirmed by endoscopy or imaging. The primary outcome at Week 52 was continued UST therapy without prohibited adjunctive treatments. A clinical prediction model was developed, and its performance was evaluated for identifying baseline factors associated with treatment success. Of the 73 patients screened between June 2022 and April 2024, 54 were included. At Week 52, 44 (81.5%) achieved treatment success, with most demonstrating improvements in obstructive symptom score, CD Activity Index (CDAI), endoscopic and computed tomography enterography (CTE) findings, and biochemical parameters. Nonsmoking status and C-reactive protein (CRP) levels predicted treatment success, with the model demonstrating 86.4% discriminative ability. No severe adverse events were reported, except for one case of leukemia (2%) and two cases of serious infections (4%). The study highlighted that UST effectively alleviated intestinal strictures in CD, with most patients achieving symptom remission, improved stricture morphology, and reduced inflammation.

Intratumoral bacteria are increasingly recognized as integral and dynamic components of the tumor microenvironment (TME), with profound implications for tumor initiation, progression, metastasis, immune remodeling, and therapeutic response. These microorganisms may originate from mucosal barrier breaches, hematogenous or lymphatic dissemination, local migration from adjacent tissues, or co-migration with metastatic cells, and can be characterized by sequencing-based, imaging, culture-dependent, and multi-omics approaches. Accumulating evidence indicates that intratumoral bacteria contribute to tumorigenesis by inducing genomic instability, DNA damage, epigenetic alterations, oncogenic signaling, and chronic inflammation. Beyond primary tumor growth, they participate in multiple steps of the metastatic cascade, including epithelial–mesenchymal transition, cytoskeletal remodeling, invasion, intravasation, extravasation, pre-metastatic niche formation, angiogenesis, and distant colonization. Intratumoral bacteria also reshape immune and non-immune compartments of the TME, exerting dual effects by promoting immune suppression or enhancing antitumor immunity depending on bacterial species, tumor context, and host immune status. In this review, we summarize the historical development, methodological advances, cancer-type-specific diversity, and mechanistic roles of intratumoral microbiota in tumor progression and metastasis. We further discuss their diagnostic and prognostic value, as well as their therapeutic implications for conventional anticancer treatments and microbiota-targeted strategies, highlighting opportunities and challenges for microbiota-guided precision oncology.

Accurate outcome prediction is essential for personalized therapy in patients with breast cancer receiving neoadjuvant therapy (NAT). In this study, we developed and validated a multimodal artificial intelligence model, the ClinicHistomics Integrated Outcome Prediction Model (CIOPM), to predict prognosis in NAT-treated breast cancer patients by integrating clinicopathological data and hematoxylin and eosin (H&E)-stained surgical specimen whole-slide images (WSIs). A total of 847 WSIs from 835 patients across four multicenter cohorts collected between January 2008 and May 2020 were enrolled in model development and external validation. The CIOPM demonstrated robust predictive performance for overall survival (OS) and disease-free survival (DFS) in the two validation cohorts (VCs), yielding C-indices of 0.933 (95% CI: 0.878–0.977) and 0.915 (95% CI: 0.850–0.960) for OS in VC 1, and 0.947 (95% CI: 0.895–0.983) and 0.937 (95% CI: 0.905–0.965) for DFS in VC 2, respectively. The CIOPM enables accurate stratification of patients with NAT-treated breast cancer into high- and low-risk groups, achieving an AUC of 0.957 for both OS and DFS prediction. Moreover, it demonstrated superior performance in ablation studies, subgroup analyses, and clinical risk model comparisons. This model provides reliable risk stratification and personalized treatment decisions.

Cellular senescence, a stress-induced, irreversible cell cycle arrest coupled with a proinflammatory secretory phenotype, has emerged as both a central driver of aging and a tractable therapeutic target. Although acute senescence contributes beneficially to tumor suppression and wound healing, chronic accumulation of senescent cells sustains systemic inflammaging and accelerates organ dysfunction. This review synthesizes current progress in aging biology into a unified mechanistic and translational framework. We first examine how primary aging hallmarks, such as genomic instability and epigenetic dysregulation, interact to trigger cellular senescence, then explore how these converging molecular processes give rise to distinct age-related pathologies across reproductive, pulmonary, hepatic, neurological, skeletal, and metabolic systems. We further evaluate emerging interventional strategies, from senolytics and senomorphics to rejuvenation approaches, while addressing key translational barriers including targeting specificity, senescence heterogeneity, and equitable access. By uniting mechanistic insight with disease-oriented and therapeutic perspectives, this review charts a strategic roadmap for deploying senescence-targeting therapies to extend human healthspan.

Current methods for assessing treatment response and prognosis in pancreatic ductal adenocarcinoma (PDAC) have intrinsic limitations, necessitating novel biomarkers. This prospective cohort study evaluated whether early dynamic changes in ctDNA predict treatment efficacy and outcomes in advanced PDAC. We enrolled 127 patients receiving first-line therapy, with peripheral blood collected at baseline (B1), first response assessment (B2), and subsequent timepoints for high-depth next-generation sequencing. The ctDNA detection rates significantly decreased from 78.7% at B1 to 55.7% at B2. Elevated CA19-9 levels, ctDNA, and maximum somatic allele frequency (MSAF) were associated with disease progression. Higher B1 ctDNA and MSAF correlated with shorter progression-free survival (PFS) and overall survival (OS), consistent with an external validation cohort. The Cox regression confirmed that MSAF and CA19-9 were significant prognostic factors. In CA19-9-negative PDAC patients, increased ctDNA levels were associated with shorter PFS. This study demonstrated that high ctDNA levels and MSAF values are indicators of poor prognosis. Conversely, a decrease or clearance of ctDNA and MSAF suggests better disease control. In addition, in CA19-9-negative patients, dynamic ctDNA monitoring was able to indicate disease control and predict patient prognosis.

Staphylococcus aureus is a leading cause of severe invasive infections and is associated with high mortality. The pore-forming α-toxin (Hla) is a key virulence determinant that drives disease severity. We identified two high-affinity anti-Hla monoclonal antibodies, Hm0399 and Hm0411, derived from the sera of volunteers vaccinated with the S. aureus vaccine rFSAV. Mechanistic analyses—including toxin neutralization assays, structure solution, and effector-function characterization—revealed that although both antibodies recognize overlapping epitopes on Hla, they confer protection through distinct and complementary mechanisms. Hm0411 potently neutralizes Hla toxicity by blocking receptor engagement through a defined salt-bridge network, whereas Hm0399 engages a hydrogen-bond interface that enhances Fc-mediated effector functions. A dual-antibody cocktail comprising Hm0399 and Hm0411 (Hm3-4) demonstrated robust therapeutic efficacy in the USA300 S. aureus sepsis model and pneumonia model. Notably, protection was not compromised by pre-existing immune imprinting. Transcriptomic profiling indicated enhanced Fcγ receptor–mediated phagocytosis and suppression of pro-inflammatory Ca²⁺ signaling pathways. In addition, combining Hm3-4 with ultra-low doses of vancomycin or linezolid synergistically improved therapeutic outcomes in experimental sepsis. Collectively, these findings establish a dual-antibody strategy targeting Hla that integrates virulence neutralization with augmentation of host immune defense, providing a framework for next-generation immunotherapies against invasive S. aureus infection.

Clear cell renal cell carcinoma (ccRCC) is among the most prevalent malignancies of the urinary system. Patients with advanced ccRCC have poor clinical outcomes. This study aimed to investigate the role of nicotinamide N-methyltransferase (NNMT) in ccRCC. Multiomics analyses revealed aberrant expression of two enzymes in the nicotinamide metabolic pathway, both of which are associated with poor prognosis, with NNMT exhibiting the most pronounced alteration. NNMT modulation per se induces a malignant phenotype, irrespective of substrate or product supplementation. Mechanistically, using western blotting and chromatin immunoprecipitation assays, we demonstrated that NNMT decreases S-adenosylmethionine, thereby reducing histone H3 lysine 9 trimethylation (H3K9me3) at the fibronectin 1 (FN1) promoter and activating FN1 transcription. Exogenous FN1 rescued the migration and invasion in NNMT knockout cells. In clinical specimens, NNMT expression levels were markedly elevated in tumor tissues and correlated with tumor stage. NNMT inhibitor suppressed FN1 expression and tumor progression both in vitro and in vivo. Collectively, our findings establish NNMT as a pivotal epigenetic regulator that drives ccRCC progression through extracellular matrix remodeling, providing novel early-stage diagnostic and therapeutic strategies for ccRCC.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disease worldwide and represents a major hepatic manifestation of systemic metabolic dysfunction. The disease is closely linked to obesity and insulin resistance and progresses from simple hepatic steatosis to metabolic dysfunction-associated steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Increasing evidence indicates that MAFLD pathogenesis involves complex interactions among dysregulated lipid metabolism, mitochondrial dysfunction, oxidative stress, inflammatory signaling, bile acid imbalance, and gut microbiota-derived metabolites, reflecting the systemic and multifactorial nature of the disease. However, despite substantial progress in understanding these mechanisms, the integrated regulatory networks driving MAFLD progression and their translational therapeutic implications remain incompletely characterized. In this review, we comprehensively summarize recent advances in the molecular mechanisms underlying MAFLD, focusing on metabolic dysregulation, cellular stress responses, inflammatory pathways, and regulated cell death processes. We further highlight the critical role of interorgan communication particularly the adipose–liver and gut–liver axes and discuss emerging evidence on extracellular vesicles (EVs) as mediators of metabolic and inflammatory signaling. Finally, we evaluate current and potential therapeutic strategies, emphasizing the diagnostic and therapeutic promise of EV-based approaches in MAFLD management, and identifying emerging molecular targets for improved intervention and future clinical translation opportunities.

Cancer remains a major global health challenge, and the increasing availability of multimodal biomedical data has created unprecedented opportunities for precision oncology. Recent advances in generative artificial intelligence (AI), particularly large language models (LLMs), have enabled new approaches for integrating heterogeneous data sources, including electronic health records, medical imaging, pathology, genomics, and clinical text. However, current studies remain fragmented across specific tasks, cancer types, and model architectures, and a comprehensive synthesis of how generative AI can support the entire oncology continuum is still lacking. This review provides an overview of generative AI in clinical oncology, covering LLMs, generative adversarial networks, diffusion models, and multimodal foundation models. We summarize their methodological foundations and discuss applications in cancer diagnosis, prognosis prediction, treatment planning, patient management, and clinical trial optimization. Particular attention is given to multimodal data integration, synthetic data generation, clinical reasoning, and decision support, together with current challenges related to interpretability, reliability, data privacy, regulatory governance, and real-world implementation. By consolidating recent technological advances and clinical evidence, this review highlights future priorities toward safe, trustworthy, and clinically deployable intelligent oncology systems. Emerging agent-based architectures and human–AI collaborative workflows may further expand the clinical utility of generative AI in oncology.

Osteoarthritis (OA) is a highly prevalent, heterogeneous whole-joint disorder that represents a leading cause of chronic pain, physical disability, and socioeconomic burden globally. It has emerged as a major public health challenge affecting millions of individuals. The pathogenesis of OA involves joint degeneration, biomechanical stress, systemic inflammation, metabolic disorder, subchondral bone remodeling, and cartilage matrix imbalance. Conventional diagnostic approaches fail to identify early-stage pathological changes, while current clinical interventions primarily offer symptomatic relief with limited disease-modifying efficacy. However, effective early biomarkers, clear stratification mechanisms, and precision targeted therapies for OA remain largely insufficient. Therefore, it is particularly imperative to elucidate the advances in the pathophysiological mechanisms of OA and explore novel biomarkers as well as targeted therapeutic strategies. This review systematically updates the latest epidemiological features of OA, assesses imaging and fluid-derived biomarkers for early and accurate diagnosis, and reorganizes evidence-based pharmacological, nonpharmacological, interventional, surgical, and emerging therapies. By clarifying the key pathophysiological characteristics of OA and conducting an in-depth analysis of current diagnostic and therapeutic strategies, this review establishes a theoretical foundation for OA precision medicine, effectively accelerates the clinical translation of novel biomarkers and targeted therapies, and ultimately alleviates the global socioeconomic and disease burden attributable to OA.

Epilepsy is a common neurological disorder with a substantial global burden. Despite major advances in diagnosis and therapy, nearly one-third of patients remain resistant to antiseizure medications, highlighting persistent gaps in understanding epileptogenesis and disease progression. Here, we review epidemiological evidence, time-dependent seizure patterns, and pathogenic mechanisms that contribute to epilepsy. We discuss how genetic variants, ion-channel dysfunction, altered synaptic transmission, neuroinflammation, metabolic and mitochondrial stress, structural remodeling, network reorganization, and epigenetic regulation converge to destabilize neural circuits. These processes interact across disease stages and promote persistent hyperexcitability. We further summarize how mechanistic advances are reshaping clinical management, including precision diagnostics, pharmacotherapy, surgery, neuromodulation, dietary and lifestyle intervention, chronotherapy, biomarker-guided stratification, and emerging disease-modifying approaches such as immunotherapy, pathway-targeted treatment, RNA-based therapeutics, and gene-directed strategies. Data-driven tools for seizure detection and forecasting are also discussed as complementary approaches for individualized care. Overall, current evidence supports a shift from empirical seizure suppression toward mechanism-guided and individualized care. Future progress will require closer integration of molecular discovery, validated biomarkers, and real-world implementation to achieve earlier, more equitable, and potentially disease-modifying treatment.

CD8⁺ tissue-resident memory T (T_RM) cells play a pivotal role in local immune regulation. These noncirculating T cells are uniquely positioned to orchestrate rapid site-specific immune responses, making them central to understanding tissue-specific immunity. Prior work has demonstrated that CD8⁺ T_RM cells possess dual functions: they are essential for immune defense against pathogens and malignancies, yet also drive pathological inflammation in autoimmune disorders. Furthermore, emerging evidence has begun to elucidate the intrinsic molecular mechanisms controlling this functional duality and to develop intervention strategies for its precise modulation. Here, we review current knowledge of the origin, transcriptional regulation, phenotypic characteristics, and functions of CD8⁺ T_RM cells. We discuss how T_RM cells correlate with clinical outcomes in diverse cancer types. Furthermore, we explore immune checkpoint inhibitors and other immunotherapies that target T_RM cells and their therapeutic implications from preclinical and translational human research. This review provides a comprehensive understanding of the molecular and cellular mechanisms governing T_RM cell activity and details their roles in health and disease. Ultimately, the framework of tissue immune networks reveals that leveraging T_RM cell development, tissue residency, and metabolism processes enables the design of innovative treatments for these diseases.

Triple-negative breast cancer (TNBC) has a poor prognosis and limited treatment options. Although programmed death protein 1 (PD-1) inhibitor-based chemotherapy and its combination with antiangiogenic agents are increasingly used clinically, comparative effectiveness data are lacking. This real-world study compared chemoimmunotherapy (IC) versus chemoimmunotherapy plus antiangiogenic therapy (ICA) in advanced TNBC. Among 218 eligible patients, the ICA group (n = 119) showed a significantly higher disease control rate (DCR) than the IC group (n = 99) (85.7 vs. 73.7%, p = 0.009). Notable numerical improvements were observed in high-risk subgroups: in patients with ≥3 prior lines (n = 56), ICA improved DCR by 26.0% (81.6 vs. 55.6%, p = 0.039) and prolonged PFS by 2.9 months (5.3 vs. 2.4 months, p = 0.031). In those with brain metastases (n = 24), ICA increased DCR by 50.0% (83.3 vs. 33.3%, p = 0.017, posthoc power = 55.4%), with extended progression-free survival (PFS) (+4.0 months) and overall survival (OS) (+12.6 months). Early recurrence patients (disease-free interval (DFI) < 12 months, n = 54) showed a 28.6% higher DCR with ICA (78.6 vs. 50.0%, p = 0.024). This study highlights the potential of adding antiangiogenic therapy to chemoimmunotherapy, particularly for high-risk or refractory advanced TNBC patients, suggesting a strategy that may overcome programmed death ligand 1 (PD-L1)-related resistance and warrants prospective validation.

Hypoalbuminemia is a recognized risk factor for postoperative pulmonary complications (PPCs), but whether preoperative albumin infusion improves pulmonary outcomes after cardiac surgery remains unclear. In this single-center, randomized, double-blind, controlled pilot trial (ChiCTR2300076609), 80 elderly patients with preoperative albumin concentrations <40 g/L who underwent elective cardiac surgery with cardiopulmonary bypass were randomly assigned to receive 100 mL of 20% albumin (40 patients) or saline before surgery (40 patients). The primary outcomes were PPC severity and incidence during hospitalization, and perioperative immune cell changes were also explored. All randomized participants completed the trial. Compared with the controls, the patients in the albumin group had lower PPC severity (median [IQR], 1 [1–2] vs. 2 [2–3]; mean difference, −0.75; 95% CI, −1.15 to −0.35; p = 0.001) and a lower incidence of PPCs (30% vs. 57.5%; risk difference, −0.275; 95% CI, −0.48 to −0.07; p = 0.013). Additionally, the Th17 cell proportion and γδTreg cell proportion were significantly decreased and increased, respectively, in the albumin group after surgery (p < 0.001). These findings suggest that preoperative albumin supplementation may reduce PPC risk and modulate immune responses, warranting confirmation in larger multicenter trials.

Postpartum venous thromboembolism (VTE) is a serious complication, and electrolytes may play a role in coagulation homeostasis, but their associations with postpartum VTE remain unclear. A total of 25,792 pregnant women from Chinese multicenter cohort between January 2017 and December 2024 were included, and the occurrences of postpartum VTE within 6 weeks after delivery were followed. Here, we show that dysregulated perinatal electrolyte profiles and a reduced serum calcium (Ca)/potassium (K) ratio are novel and independent risk factors for postpartum VTE, with hemoglobin and D-dimer levels mediating such associations. Restricted cubic spline analyses showed that low serum Ca (overall association p = 0.032) and high serum K (overall association p = 0.036) were associated with increased postpartum VTE risk. Serum magnesium exhibited a nonlinear inverse U-shaped association with VTE risk (nonlinear p = 0.021). Low serum Ca/K ratio was linked to elevated VTE risk (overall association p = 0.004), with a nonlinear relationship (nonlinear p = 0.042) and an inflection point at 0.55. Notably, a serum Ca/K ratio below 0.55 is a promising new biomarker for predicting the risk of postpartum VTE. Mediation analyses suggested that the protective effect of a higher Ca/K ratio might be partially explained by its association with higher hemoglobin levels (34.7% mediation, p = 0.036) and lower D-dimer levels (4.6% mediation, p = 0.018). This study suggests that strategies aimed at optimizing perinatal electrolyte balance and the monitoring and management of anemia may help reduce the burden of postpartum VTE.

Pyroptosis is a tightly regulated, proinflammatory form of programmed cell death defined by gasdermin-mediated membrane pore formation and cytokine release. By coupling cell death to innate immune activation, pyroptosis occupies a unique position at the interface of host defense and tissue pathology. Recent advances have demonstrated that pyroptosis is activated through multiple molecular routes, including canonical and noncanonical inflammasome pathways, Caspase-3/8–gasdermin axes, and granzyme-dependent mechanisms. Importantly, pyroptosis does not operate in isolation but engages in extensive crosstalk with other programmed cell death modalities, such as apoptosis, necroptosis, ferroptosis, NETosis, and the integrative process of PANoptosis, sharing key regulators including caspases, inflammasomes, and gasdermins. Despite rapid progress, a unified framework integrating pyroptosis-specific mechanisms with interaction networks, temporal dynamics, and disease relevance is still lacking. In this review, we systematically dissect the molecular pathways governing pyroptosis, emphasize its functional interplay with other cell death programs, and discuss emerging concepts such as cell-type specificity and sublytic versus lytic outcomes. We further examine the contribution of pyroptosis to cancer, infectious, autoimmune, metabolic, and cardiovascular diseases, and critically evaluate therapeutic strategies aimed at either inhibiting excessive pyroptosis or exploiting it for immunogenic cell death. Collectively, this review offers a perspective-enhancing, mechanistic, and translational significance.

Combined immune checkpoint inhibitor (ICI) and chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, reliable biomarkers predictive of clinical benefit are lacking. We analyzed 54 patients with advanced NSCLC treated first-line with ICI plus chemotherapy. Pretreatment tumor biopsies underwent targeted DNA and RNA-seq. Plasma samples for circulating tumor DNA (ctDNA) profiling were collected at multiple timepoints. Associations between genomic, transcriptomic, and ctDNA features and objective response rate (ORR) and progression-free survival (PFS) were assessed. Genomic analysis revealed that LRP1B mutations predicted longer PFS (HR = 0.35, p = 0.034), whereas FBXW7 mutations were associated with shorter PFS (HR = 5.39, p = 0.001). Exploratory transcriptomic analysis identified high SPP1 and LHCGR expression as predictors of poor prognosis, while high IL24 expression correlated with longer PFS. CD8⁺ effector memory T-cell infiltration was significantly higher in responders (p = 0.029). Longitudinal ctDNA analysis showed that positivity at C2D1 (HR = 5.18, p = 0.004), C3D1 (HR = 17.81, p < 0.001), and C4D1(HR = 3.91, p = 0.018) was associated with inferior PFS. This multi-omics analysis highlights the potential of integrating genomic, transcriptomic, and ctDNA biomarkers to optimize immunotherapy strategies in NSCLC.

De novo protein design enables the creation of proteins with entirely novel structures and biological functions from scratch, offering a promising new paradigm for cancer immunotherapy. Emerging methodologies are integrating principles of rational design, including specificity, modularity, and adaptability, into the development process from the outset. This innovative strategy holds the potential to advance how people understand and intervene against malignancy, through the strategic utilization of immune checkpoint regulation, cytokine engineering, cellular therapy, and signaling pathway remodeling, with each approach demonstrating distinct mechanisms to augment antitumor immune responses. To further optimize these strategies, advanced computational tools and synthetic biology techniques are now being actively deployed to rationally design immune-modulatory proteins for enhanced cytokine engineering, and to significantly enhance the efficacy of cellular immunotherapies through precision-engineered chimeric antigen receptor T-cell immunotherapy constructs and bispecific antibodies, collectively addressing the key limitations of current therapeutic approaches. To this end, this review discusses how the latest advances in these techniques can deepen our understanding of the usage of de novo-designed proteins in cancer immunotherapy, while also highlighting the key limitations that persist in the field.

Dexmedetomidine (Dex), an α2-adrenergic receptor (α2-AR) agonist, is widely used for its antihyperalgesic effects in perioperative pain management, yet its underlying mechanisms remain largely undefined. Here, we identify a rapid, circuit-specific mechanism by which Dex reverses stress-induced hyperalgesia (SIH) in mice. Stress exposure strengthens excitatory drive from the orbitofrontal cortex (OFC) to the anterior insula cortex (AIC), shifting the excitatory/inhibitory balance toward excitation and increasing the intrinsic excitability of AIC glutamatergic neurons. Viral tracing and optogenetics reveal a direct OFC–AIC glutamatergic projection. Optogenetic or chemogenetic activation of this pathway in otherwise naïve mice potentiates glutamatergic synaptic transmission and is sufficient to induce hyperalgesia, phenotyping SIH. Dex rapidly suppresses these effects by engaging presynaptic α2-ARs on OFC terminals, thereby reducing transmitter release at OFC–AIC synapses. Consistently, chemogenetic silencing of AIC neurons or of the OFC–AIC projection alleviates hyperalgesia in SIH mice. These findings define the OFC–AIC glutamatergic circuit as a key substrate for stress-related pain amplification and uncover a rapid presynaptic α2-AR “brake” as the mechanism underlying Dex's antihyperalgesic action, highlighting a tractable therapeutic entry point for stress-exacerbated pain states.

Diabetic retinopathy (DR), a major cause of blindness worldwide, poses a substantial and escalating burden on public health. The limitations of current therapeutic modalities highlight the pressing need for continued innovation in therapeutic interventions. This review comprehensively delineated the knowledge architecture, research focal points, and emerging directions in DR therapeutics. Targeted biological agents have recently emerged as principal research directions in DR therapy and hold substantial promise. They are expected to achieve the goals of blocking disease progression more persistently, effectively, and less invasively than nonbiological therapeutics through multitarget synergy and long-acting sustained-release formulations. In clinical practice, the paradigm of DR therapy has shifted toward personalized and precision medicine, with optimized subthreshold micropulse laser as a promising adjunctive therapy for enhancing long-term treatment outcomes. Looking ahead, therapeutic monitoring in DR may evolve beyond conventional morphological grading to incorporate multimodal precision diagnostics, artificial intelligence-driven broad-spectrum screening, and biomarker-based early warning systems. This review concludes with a discussion on prospects and challenges in DR therapeutics, with special emphasis on emerging drug candidates, recent clinical trial findings, and novel insights that may inform the next generation of therapeutic interventions for DR.

Regulatory B cells (Bregs) are a functionally defined yet phenotypically heterogeneous subset of lymphocytes that are essential for maintaining immune homeostasis. Their canonical function is regulated through the secretion of interleukin-10 (IL-10), a potent anti-inflammatory cytokine. However, accumulating evidence indicates that other molecules, such as IL-35 and transforming growth factor-β, and that of contact-dependent pathways, such as Programmed Cell Death Ligand-1 (PD-L1) and Programmed Cell Death-1 (PD-1), also play indispensable roles in their regulatory arsenal. This review examines the immunoregulatory roles of Bregs across diverse clinical contexts, including infectious diseases, cancers, autoimmune disorders (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and uveitis), and organ transplantation. Crucially, we highlight a fundamental functional dichotomy: although Bregs confer protection against autoimmunity and promote transplant tolerance, they concurrently drive the progression of chronic infections and malignancies by dampening antipathogen and antitumor immune responses. This functional dichotomy highlights the complexity of immune regulation, where Bregs act as critical nodes balancing health and pathology. The immense therapeutic potential by modulating Bregs activity and unresolved questions that will guide the future frontiers of Bregs research are essentially discussed.

Endometriosis is a chronic estrogen-dependent gynecological disorder characterized by the ectopic growth of endometrial-like tissue outside the uterine cavity, affecting approximately 10% of women of reproductive age worldwide. It is a leading cause of chronic pelvic pain, dysmenorrhea, and infertility, imposing a substantial burden on individual health and healthcare systems. Despite decades of research, the pathogenesis of endometriosis remains incompletely elucidated, and clinical management is often limited by delayed diagnosis and suboptimal treatment efficacy. This review provides a comprehensive and updated overview of endometriosis, covering its updated epidemiology, established and emerging risk factors, and key molecular mechanisms including inflammation, epigenetic regulation, hormonal imbalance, oxidative stress, and abnormal cell invasion and proliferation. We further summarize current diagnostic approaches, including imaging modalities, laparoscopy, and biomarkers, as well as clinical management strategies such as hormonal therapy, surgical intervention, and emerging targeted treatments. Finally, we discuss existing diagnostic and therapeutic challenges, unresolved questions, and future directions toward precision medicine and noninvasive management. This review aims to integrate recent advances and provide an updated framework for understanding and improving the clinical care of endometriosis. This review also highlights actionable translational directions for noninvasive early diagnosis, precision targeted therapy, and postoperative recurrence prevention, providing a key theoretical framework for translating basic research findings into clinical practice.

Intracranial efficacy of crizotinib and optimal postprogression therapies in c-ros oncogene 1 (ROS1)-positive non–small cell lung cancer(NSCLC) remain under-explored. We performed a multicenter real-world study across 17 Chinese hospitals (2015–2024) in 325 ROS1-positive NSCLC patients to evaluate the intracranial efficacy of crizotinib and postprogression treatment strategies. Crizotinib achieved an overall response rate(ORR) of 78.5% and a median progression-free survival (PFS) of 22.4 months. Patients with baseline brain metastases had a 66.7% intracranial response rate and a median central nervous system (CNS)-PFS of 22.2 months, demonstrating intracranial benefit. After progression, next-generation ROS1 inhibitors (active against the G2032R resistance mutation, for example, taletrectinib and repotrectinib) significantly prolonged PFS compared to older-generation targeted agents (median 13.9 vs. 4.4 months), especially among patients with secondary ROS1 resistance mutations (ORR 66.7% vs. 14.3%). However, due to greater availability in China, earlier agents like lorlatinib and entrectinib were commonly used after crizotinib failure. In our cohort, lorlatinib demonstrated superior efficacy to entrectinib, with a trend toward longer PFS and higher overall (34% vs. 7%) and intracranial (50% vs. 0%) response rates. This large real-world study confirms crizotinib's intracranial benefit and underscores the importance of next-generation ROS1 inhibitors and older-generation agents like lorlatinib—for improved patient outcomes after crizotinib resistance.

Concurrent chemoradiotherapy (CCRT) followed by intrauterine brachytherapy is the standard treatment for locally advanced cervical cancer (LACC), yet its efficacy is frequently constrained by an immunosuppressive tumor microenvironment (TME). This randomized, single-center, Phase II trial (n = 18; 2:1 allocation; high-risk Stages III–IVA LACC) investigated whether adding immunotherapy to CCRT (CICRT) could enhance early tumor regression and overcome immune suppression. In this exploratory analysis, CICRT demonstrated a numerical advantage in tumor reduction over CCRT alone, although the difference did not reach conventional statistical significance (mean residual tumor volume: 3.0% vs. 7.4%, p = 0.080, 95% CI: −9.3%–0.6%, η² = 0.180). Single-cell RNA sequencing of paired biopsies (n = 12) revealed that CICRT was associated with pro-inflammatory remodeling, characterized by the upregulation of MHC-II and chemotaxis-related genes in malignant cells and cancer-associated fibroblasts. Notably, CICRT reduced regulatory T cell niches and exhausted CD8⁺ T cells, alongside a phenotypic shift in tumor-associated macrophages toward an inflammatory state. These findings demonstrate the potential of CICRT to enhance early tumor regression and mitigate TME suppression, providing an exploratory biological rationale for its therapeutic activity in LACC.

Atherosclerosis is a multifactor condition and driving force behind many cardiovascular diseases. Moreover, it remains a leading cause of mortality worldwide. The current therapies, including statins and fibrates, focus mainly on lipid lowering. However, this condition is characterized by various biological pathways, particularly the oxidized LDL uptake by macrophages, chronic inflammation, or vascular smooth muscle cells proliferation, migration, and phenotypic switching, which forces the researchers to explore the numerous molecular pathways standing behind those processes. Despite a lot research on this topic was conducted, the need of finding new therapeutic methods based on the molecular pathogenesis still remains. In this review, we summarize the involvement of the lead signaling pathways in atherosclerosis: transforming growth factor beta (TGF-β), mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), as well as the functions of cell cycle proteins in its pathogenesis. We are going to put an emphasis on the cyclin-dependent kinases (CDKs) 5 and 9, as the driving forces behind the pathological conditions. Furthermore, we describe the novel therapeutic interventions, including noncoding RNA strategies and proteolysis targeting chimeras (PROTACs), as they are important candidates for future therapies. Our insights may help in the thorough understanding of the atherosclerosis pathogenesis and finding the future therapeutic interventions.

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) exhibits intrinsic resistance to epidermal growth factor receptor (EGFR)-targeted therapies owing to constitutive downstream pathway activation. Nevertheless, IgG1 antibodies may retain therapeutic activity through natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), thereby bypassing EGFR downstream signaling. However, whether EGFR-targeted IgG1 antibody-mediated ADCC remains effective in KRAS-mutant PDAC, and what determines therapeutic responsiveness, remain unclear. Here, we investigated whether nimotuzumab-mediated ADCC remains effective despite oncogenic KRAS signaling and explored the determinants of its therapeutic efficacy. Using complementary in vitro and in vivo models, including PDAC cell–NK cell co-culture systems, 3D tumor spheroids, and immunodeficient mouse models (subcutaneous and circulating tumor cell-derived xenografts), we demonstrated that combined nimotuzumab and adoptive NK cell therapy exerts potent antitumor efficacy in PDAC. Mechanistically, this treatment drives robust NK cell functional activation (CD107a/IFN-γ/TNF-α), enhances tumor homing, and induces immunogenic cell death. Collectively, our findings demonstrate that KRAS mutations do not compromise nimotuzumab-mediated ADCC, whereas tumor EGFR expression serves as a predictor of therapeutic responsiveness. Ultimately, this study establishes EGFR-directed NK cell immunotherapy as a promising therapeutic strategy for KRAS-mutant PDAC and provides a rationale for integrating targeted antibodies with cellular immunotherapies in other EGFR-expressing malignancies.

Mitophagy is a conserved cellular process that removes dysfunctional or excess mitochondria. Increasing evidence suggests that impaired mitophagy plays a crucial role in AD development. Promoting mitophagy has been shown to be protective in models of AD, representing an important target of Alzheimer's disease (AD). However, the molecular mechanisms underlying impaired mitophagy in AD are still elusive. Here, we provide evidence that highly expressed acylglycerol kinase (AGK), a mitochondrial lipid kinase associated with mitochondrial protein transport, glycolysis, and platelet formation, is a key mediator of mitophagy in AD. We found that AGK promoted the binding of ATPase family AAA domain containing 3A to translocase of the inner mitochondrial membrane 23 and sequentially increased mitochondrial import of PTEN-induced putative kinase 1, leading to the decrease of mitophagy. Further investigations revealed that the AGK downregulation in neuronal cells and APP/PS1 mice enhanced mitophagy, increased mitochondrial membrane potential, decreased pathological Tau/Aβ and neuroinflammation, and alleviated cognitive dysfunctions in the mice. Altogether our findings indicate that AGK plays a critical role in mediating mitophagy defects in AD; furthermore, downregulation of AGK promotes mitophagy and the decrease of Aβ and pathological Tau, providing an encouraging therapeutic treatment for AD.