J Asthma Allergy. 2026 Mar 19;19:575312. doi: 10.2147/JAA.S575312. eCollection 2026.

ABSTRACT

Systems biology approaches have contributed to advancing our understanding of complex respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). This systematic review evaluates the application of systems biology methodologies in respiratory medicine, focusing on multi-omics data integration and computational techniques for biomarker discovery and mechanistic understanding. Following PRISMA 2020 guidelines, we conducted a comprehensive literature search across Web of Science and Scopus databases, identifying 117 peer-reviewed documents published from 2010 to 2024. The review methodology employed bibliometric analysis combined with qualitative synthesis of included studies. Results demonstrate steady growth in systems biology applications for asthma and COPD research, with publication rates increasing by approximately 0.5 articles per year (R² = 0.73, p < 0.001). Bibliometric analysis identified five major research clusters: systems biology as a foundational methodological framework (Basic Theme), COPD-focused research as the most developed area (Motor Theme), gene expression analysis, disease classification approaches, and specialized lung disease investigations (Niche Theme). Multi-omics integration studies achieved 82-91% accuracy in disease classification tasks, with transcriptomics-based asthma endotyping validated in over 1500 patients across multiple cohorts. Network analysis approaches identified hub genes (IL-6, TNF-α, MMP9) replicated across three independent studies. Machine learning applications demonstrated 80-90% accuracy for diagnostic and prognostic tasks, though external validation remains limited, with only 15% of reviewed studies including independent validation cohorts. Significant challenges persist in data integration, computational reproducibility, and clinical translation. Most studies employed modest sample sizes (median n=89), and population diversity was limited, with 89% conducted in European-ancestry populations. This review provides a comprehensive assessment of systems biology progress in respiratory medicine, identifies methodological gaps, and highlights the need for standardized protocols, larger collaborative studies, and rigorous external validation to advance clinical implementation of systems biology findings in asthma and COPD management.

PMID:41878747 | PMC:PMC13007689 | DOI:10.2147/JAA.S575312

Immunotherapy. 2026 Mar 24:1-13. doi: 10.1080/1750743X.2026.2648431. Online ahead of print.

ABSTRACT

The gut microbiota (GM) has emerged as a key modulator of cancer development and therapeutic response beyond the gastrointestinal tract. In extra-intestinal cancers, GM composition influences oncogenesis, with specific microbial taxa and their metabolites linked to either increased or decreased cancer risk, as highlighted by Mendelian Randomization studies. Beyond cancer initiation, GM plays a critical role in shaping the efficacy and toxicity of anticancer therapies, particularly immunotherapy. We searched PubMed and ClinicalTrials.gov using the terms"gut microbiota," "immune checkpoint inhibitors," "faecal microbiota transplantation," "solid tumor" in oncology patients. Evidence indicates that SCFA-producing bacteria, Akkermansia muciniphila, and members of Lachnospiraceae and Ruminococcaceae families enhance responses to immune checkpoint inhibitors (ICIs), whereas dysbiosis and immunosuppressive bacteria are associated with poor outcomes and immune-related adverse events. Therapeutic modulation of the GM through probiotics, prebiotics, fecal microbiota transplantation, and dietary interventions shows promise in optimizing immunotherapy efficacy, yet standardized clinical protocols remain lacking. Integrating GM profiling with multi-omics and artificial intelligence approaches offers a path toward personalized microbiota-targeted interventions to improve patient outcomes. This review critically summarizes current evidence linking GM to cancer immunotherapy, discusses mechanistic insights, and outlines future perspectives for translating microbiota modulation into clinical practice.

PMID:41873461 | DOI:10.1080/1750743X.2026.2648431

J Ethnopharmacol. 2026 Mar 21:121548. doi: 10.1016/j.jep.2026.121548. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: The Tingli Dazao Xiefei Decoction (TD) is a traditional phlegm-eliminating prescription composed of Descurainia sophia (L.) Webb. ex Prantl (TLZ) and Ziziphus jujuba Mill. (DZ), which can relieve lung, heart and kidney injury in asthma. TLZ acts as the monarch drug in the TD. Based on the research mode of "material basis of traditional Chinese medicinal properties can be divided and combined", we have confirmed that the flavonoid glycosides components /the oligosaccharide components/the fatty oil component (FG/Oli/FO) are effective components of TLZ. However, the compatibility mechanism of the TD, and the contribution of the effective components of TLZ to the efficacy were still unclear.

AIM OF THE STUDY: To clarify the compatibility mechanism of TD, and the contribution of the effective components of TLZ to the efficacy from a comprehensive perspective of lung, heart, and kidney.

METHODS: First, we chose the asthma model corresponding to the efficacy of TD in purging the lungs and relieving asthma, and the rats were divided into the normal (NC) group, model (M) group, dexamethasone (DEX) group, and treatment groups of TD/TLZ/DZ/FO+DZ/Oli+DZ/FG+DZ. Second, metabolomics and network pharmacology were applied to elucidate the comprehensive protective effect of TD/FG+DZ/Oli+DZ/FO+DZ. Third, the multi-omics results were validated using Western blotting, RT-qPCR, flow cytometry, and immunofluorescence.

RESULTS: FO+DZ/Oli+DZ/FG+DZ had different degrees of protective effects against lung/heart/kidney injury in asthma. In metabolomics research, the principal component analysis (PCA) and cluster analysis results showed that the TLZ group was closer to TD group than DZ group, the FO+DZ and Oli+DZ group clustered with TD/NC groups in the lung and kidney, and the FO+DZ and FG+DZ group clustered with TD/NC groups in the heart. Pathway enrichment analysis suggested that the comprehensive protective effect of TLZ and its effective components combined with DZ on lung/heart/kidney may be achieved by regulating the arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and unsaturated fatty acid biosynthesis. Multi-organ metabolomics and network pharmacology revealed consistent biological functions in KEGG pathways. Validation experiment showed that TLZ and its effective components combined with DZ could reverse the abnormal expression of proteins and RNA related to inflammation, airway remodeling, excitotoxicity, and energy-supply, apoptosis at different levels. Furthermore, FO+DZ may reduce asthma damage by inhibiting the FABP4/PPAR-γ/NF-κB signaling pathway.

CONCLUSION: TLZ played the key role in TD, and FO had the best therapeutic effect on each organ; the efficacy of Oli was mainly reflected in reducing lung and kidney damage, and FG was mainly involved in enhancing energy metabolism in the heart. These findings proved that traditional Chinese medicine could exert comprehensive efficacy in a 'multi-components trigger multi-channel' way.

PMID:41871629 | DOI:10.1016/j.jep.2026.121548

Sci China Life Sci. 2026 Mar 16. doi: 10.1007/s11427-025-3273-6. Online ahead of print.

ABSTRACT

Phenotypic diversity of malignant cells within a tumor underlies intratumor heterogeneity (ITH), a key determinant of cancer metastasis and treatment failure. However, the molecular mechanisms driving this heterogeneity are poorly understood. Here, we curated and analyzed a cohort of 3' tag-based single-cell RNA-seq covering 12 common cancer types. We identified thousands of poly(A) site (PAS) peaks representing the 3' ends of previously unannotated transcripts, whose expression is widely associated with diverse malignant cellular states. By integrating multi-omics data, we characterized the expression patterns and epigenetic landscape of these unannotated PAS peak-associated transcripts (UPTs). The expression heterogeneity of UPTs was supported by multi-region sampling bulk RNA-seq data and recapitulated within cancer cell lines. As proof of principle validation, functional experiments confirmed that two noncoding UPTs promoted the proliferation and migration of lung cancer cells. Our results suggest that epigenetic activation of unannotated noncoding transcripts might represent a previously unrecognized mechanism contributing to transcriptomic ITH.

PMID:41870780 | DOI:10.1007/s11427-025-3273-6

Discov Oncol. 2026 Mar 23. doi: 10.1007/s12672-026-04893-6. Online ahead of print.

ABSTRACT

BACKGROUND: Lung cancer remains the leading cause of cancer-related mortality worldwide. This study aimed to develop prognostic prediction models for lung squamous cell carcinoma (LUSC) through multi-omics integration using Mendelian randomization analysis.This study addresses a critical gap in lung cancer research through two complementary approaches in major lung cancer subtypes: (1) hypothesis-generating multi-omics analysis in LUSC to identify prognostic biomarkers and characterize the metabolic-immune landscape. This integrated framework provides both predictive tools for personalized medicine and mechanistic insights into metabolic causality.

METHODS: Multi-omics analysis was performed using TCGA data, including RNA-seq, DNA methylation, and whole-exome sequencing. Machine learning models incorporating 15 algorithms were developed and externally validated in two independent GEO cohorts. Mendelian randomization analysis assessed causal relationships between 32 lipid metabolites and SCLC risk. RT-qPCR experiments validated key prognostic genes in lung squamous cell carcinoma (LUSC) cell lines.

RESULTS: The optimal machine learning model (StepCox [forward] + Random Survival Forest) demonstrated superior performance with C-index of 0.73 in internal testing and 0.71 and 0.68 in external validation cohorts. High CD8 + T cell and M1 macrophage infiltration was associated with favorable prognosis. Most lipid metabolites showed no significant causal associations with SCLC risk after multiple testing correction, though two phosphatidylcholine metabolites demonstrated potential protective effects. RT-qPCR validation confirmed significant upregulation of all four key genes in LUSC cell lines.

CONCLUSIONS: This study successfully developed robust machine learning-based prognostic models for LUSC with clinical utility for risk stratification and provided evidence that lipid alterations in lung cancer are likely downstream consequences rather than causal drivers of tumorigenesis.

PMID:41870745 | DOI:10.1007/s12672-026-04893-6

J Cancer. 2026 Mar 4;17(3):614-625. doi: 10.7150/jca.127511. eCollection 2026.

ABSTRACT

Malignant pleural effusion (MPE) and malignant ascites (MA) are common complications in advanced-stage cancers, often signifying disease progression and resistance to treatment. Compared to tissue biopsies or surgical specimens, materials derived from effusions offer advantages such as minimal invasiveness, ease of accessibility, and the feasibility of repeated collection during therapeutic interventions. Organoids generated from tumor cells in effusions, termed fluid-derived organoids (FDOs), have demonstrated the ability to maintain genetic heterogeneity and accurately replicate patient-specific tumor phenotypes. These characteristics position FDOs as promising models for investigating drug resistance mechanisms and informing personalized oncology strategies. In the context of lung cancer, organoids derived from pleural effusions have been employed to study acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and immunotherapy. Similarly, in ovarian and gastrointestinal cancers, organoids derived from ascites have proven to be valuable platforms for examining chemotherapy resistance and conducting drug sensitivity testing. FDOs have shown significant potential for translational applications by effectively correlating ex vivo drug responses with clinical outcomes, thus facilitating real-time monitoring of resistance evolution. However, several challenges remain, such as achieving culture standardization, maintaining the integrity of tumor microenvironment components, and integrating with multi-omics approaches. This review provides a comprehensive overview of recent advancements in the use of pleural effusion- and ascites-derived organoids for drug resistance research, underscores their applications in personalized oncology, and explores future research directions.

PMID:41869438 | PMC:PMC13003542 | DOI:10.7150/jca.127511

Int J Chron Obstruct Pulmon Dis. 2026 Jan 17;21:553092. doi: 10.2147/COPD.S553092. eCollection 2026.

ABSTRACT

BACKGROUND: As a relatively common respiratory disease, chronic obstructive pulmonary disease (COPD) has a high incidence and mortality rate. Mitochondrial dysfunction has been implicated in COPD pathogenesis, but the causal genes and underlying molecular mechanisms remain unclear.

METHODS: We performed a summary data-based Mendelian Randomization (SMR) study integrating summary data from genome-wide association studies (GWAS) with blood-based methylation (mQTL), expression (eQTL), and protein quantitative trait loci (pQTL) to identify mitochondrial-related genes causally associated with COPD. Significant findings were validated using two-sample MR, independent lung tissue transcriptomic data (GSE76925), and weighted gene co-expression network analysis (WGCNA) to assess transcriptional consistency and functional convergence.

RESULTS: Our integrative SMR and colocalization analyses identified 77 mitochondrial genes linked to COPD risk, including GPX1, TUFM, COQ5, BPHL, and NAGS. A methylation-to-expression regulatory cascade was observed, with hypermethylation at GPX1 cg24011261 associated with increased gene expression and higher COPD risk-despite its role as an antioxidant enzyme. Two-sample MR confirmed robust causal effects of GPX1, BPHL, TUFM and COQ5 expression on COPD. These findings were replicated in lung tissue: GPX1, COQ5, and TUFM were significantly upregulated in COPD patients (GSE76925). WGCNA revealed that these genes reside within a highly interconnected turquoise module strongly correlated with COPD status (r = 0.43, p < 0.001) and enriched in oxidative phosphorylation and mitochondrial energy metabolism pathways.

CONCLUSION: This study provides systematic genetic and transcriptomic evidence that mitochondrial-related genes, particularly GPX1 and TUFM, exert causal effects on COPD risk through regulatory cascades and coordinated network dysregulation. The convergence of genetic, epigenetic, and co-expression evidence underscores mitochondrial dysfunction as a central mechanism in COPD pathogenesis and highlights potential targets for future therapeutic development.

PMID:41868721 | PMC:PMC13003660 | DOI:10.2147/COPD.S553092

J Inflamm Res. 2026 Mar 17;19:581764. doi: 10.2147/JIR.S581764. eCollection 2026.

ABSTRACT

Immune checkpoint inhibitors (ICIs) have significantly improved the clinical outcomes for patients with non-small cell lung cancer (NSCLC). However, patient heterogeneity and the limitations of current biomarkers contribute to variations in therapeutic responses. Identifying potential beneficiaries of immunotherapy and predicting efficacy remain critical challenges. In recent years, artificial intelligence (AI) has become increasingly applied in cancer treatment, particularly for modeling clinical data and predicting patient prognosis. By integrating multi-omics data such as radiomics, pathomics, genomics, transcriptomics, proteomics, and microbiomics, AI enables comprehensive biomarker discovery and facilitates prediction of immunotherapy responses and potential toxicities in NSCLC patients. Despite these advancements, challenges such as data standardization, limited interpretability, and technical barriers persist. This review summarizes the application of AI in predicting immunotherapy efficacy for NSCLC patients and discusses the challenges and future directions in the context of precision medicine.

PMID:41867453 | PMC:PMC13005593 | DOI:10.2147/JIR.S581764

Curr Med Chem. 2026 Mar 17. doi: 10.2174/0109298673415187251212085809. Online ahead of print.

ABSTRACT

BACKGROUND: Solanum incanum L. (S. incanum) is a Traditional Chinese Medicine (TCM) known for its heat-clearing and detoxifying properties. This study evaluates the anti-cancer potential of S. incanum in lung and colorectal adenocarcinoma. Also, we aim to confirm the connection between the lung and the large intestine, as proposed in TCM theory.

METHODS: This study employed network pharmacology analysis, MTT and morphological analysis, Western blotting, and molecular docking to investigate the anti-cancer effects of S. incanum, particularly through its activation of the TRAIL-mediated extrinsic apoptotic pathway.

RESULTS: This study identified 15 active compounds in S. incanum, with glycosylated alkaloids such as α-solanine and solasonine highlighted as key bioactive compounds. KEGG and GO analyses revealed that S. incanum influences apoptosis-related pathways, particularly the extrinsic apoptotic pathway, regulating mediators such as CASP3, CASP8, and various TNF- related receptors. The anticancer potential was assessed through cellular studies using A549 and HT29 cell lines, with MTT cell viability assays showing that α-solanine induces apoptosis, with IC50 values between 20 and 30 μM. Western blot analysis demonstrated that S. incanum activates apoptosis via the TRAIL-mediated extrinsic apoptotic pathway, promoting CASP8, CASP3, and PARP1 cleavage in a dose-dependent manner, affecting DNA synthesis. Molecular docking further identified α-solanine and solasonine as compounds that bind to critical proteins in the TRAIL-related apoptotic pathway, confirming their roles in promoting apoptosis.

DISCUSSION: The shared activation of the TRAIL-mediated apoptotic pathway in both lung and colorectal adenocarcinoma models suggests a common molecular mechanism. These findings provide experimental evidence linking traditional ethnopharmacological concepts with apoptosis-related anti-cancer activity.

CONCLUSIONS: This study emphasizes that the main compound of S. incanum, α-solanine, supports the ethnopharmacological concept of "Exterior-interior Pairing of the Lung and Large Intestine", thereby demonstrating that both lung and colorectal adenocarcinomas share a common anticancer pathway through a TRAIL-related apoptotic mechanism.

PMID:41863159 | DOI:10.2174/0109298673415187251212085809

J Transl Med. 2026 Mar 20. doi: 10.1186/s12967-026-08022-3. Online ahead of print.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) is a predominant contributor to cancer‑related mortality globally. Lung‑associated fibroblasts (LAFs) are intricately linked to tumorigenesis and the tumor microenvironment (TME), but their heterogeneity and prognostic relevance in LUAD remain incompletely understood. This study aimed to systematically characterize LAF subsets across the spectrum of pulmonary disease, identify LAF subpopulations associated with LUAD prognosis, and construct a robust LAF‑based prognostic signature.

METHODS: We employed a multi-omics approach, leveraging bulk RNA data of 2719 patients from 19 LUAD cohorts, single-cell RNA (scRNA) sequencing data of 368,904 cells from 93 samples, and spatial transcriptomics data of 15,673 spots from 6 samples to characterize the landscape of LAFs across various stages of pulmonary disease. We employed multiple advanced machine learning algorithms to construct and validate a robust nuclear division LAFs (nLAFs) risk score (nLRS) prediction model.

RESULTS: We observed a dynamic and gradual increase in the proportion of LAFs during the progression of LUAD. Throughout this process, we identified nine LAFs subtypes and found nLAFs are significantly associated with the prognosis of LUAD. Utilizing 100 machine learning algorithm combinations and integrating nLAFs marker genes, we developed a five gene based nLRS model, which demonstrated superior performance than other 49 published models in predicting clinical outcomes for LUAD. Additionally, we observed distinct biological functions and immune cell infiltration in the TME between high and low nLRS groups. Exploratory analysis of pan-cancer immunotherapy cohorts suggested that patients with high nLRS scores may exhibit resistance to immunotherapy in some cancer types, but prospective validation in LUAD-specific cohorts is required. Conversely, high nLRS patients displayed increased sensitivity to chemotherapeutic and targeted therapies in preclinical models.

CONCLUSION: Our study introduces a candidate five-gene signature derived from nLAFs that may serve as a robust prognostic biomarker pending prospective validation, offering insights into personalized therapeutic strategies for LUAD patients.

PMID:41862916 | DOI:10.1186/s12967-026-08022-3

Nat Commun. 2026 Mar 20;17(1):2655. doi: 10.1038/s41467-026-70193-w.

ABSTRACT

Pulmonary fibrosis represents a progressive interstitial lung disease marked by excessive extracellular matrix deposition and architectural distortion. Vascular endothelial cells critically contribute to fibrogenesis through paracrine secretion of pro-fibrotic mediators, yet their mechanobiological regulation remains elusive. Using integrated single-cell multi-omics profiling of human pulmonary fibrosis specimens and experimental fibrosis models induced by bleomycin or silica, we identify mechanosensitive Piezo1 upregulation in Endothelial cells as a hallmark of fibrotic progression. Endothelial-specific Piezo1 knockout significantly attenuates Bleomycin-induced fibrotic remodeling in male mice, establishing its pathogenic necessity. Mechanistically, PIEZO1 activation promotes pulmonary fibrosis development via CAPN2-mediated STAT3 phosphorylation, which may regulate the secretion of the pro-fibrotic molecule interleukin-33. These findings suggest that the endothelial PIEZO1-CAPN2-STAT3-IL33 axis is a potential therapeutic target for PF intervention.

PMID:41862476 | PMC:PMC13004862 | DOI:10.1038/s41467-026-70193-w

Redox Biol. 2026 Jan 14;92:104026. doi: 10.1016/j.redox.2026.104026. Online ahead of print.

ABSTRACT

Primary graft dysfunction (PGD) caused by ischemia-reperfusion injury (IRI) is a major complication after lung transplantation, yet its underlying mechanisms remain unclear. Triggering receptor expressed on myeloid cells 1 (Trem1) is an important mediator of inflammation, but its role in neutrophil function and metabolic reprogramming during lung IRI is not well understood. In this study, we used a murine orthotopic lung transplantation model with cold ischemia and reperfusion, and Trem1 knockout (Trem1-/-) and myeloid-specific Trem1 conditional knockout mice (Lysm^CreTrem1^fl) to explore the role of Trem1 in neutrophil recruitment, neutrophil extracellular trap (NET) formation, and metabolism. Our results show that Trem1 expression increases in both mouse and human lungs after reperfusion and correlates with neutrophil infiltration and lung injury. Trem1 deficiency significantly reduced neutrophil and macrophage recruitment, NET formation, and tissue damage. Multi-omics analysis revealed that Trem1 deletion suppressed oxidative phosphorylation (OXPHOS) and induced a metabolic shift in neutrophils toward glycolysis. In clinical samples, the abundance of TREM1+ neutrophils was correlated with PGD severity and OXPHOS activity. These findings identify Trem1 as a key regulator of neutrophil metabolism and recruitment in lung IRI, and suggest that targeting Trem1 may provide a novel therapeutic strategy to mitigate PGD and improve lung transplant outcomes.

PMID:41861599 | DOI:10.1016/j.redox.2026.104026

Drug Des Devel Ther. 2026 Jan 6;20:565059. doi: 10.2147/DDDT.S565059. eCollection 2026.

ABSTRACT

Osteosarcoma is a primary bone malignancy of adolescents and young adults with marked heterogeneity and a high metastatic propensity. Five-year survival exceeds 70% in localized disease but falls to about 20% with pulmonary metastasis or chemoresistance, and overall outcomes have plateaued for decades. Extracellular vesicles (EVs) have emerged as critical mediators of osteosarcoma progression and metastasis. EVs remodel the tumor microenvironment (TME) by promoting immune evasion, extracellular matrix reprogramming, and angiogenesis, while also facilitating invasion, epithelial-mesenchymal transition (EMT)-like plasticity, and formation of lung pre-metastatic niches through organotropic integrins and glycoproteins. Their cargo, including proteins, lipids, and nucleic acids, drives intercellular communication that sustains proliferation, migration, and therapy resistance under metabolic or hypoxic stress. Clinically, the stability of EVs in body fluids and their tumor-specific molecular signatures highlight their promise as liquid-biopsy biomarkers for early diagnosis, prognosis, and treatment monitoring. Therapeutically, EVs are being engineered as delivery vehicles for drugs or RNA therapeutics, and interventions targeting their biogenesis, cargo sorting, or uptake are under exploration. Future research should integrate single-EV multi-omics, longitudinal cohort validation, and causal perturbation models to delineate functional mechanisms. Rational strategies that modulate EV dynamics and incorporate standardized analytic pipelines may transform EVs into actionable biomarkers and therapeutic targets, offering new avenues to overcome resistance and improve clinical outcomes in osteosarcoma.

PMID:41858917 | PMC:PMC12998350 | DOI:10.2147/DDDT.S565059

Eur Respir J. 2026 Mar 19;67(3):2502148. doi: 10.1183/13993003.02148-2025. Print 2026 Mar.

ABSTRACT

While PAK2 marks fibrotic fibroblast niches in IPF, causal validation, multicellular contextualisation and lung-targeted delivery are required before clinical translation. Spatial omics should guide not only discovery but also therapeutic decision-making. https://bit.ly/4hqQS3F

PMID:41856567 | PMC:PMC13000392 | DOI:10.1183/13993003.02148-2025

Clin Cancer Res. 2026 Mar 18. doi: 10.1158/1078-0432.CCR-25-4153. Online ahead of print.

ABSTRACT

PURPOSE: Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear.

EXPERIMENTAL DESIGN: This multicenter retrospective and prospective study included mNSCLC patients receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into <1 Gy, 1-3 Gy, and >3 Gy groups and treatment outcomes were compared. The blood and fecal samples were subjected to multi-omics profiling.

RESULTS: g>309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1-3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months) (P < 0.01), which was consistent across subgroups. Compared with 1-3 Gy, SIMRD >3 Gy (Hazard ratio [HR] = 4.87, P < 0.001) and <1 Gy (HR = 1.85, P < 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1-3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1-3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells.

CONCLUSIONS: ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1-3 Gy range, likely through modulation of the gut microbiota-metabolite-immune axis.

PMID:41849236 | DOI:10.1158/1078-0432.CCR-25-4153