搜索结果：Translational cancer research

The convergence of synthetic biology and nanotechnology has created new opportunities for cancer diagnosis and therapy. Engineered microorganisms exhibit unique tumor-targeting, colonization, and immunomodulatory capabilities, while nanomaterials provide versatile platforms for drug delivery, imaging, and controlled therapeutic release. This review summarizes recent advances in the application of engineered microorganisms and nanomaterials in oncology, with a focus on their mechanisms of action, therapeutic potential, and translational challenges. We discuss the roles of the tumor microbiome in cancer progression, microbial engineering strategies for tumor targeting and immune regulation, and the development of nanomaterial-based delivery systems and immunotherapies. Particular attention is given to microbe-nanomaterial hybrid platforms, which combine the advantages of both systems to enhance therapeutic efficacy and modulate the tumor microenvironment. Finally, key challenges related to biosafety, biocompatibility, regulatory approval, and clinical translation are highlighted. The integration of engineered microorganisms and nanomaterials represents a promising strategy for next-generation precision oncology and may accelerate the development of more effective and personalized cancer therapies.

Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer worldwide. The gut microbiota profoundly influences this cancer by modulating immune responses and therapeutic efficacy. Recently, live biotherapeutic products (LBPs), comprising live resident microorganisms in the gut, have emerged as promising agents to reprogram host immunity and enhance treatment efficacy in preclinical CRC models. However, translation of these findings to clinical practice remains limited due to heterogeneous study designs, poorly defined mechanisms in human hosts, unresolved manufacturing and safety concerns, and lack of personalized treatment strategies. This review briefly introduces LBPs as a new class of medicines, categorize them as single strains, composite strains, and engineered strains, and details their multifaceted mechanisms against CRC, including direct immunomodulation to enhance anti-tumor activity, production of protective metabolites like short-chain fatty acids (SCFAs), and restoring gut microbiota. Additionally, the synergistic potential of LBPs with conventional chemo- and immunotherapies and current LBPs in clinical trials for CRC are summarized, highlighting their translational progress. We further address the manufacturing, regulatory, and safety barriers constraining clinical adoption and propose strategies for integrating preclinical and clinical evidence to meet patient needs. By consolidating current knowledge of LBPs as an emerging oncology drug class, this review offers a practical framework for advancing LBPs from preclinical promise to clinical practice, supporting the development of personalized medicine.

Hybrid Nanosystems (HNSs) are a type of advanced drug carrier that can be made from various materials, including organic compounds, inorganic particles, lipids, polymers, and biomimetic components. This combined framework facilitates functionalities such as medication distribution, imaging support, and modification of therapeutic responses. This renders them highly promising for oncological therapy. The main goal of this study was to identify studies on HNSs that investigated their development, underlying characteristics, and therapeutic efficacy. A comprehensive review of the literature was performed, utilizing platforms such as Google Scholar, Scopus, Web of Science, and PubMed. It systematically collected data on various aspects, including cancer types studied, nanomaterial compositions, targeting techniques, combination therapies, safety profiles, and therapeutic significance. The analysis encompassed findings from 197 preclinical and clinical studies published between 2010 and 2025. This study highlights recent advancements in cancer treatment methods, their mechanisms of action, and the critical challenges that must be addressed prior to clinical application. The findings indicate that HNSs are under investigation for several cancer types, including breast, lung, liver, colon, and brain tumors. These technologies facilitate targeted drug delivery, initiate programmed cell death (apoptosis), inhibit cancer proliferation, and assist in real-time imaging for diagnostic applications. An analysis of 197 research papers published from 2010 to 2025 revealed that HNSs markedly improve anticancer efficacy by optimizing drug transport, tumor targeting, and multimodal therapy strategies. HNS-based systems attained tumor suppression rates of 70-90%, enhanced apoptosis, diminished systemic toxicity, and successfully addressed multidrug resistance and immune evasion. Multifunctional platforms that integrate chemotherapy, phototherapy, gene therapy, and immunotherapy have shown significant synergistic effects, with combination indices between 0.4 and 0.8. Despite the highly encouraging preclinical results, additional studies are necessary to evaluate long-term safety, scalability, and regulatory obstacles for effective clinical translation. The results highlight the growing promise of hybrid nanostructures as sophisticated cancer therapies that can combine targeted delivery, multimodal treatment, and diagnostic capabilities on a single platform. Their capacity to overcome significant drawbacks of traditional medicines, such as multidrug resistance, inadequate bioavailability, and off-target toxicity, highlights their translational significance. Nonetheless, additional endeavours are necessary to ensure long-term safety, manufacturing uniformity, and regulatory structures to enable effective clinical implementation. Hybrid nanostructures have emerged as promising multifunctional platforms for cancer therapy, exhibiting increased tumour targeting, improved therapeutic efficacy, and diminished systemic toxicity across many cancer types. Their capacity to amalgamate drug administration, imaging, and combination therapies provides considerable benefits compared to traditional treatments. Nonetheless, thorough long-term safety investigations, scalable production methodologies, and defined regulatory frameworks are crucial to expedite their effective clinical translation.

Cancer metabolism is characterized by profound reprogramming, yet the mechanisms enabling rapid and precise adaptation remain incompletely understood. This review establishes post-translational modifications (PTMs) as the central processing unit of oncogenic metabolic reprogramming. PTMs execute a conserved three-tiered regulatory logic: they interpret oncogenic and environmental signals, command metabolic flux, and cement malignant phenotypes through epigenetic and feedback mechanisms. We systematically demonstrate how this PTM-driven logic governs key pillars of cancer metabolism-glucose, lipid, amino acid, and nucleotide utilization-and extends its command to critical cell fate execution programs, including mitochondrial dynamics, autophagy, and ferroptosis. Furthermore, we delineate how PTMs act as master regulators of immunometabolic reprogramming within the tumor microenvironment (TME), directly linking tumor metabolism to T cell exhaustion, myeloid cell polarization, and immune evasion. By integrating recent advances on the determinants and crosstalk of PTM networks, we describe how metabolic plasticity and heterogeneity are encoded at the PTM level, with metabolic gradients shaping distinct "PTM geographies" within tumors. Finally, we translate these insights into clinical prospects, highlighting PTM-based biomarkers, PTM-targeted drugs and emerging therapeutic strategies, including targeted protein degradation, PTM-targeted vaccines and dietary interventions. Deciphering this PTM-encoded program reveals a new landscape of therapeutic vulnerabilities, shifting the paradigm toward rationally targeting the fundamental computational logic that sustains tumors.

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease state with limited durable responses to existing therapies, including taxane-based chemotherapy. Resistance mechanisms are multifactorial and incompletely addressed by current treatments. Drug repurposing offers an accelerated pathway for the development of novel therapeutic strategies in treatment-resistant disease. This review synthesizes preclinical mechanistic data and clinical experience with itraconazole (ITZ), a clinically approved triazole antifungal, across prostate cancer and other malignancies. We evaluate the signaling pathways targeted by ITZ, barriers to its clinical translation, and opportunities for biomarker-driven combination therapy. ITZ functions as a pleiotropic anticancer compound that modulates multiple pathways implicated in prostate cancer progression and therapeutic resistance, including Hedgehog/GLI, PI3K/AKT/mTOR, and Wnt/β-catenin signaling, as well as drug efflux transporters. Preclinical studies demonstrate that ITZ reverses ABCB1-mediated docetaxel resistance, suppresses Hedgehog/GLI1 signaling, and inhibits cancer cell proliferation and invasion. Despite compelling mechanistic rationale, clinical activity in mCRPC has been modest, with limited durable responses, underscoring a translational disconnect. Advancement of ITZ into clinical practice is constrained by pharmacokinetic challenges, dose-limiting toxicities, and the lack of validated predictive biomarkers to identify responsive patient subsets. Emerging evidence further suggests potential synergy with immune checkpoint inhibitors through tumor microenvironment modulation, though this remains unexplored in prostate cancer. ITZ represents a potential adjunctive strategy to standard therapies within rationally designed, biomarker-stratified combination regimens for mCRPC. Target populations include patients with PTEN-null tumors (elevated Hh/GLI and PI3K/AKT signaling), ABCB1-overexpressing tumors (taxane resistance), or those progressing after AR pathway inhibitor therapy. Clinical advancement will require pharmacological optimization, development and validation of patient stratification biomarkers (GLI1/PTCH1, PTEN status, ABCB1 expression), and integration with therapies targeting complementary resistance pathways.

The human gut microbiota constitutes the largest and most metabolically active microbial ecosystem in the body, and accumulating evidence links dynamic alterations in microbial composition and function to the initiation, progression, and treatment responses of multiple gastrointestinal (GI) cancers, including esophageal, gastric, hepatocellular, pancreatic, and colorectal malignancies. This review synthesizes current evidence on dysbiosis signatures, mechanistic pathways, and translational opportunities across major GI cancer types, with a focus on microbe-derived metabolites and microbe-associated molecular patterns that shape inflammation, epithelial barrier integrity, and antitumor immunity. Across GI cancers, recurrent patterns include enrichment of pro-inflammatory/pathobiont taxa, depletion of homeostasis-maintaining and butyrate-producing commensals, and perturbations in metabolic axes centered on bile acids and short-chain fatty acids. Mechanistically, these changes can remodel the tumor microenvironment via epithelial and immune signaling, epigenetic regulation, and metabolic reprogramming. Importantly, the gut microbiota is increasingly recognized as a modifiable determinant of the efficacy and toxicity of immune checkpoint blockade, adoptive cell therapies, chemotherapy, and radiotherapy. Despite rapid advances, key challenges persist in translating microbiome research into cancer care, including validation, standardization, variability, and safety. Future success likely depends on function-oriented, targeted modulation, supported by multi-omics, strong causal evidence, and clinical trials.

Equitable participation in clinical research is essential to generating broadly generalizable findings and advancing public health. Yet persistent sociodemographic disparities, driven by mistrust, limited access, and inadequate community engagement, continue to exclude underrepresented racial and ethnic groups from research. To address these barriers, the University of Texas Southwestern Medical Center developed a comprehensive, multi-component community engagement model designed to build trust and enhance research readiness among UREG. The model integrates eight synergistic programs aligned across the five-level Social Ecological Model, including HealthStreet screening events, a Health Needs Assessment, the Community Research Registry, the North Texas Community Health Coalition, Community Engagement Grand Rounds, the Spanish Language Resource, the Community Advisory Panel, and a Community Health Grant Program. These initiatives collectively provide culturally informed outreach and structured pathways for bidirectional input from community members. Since 2023, the model has achieved substantial impact, including 5069 community-based health screenings, over 100 consultations to investigators, and more than $44 million in funded grants. Findings demonstrate that sustained, multi-level engagement can strengthen trust, expand research access, and support more equitable translational science.

Metastatic disease remains the primary cause of cancer mortality, yet the identification of robust therapeutic targets is hampered by tumor heterogeneity and microenvironmental complexity. A key challenge lies in identifying epigenetic regulators that can simultaneously inhibit tumor progression and harness immunity. Here, we leverage single-cell transcriptomics from 120 liver cancer patients to identify E1A-like inhibitor of differentiation 1 (EID1) as the sole histone acetylation regulator upregulated in both tumor cells and effector lymphocytes within metastatic sites. Systemic Eid1 deletion markedly suppresses lung metastasis in melanoma, liver cancer, and breast cancer models. This protection is mediated dominantly by natural killer (NK) cells and type I/II interferons (IFNs), as evidenced by antibody-based cell depletion and cytokine neutralization. Eid1-deficient NK cells exhibit a hyperactivated state with robust proliferation, and their adoptive transfer confers superior metastatic suppression. Notably, Eid1 deficiency augments the accumulation of NK cells and dendritic cells (DCs) in lung metastases and induces a close spatial and transcriptional DC-NK interplay for metastatic defense. Mechanistically, loss of Eid1 upregulates formyl peptide receptor 1 (FPR1) and its ligand annexin A1 (ANXA1) on DCs and NK cells, enabling a FPR1-dependent DC-NK crosstalk that strengthens type I and II IFN responses against tumor dissemination. Conditional knockout demonstrated that intratumoral accumulation of NK cells and DCs is determined by cell-intrinsic Eid1. Critically, targeted Eid1 silencing delivered by nanoparticles significantly enhanced Fpr1 expression and NK activation, eventually suppressing tumor dissemination. Collectively, our study uncovers a previously unrecognized role of EID1 in promoting cancer metastasis by dampening the DC-NK joint immunosurveillance and establishes the therapeutic potential of EID1 inhibition in NK cell transfer and siRNA-based strategies.

Fish cell lines are indispensable in vitro systems that support diverse research areas, including virology, immunology, ecotoxicology, and biomedical science. Fish represent the most species-rich vertebrate group with remarkable genomic diversity, providing valuable resources for specialised cellular models. Since the establishment of the first fish cell line (RTG-2) in 1962, the global repository has expanded to approximately 918 authenticated cell lines derived from over 211 species. This review presents a comprehensive overview of the historical progression, global repositories, and current standards for cell line authentication. It summarises methodological advances in primary culture initiation, the development of continuous cell lines, and improvements in cryopreservation techniques. This review also critically explains the wide-ranging applications of fish cell lines in aquatic virology, vaccine development, and standardised ecotoxicological assays. The translational potential in biomedical research is also highlighted, particularly in cancer biology, regenerative medicine, and drug discovery, largely driven by the use of genetically tractable model species such as zebrafish (Danio rerio) and medaka (Oryzias latipes). Key challenges are also discussed, including mycoplasma contamination, cross-species misidentification, limitations in cryopreservation protocols for marine-derived cells, and the need for robust, open-access digital biobanking systems. Future perspectives encompass emerging technologies such as 3D organoids, organ-on-a-chip platforms, CRISPR-based genome editing, and serum-free culture systems. Integration of these innovations with omics approaches and adverse outcome pathway frameworks is expected to enhance the utility of fish cell lines, advancing research in aquaculture, environmental monitoring, and food security, while aligning with the principles of the 3Rs and the United Nations Sustainable Development Goals.

Lynch syndrome (LS) is a cancer susceptibility syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. Due to increased risk of colorectal cancer (CRC), enhanced colonoscopic surveillance is recommended for heterozygote MMR carriers. Using a registry of English patients with LS linked to digital National Health Service records, we aimed to assess adherence of MMR carriers to national surveillance guidelines and to determine the impact of surveillance on CRC incidence and mortality. We described the frequency of colonoscopies in 4732 MMR carriers and used logistic regression to determine predictors of surveillance adherence. For MMR carriers with a record of surveillance and those without, we estimated age-specific annual CRC incidence rates (AS-AIRs) and cumulative lifetime risks; assessed for stage shift by comparing CRC stage distributions and stage-specific AS-AIRs; and estimated risks of death from CRC and any cause using Kaplan-Meier methods and Cox proportional hazards regression. Surveillance at a mean interval of ≤3 years (n=3028) was associated with a decrease in CRC-specific and all-cause mortality, without an associated change in total CRC incidence, even after multivariate adjustment. No strong evidence of stage shift was observed. Colonoscopic surveillance at a mean interval of ≤2 years (n=1569) was associated with an increase in total CRC incidence. Incidence of early-stage cancers was also higher, with no corresponding decrease in late-stage cancers, which may reflect the short follow-up period, spectrum bias, or the impact of overdiagnosis. The observed reduction in all-cause mortality among regularly surveilled MMR carriers may indicate an impact of surveillance on CRC-specific mortality, though in the context of a non-randomised study could also reflect the influence of selection bias.

Precision oncology relies on tumor molecular profiles to predict drug responses. Instead of using conventional molecular features directly, we construct predictive signatures based on gene essentiality. Here, we present DrGee, an essentiality-centered platform that infers drug sensitivity solely from gene expression profiles. The built-in DeepEEAA model integrates gene expression, gene essentiality, drug-protein affinity, and drug-gene associations to quantitatively predict IC50 values. DeepEEAA achieved competitive predictive performance on independent cell line datasets (R2 = 0.764; MSE = 0.9345), outperforming recent benchmark deep learning methods. DrGee prioritized four candidate drugs for the 95-D lung cancer cell line, among which BI-97C1 and trimetrexate were validated by in vitro assays and mouse xenograft experiments. Robust predictive performance was further confirmed in OVCAR8 ovarian cancer cells. In TCGA cohorts, essentiality-driven predictions stratified patients with significantly different overall survival outcomes (AUC-PR = 0.825), highlighting the translational potential of DrGee.

The clinical utility of 18F-fluoroglutamine (18F-FGln) PET/CT for characterizing metabolic heterogeneity and improving lung cancer staging remains underexplored. In this prospective study, 31 patients with 36 primary lung lesions underwent dual-tracer (18F-FDG/18F-FGln) PET/CT. A metastatic cohort (n&#x2009;=&#x2009;28) was analyzed for distant staging. Diagnostic performance was assessed using ROC analysis, logistic regression, and radiomic texture parameters (volume, mass, CT histogram features). For primary lesions, 18F-FDG showed marginally higher detection rates (86.1% vs. 80.6%) and significantly greater avidity (SUVmax: 9.15&#x2009;&#xb1;&#x2009;0.16 (FDG) vs. 3.94&#x2009;&#xb1;&#x2009;1.57 (FGln), P&#x2009;<&#x2009;0.001). CT texture analysis revealed kurtosis as an independent predictor of 18F-FGln uptake (OR&#x2009;=&#x2009;1.16, P&#x2009;=&#x2009;0.025), correlating with metabolic-structural coupling (r&#x2009;=&#x2009;0.445, P&#x2009;=&#x2009;0.009). In nodal staging, 18F-FGln identified improved diagnostic performance than 18F-FDG (AUC: 0.92 vs. 0.62). Metastatic lymph nodes showed higher 18F-FGln uptake, with increased SUVmax (3.57&#x2009;&#xb1;&#x2009;1.23 vs. 2.03&#x2009;&#xb1;&#x2009;0.47, P&#x2009;<&#x2009;0.001) and TBR (2.11&#x2009;&#xb1;&#x2009;0.92 vs. 0.93&#x2009;&#xb1;&#x2009;0.21, P&#x2009;<&#x2009;0.001). Multivariate analysis identified 18F-FGln SUVmax (OR&#x2009;=&#x2009;32.79, P&#x2009;<&#x2009;0.001) and CT density (OR&#x2009;=&#x2009;0.90, P&#x2009;<&#x2009;0.001) were predictors of metastatic lymph nodes (LNs). For distant metastases, 18F-FGln detected more distant lesions (86 vs. 70), particularly in bone (SUVmax 7.48&#x2009;&#xb1;&#x2009;3.03 vs. 6.80&#x2009;&#xb1;&#x2009;4.48) and brain (TBR 7.04&#x2009;&#xb1;&#x2009;2.96 vs. 0.88&#x2009;&#xb1;&#x2009;0.30, P&#x2009;<&#x2009;0.001), altering staging in 3 cases. 18F-FGln PET/CT showed promising clinical potential in lung cancer, particularly in nodal staging, with higher diagnostic performance compared with 18F-FDG. It also demonstrated improved detection of bone and cerebral metastases in selected patients. Furthermore, 18F-FGln uptake correlated with CT-derived texture features, especially kurtosis, suggesting a possible association with tumor heterogeneity. Despite several false-negative cases, these results indicate that 18F-FGln may serve as a complementary metabolic imaging biomarker in lung cancer. Multicenter validation studies are needed to confirm these findings. ChiCTR2000037834 Retrospectively Reg Date&#xff1a;2020-09-02.

Organ-selective immunomodulation is increasingly viewed as a route to improve the therapeutic index of cancer immunotherapy, yet most agents are still delivered systemically, where limited tumor exposure and immune-related toxicities remain common. The lung is an attractive site for local intervention because it is directly accessible and immunologically specialized. However, effective pulmonary delivery is constrained by mucociliary clearance, airway mucus, alveolar macrophage uptake, and epithelial barriers. Nanomaterials can be rationally engineered to address these constraints, increasing pulmonary retention and concentrating immunotherapeutics within the lung tumor microenvironment while reducing systemic burden. This Review summarized the key physiological barriers for pulmonary immunotherapeutic delivery and discusses how nanomaterial properties shape deposition, retention, cellular partitioning, and downstream immune activation. We critically evaluate representative inhalable platforms across major immunotherapeutic modalities, including vaccines, immune checkpoint blockade, innate immune agonists (e.g., STING agonists), cytokine regulation, and emerging in situ immune-cell engineering strategies. We also highlight translational considerations. Together, these advances support inhalable immunotherapeutic nanomedicines as a complementary approach to current lung cancer treatment and a broader framework for pulmonary immune modulation.

Although concurrent chemoradiation (CCRT) is the standard of care for locally advanced cervical cancer, oncological outcomes remain suboptimal. Noninvasive monitoring of treatment responses could improve therapeutic management. This study investigated the temporal dynamics of extracellular vesicle (EV)-enriched urinary proteomes in patients with locally advanced cervical cancer undergoing CCRT to identify physiobiological shifts and proteins associated with treatment response and survival. Urine samples from 42 patients were collected longitudinally before, 1 month post-, and 3 months post-CCRT completion (126 samples). Urinary EVs were enriched using strong-anion-exchange magnetic beads. Proteomic profiling was performed using liquid chromatography-tandem mass spectrometry. Differential protein abundance and time-varying Cox regression analyses were used to correlate the proteomic signatures with CCRT response and overall survival. Analysis of longitudinal samples yielded 2,352 quantifiable proteins. Of these, 1,055 exhibited significant temporal shifts. Pathway analysis revealed that tumors and virus-associated proteins peaked at 3 months posttreatment, corresponding to the clinical response assessment window. By 3 months, nonresponders exhibited pronounced suppression of adaptive immune pathways and up-regulation of protein homeostasis and degradation pathways. Time-varying survival analysis identified 8 proteins driven by an altered T-complex ring complex/chaperonin containing T-complex protein 1, ribosomal proteins, and immune-related proteins associated with overall survival. Six of these were expressed in cervical tumor tissues based on the Human Protein Atlas. Overall, EV-enriched urinary proteomics provides a noninvasive liquid biopsy method for monitoring biological dynamics during CCRT. The observed immune suppression in nonresponders and the 8-protein prognostic signature offer preliminary insight into survival patterns and could help guide future studies on adjuvant immune-enhancing approaches.

Metronomic chemotherapy with oral capecitabine + vinorelbine (Cape + VNL) provides synergistic cytostatic activity and antiangiogenic and immunomodulatory effects, potentially offering prolonged disease control with limited toxicity in HER2-negative metastatic breast cancer (MBC). However, efficacy in the real-world (RW) setting, especially in late lines, and the impact of dihydropyrimidine dehydrogenase (DPYD) polymorphisms on dose reduction and safety remain limited. In this retrospective study, 200 patients with human epidermal growth factor receptor 2 (HER2)-negative MBC were treated at the ASST Cremona Hospital (2015-2023) with metronomic Cape (1000 mg twice daily, in normal metabolizers; 500 mg twice daily, in DPYD variant carriers) + VNL (20 mg/day, once daily, 5-days-on/2-days-off). All patients underwent pretreatment DPYD genotyping and dose adjustment. Treatment was administered in the second-to-fourth setting. The primary end point was time-to-next treatment or death (TNTD); secondary end points included overall survival (OS), disease control rate (DCR) &#x2265;24 weeks, overall response rate (ORR), safety, and genotype-toxicity correlations. The median age was 61 years, and DPYD variants were present in 14.5% of patients; 34%, 41%, and 25% received therapy as second-, third-, and fourth-line treatment. The median TNTD was 22.0 weeks, and the OS was 64.0 weeks. The DCR was 38.5%, and the ORR was 22.0%. Efficacy was comparable between DPYD variant carriers and normal metabolizers (all P values > .05). In later lines, Eastern Cooperative Oncology Group performance status 2 and >2 metastatic sites were independent negative prognostic factors (all values P < .05). Overall, 7.5% grade 3 toxicities occurred, especially in variant carriers without dose reduction and grade 4-5 events. These RW data suggest that metronomic Cape + VNL may represent a clinically active and manageable option in heavily pretreated HER2-negative MBC. Our findings support prospective evaluation of DPYD-guided dose individualization as a strategy to optimize the benefit-risk balance of fluoropyrimidine-based metronomic regimens.

Immune checkpoint inhibitor (ICI) therapy has become standard of care for late stage non-small cell lung cancer (NSCLC), producing durable responses in a subset of patients. However, inflammatory side eKects termed immune-related adverse events (irAEs) occur in up to 40% of ICI-treated NSCLC patients. Current approaches to alleviate irAEs include treatment with immune-suppressing corticosteroids. However, these treatments may undermine the eKicacy of ICIs by suppressing both the irAE and the anti-tumour immune response. To identify more specific therapeutic targets, a better understanding of the complex immunopathology underlying the development of irAEs in NSCLC is required. In this study, pre-treatment blood samples were prospectively collected from 72 NSCLC patients, including 23 who subsequently developed irAEs. Of these 72 samples, PBMCs from 59 were characterised using high-parameter mass cytometry. Plasma from 30 samples was analysed using the SomaScan platform that provides in depth characterisation of over 10,000 proteins, and the plasma metabolome of 30 samples was explored using liquid chromatograph-mass spectrometry (LC-MS). A unique peripheral immunophenotype was observed in patients who subsequently developed irAEs, characterised by decreased memory B cell abundance, heightened Th2 immunity, and an increase in plasma cytokines. Investigation into baseline metabolites revealed dysregulation of fatty acid metabolism associated with development of irAEs. Analysis of additional paired PBMC (n = 17) and plasma (n = 12) samples collected early on treatment allowed exploration of the immunological, proteomic, and metabolic changes associated with irAE development. ICItreatment of patients who developed irAEs induced a significant increase in the abundance of CD8 memory cells and plasma histones. This points to the induction of a strong and potentially pathogenic immune response early following ICI treatment in patients who subsequently develop overt toxicity. Overall, through application of a high-parameter multiomic approach, we have identified key cellular, proteomic and metabolomic features that predispose patients to developing immunotherapy toxicity. These findings provide insight into the complex biology underlying the development of ICI-related adverse events and inform potential treatment strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, and cardiovascular disease remains the leading cause of death in this population. Statins are therefore a cornerstone of therapy in MASLD because of their antiatherosclerotic efficacy. Less attention has been paid to the possibility that part of the hepatic benefit observed in MASLD cohorts-including lower aminotransferase levels, slower fibrosis progression, reduced decompensation and lower hepatocellular carcinoma incidence-may reflect direct hepatic effects beyond LDL reduction. Although the evidence is predominantly observational, the direction and magnitude of the association have remained broadly consistent across independent cohorts. Recent studies have strengthened this signal, including a post hoc analysis of the PROSPER trial showing attenuation of excess mortality in individuals with elevated FIB-4, and a large Veterans Affairs cohort demonstrating a dose-dependent association between cumulative statin exposure and lower primary liver cancer risk in MASLD. This review integrates the preclinical, observational and indirect randomized evidence supporting the biological plausibility of liver-directed effects of statins. Mechanistically, the argument centres on inhibition of the mevalonate pathway as a molecular hub linking lipotoxicity, NLRP3-dependent inflammation, fibrogenesis and carcinogenesis through impaired prenylation of small GTPases. A fifth axis, intrahepatic hemodynamics mediated through KLF2/eNOS signaling, is supported by randomized evidence in compensated cirrhosis. In contrast, the LIVERHOPE-EFFICACY trial showed no benefit in decompensated cirrhosis, helping define the therapeutic window. Within the limitations of the available evidence, we propose a conceptual reframing: in MASLD, statins may act not only as cardiovascular drugs, but also as agents with potentially relevant hepatic effects mediated through a shared molecular substrate.

To describe cell-free DNA (cfDNA)-inferred putative clonal hematopoiesis (CH) candidates during first-line platinum-based chemotherapy followed by poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance in ovarian cancer. In SCRUM-Japan MONSTAR-SCREEN-1, we analyzed clinically reported paired tumor tissue and plasma cfDNA profiling (324-gene assays). Baseline (B1) data were assessed in 35 treatment-na&#xef;ve patients; longitudinal cfDNA was available at B1, after platinum without progression (B2), and during/after PARPi without progression (B3) in 8 patients. Putative CH candidates were defined as pathogenic variants (variant allele frequency <40%) in prespecified CH-related genes detected in plasma but not detected in matched tumor tissue at clinical reporting thresholds. At B1, putative CH candidates were reported in 19/35 patients (54.3%), most commonly DNMT3A; positivity was associated with age &#x2265;60 years. In the longitudinal cohort, tumor-derived TP53 variants were below the assay reporting threshold at B3 in all patients, whereas putative CH TP53 variants were reported in 0/8 patients at B1 and 6/8 patients at B3. DNA damage response gene candidates (TP53/ATM/CHEK2) more frequently became detectable above the reporting threshold during B2-B3 than during B1-B2, while epigenetic-gene candidates showed relatively stable detectability. No therapy-related myeloid neoplasm events were observed during follow-up. This paired tissue-plasma longitudinal analysis highlights an interpretive challenge in cfDNA testing during first-line platinum-to-PARPi maintenance therapy: putative CH candidates may become detectable as tumor-derived cfDNA declines. Given cfDNA-only inference without matched WBC sequencing and the small serial cohort, these observations are supportive of prior reports of CH dynamics but require validation in larger WBC-integrated cohorts. UMIN-CTR Clinical Trial Identifier: UMIN000036749.

Phase II and III trials have demonstrated progression-free survival (PFS) benefits of pyrotinib plus capecitabine over lapatinib plus capecitabine in HER2-positive metastatic breast cancer (MBC). However, long-term overall survival (OS) data from a single-center cohort remain limited. This pooled analysis compared OS between the two regimens and explored outcomes across prespecified subgroups. We included patients with HER2-positive MBC from our center enrolled in a Phase Ic study, a Phase II study, or the Phase III PHOEBE trial. The primary endpoint was OS. OS was analyzed using Kaplan-Meier estimates, log-rank tests, and a multivariable Cox model adjusted for ECOG performance status, pathological grade, prior anti-HER2 therapy, trastuzumab exposure duration, trastuzumab resistance, and prior chemotherapy lines. The proportional hazards assumption was assessed using Schoenfeld residuals. Exploratory subgroup analyses used prespecified categories. At data cutoff, 82 patients were included; 53 received pyrotinib plus capecitabine and 29 received lapatinib plus capecitabine. Baseline characteristics were comparable between groups. Median OS was 74.61&#x2009;months (95% CI 41.10-not reached) with pyrotinib plus capecitabine and 30.98&#x2009;months (26.12-50.76) with lapatinib plus capecitabine (log-rank p&#x2009;=&#x2009;0.0053). Cox models suggested a reduced risk of death with pyrotinib plus capecitabine. Subgroup analyses were exploratory and should be interpreted cautiously because several subgroup estimates were imprecise. In this single-center pooled analysis, pyrotinib plus capecitabine was associated with significantly longer OS than lapatinib plus capecitabine in patients with HER2-positive MBC. These exploratory results are consistent with prior Phase II/III trials and provide evidence supporting the OS benefit of pyrotinib.