Cytokine. 2026 Apr 6;202:157144. doi: 10.1016/j.cyto.2026.157144. Online ahead of print.

ABSTRACT

BACKGROUND: The remodeling of the tumor immune microenvironment (TME) is a pivotal determinant of therapeutic efficacy and clinical outcome in Lung Adenocarcinoma (LUAD). While WNT signaling is a known oncogenic driver, the specific immunomodulatory role of WNT7A and its potential crosstalk with inflammatory pathways in LUAD remain to be fully elucidated. We sought to define the prognostic value of WNT7A and explore the molecular mechanisms by which it may foster an immunosuppressive TME.

METHODS: We performed a multi-omics analysis utilizing the TCGA-LUAD cohort (N = 508) and validated findings in an independent external cohort (GSE30219, N = 293). The prognostic significance of WNT7A was evaluated using Kaplan-Meier and multivariate Cox regression analyses. TME composition was dissected via ssGSEA, focusing on myeloid-derived suppressor cell (MDSC) infiltration. Mechanistic pathways were identified using Gene Set Enrichment Analysis (GSEA) and gene co-expression networks.

RESULTS: High WNT7A expression was identified as a significant predictor of poor Overall Survival (OS) in the TCGA cohort (P < 0.05) and validated in the external cohort (P < 0.05). Multivariate analysis confirmed WNT7A as an independent prognostic risk factor (HR = 1.085, P = 0.036). Immunologically, WNT7A expression was positively correlated with MDSC infiltration (R = 0.43, P < 0.001), suggesting a shift towards an immune-tolerant phenotype. Mechanistically, GSEA revealed a robust activation of inflammatory signaling in the high-WNT7A group. Specifically, the TNFA Signaling via NF-κB pathway was significantly enriched(NES = 2.52, P < 0.001). Consistent with this pathway activation, WNT7A showed a statistically significant positive correlation with CCL2 (P < 0.001), a critical chemokine for MDSC recruitment, implicating the NF-κB/CCL2 axis in this process.

CONCLUSION: WNT7A serves as a prognostic biomarker linked to immune evasion in LUAD, potentially by modulating the NF-κB/CCL2/MDSC axis. This study identifies WNT7A as a potential therapeutic target to remodel the immune microenvironment, providing a rationale for future investigations into WNT-targeted strategies to improve immunotherapy efficacy.

PMID:41946008 | DOI:10.1016/j.cyto.2026.157144

Cancer Immunol Immunother. 2026 Apr 2;75(4):131. doi: 10.1007/s00262-026-04374-3.

ABSTRACT

Immunotherapy has revolutionized cancer treatment, yet characterizing the spatial complexity of the tumor immune microenvironment remains a challenge. In this study, we established a comprehensive computational framework integrating multi-omics profiling across 27 cancer types to decode immune-related non-coding RNA regulatory networks. Moving beyond traditional bulk analysis, we utilized spatial transcriptomics to dissect the spatial localization of these regulators. We identified the SNHG6-BIRC5 axis as a critical driver of the "immune-cold" phenotype in lung adenocarcinoma. We provide visual evidence that this axis localizes to tumor nests and negatively correlates with T- cell infiltration, elucidating a mechanism of spatial immune exclusion. Validating the clinical relevance of these findings, genome-scale CRISPR-Cas9 screening data confirmed the functional essentiality of these targets for cancer cell survival. Furthermore, pharmacogenomic analysis revealed that high expression of this axis correlates with sensitivity to chemotherapy agents like Vinblastine, suggesting a potential stratification strategy for patients with immune-excluded tumors. To expand the clinical utility to immunotherapy prediction, we developed a pan-cancer XGBoost machine learning model incorporating 14 high-performance regulatory features. This model achieved robust performance in distinguishing immunotherapy responders from non-responders with an AUC of 0.771, outperforming traditional markers such as PD-L1. Collectively, this study highlights spatial determinants of immune exclusion and chemotherapy sensitivity- and presents a generalized machine- learning tool for precision immunotherapy stratification. The developed online resource is freely available to facilitate community-wide biomarker discovery.

PMID:41925746 | PMC:PMC13046951 | DOI:10.1007/s00262-026-04374-3

EMBO Mol Med. 2026 Mar 30. doi: 10.1038/s44321-026-00410-y. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) comprising 20-30% of cases. Immunochemotherapy (IC) is the standard first-line treatment for advanced LUSC, yet reliable predictors of therapeutic response remain unavailable. Using single-cell multi-omics profiling of paired pre- and post-treatment tumor and blood samples, we observed that patients responding to IC exhibited significantly higher baseline levels of peripheral blood monocytes, tumor-infiltrating classical monocytes, and APOBEC3A+ monocytes across both compartments compared with non-responders. These associations were independently validated in additional cohorts using routine complete blood count testing and multiplex immunofluorescence analysis of native tumor tissues. Our findings reveal monocyte-related parameters as clinically accessible indicators that link systemic immunity with the tumor microenvironment and hold promise for predicting IC responsiveness in patients with LUSC.

PMID:41912871 | DOI:10.1038/s44321-026-00410-y

Comb Chem High Throughput Screen. 2026 Mar 11. doi: 10.2174/0113862073398293251205055042. Online ahead of print.

ABSTRACT

INTRODUCTION: This study aimed to investigate the protective effects of Siji Kangbingdu Mixture (SKM) against acute lung injury (ALI) in mice and to elucidate its underlying mechanisms.

METHODS: ALI was induced in Kunming mice via intranasal administration of LPS (5 mg/kg), followed by oral SKM treatment for 7 days. Lung wet-to-dry (W/D) ratio, histopathology, multiomics analysis, and network pharmacology were performed. Key targets and pathways were identified through dynamic KEGG analysis and validated by Western blotting.

RESULTS: SKM treatment ameliorated alveolar hemorrhage, alveolar wall disruption, septal thickening, edema, and inflammatory cell infiltration. Integrated multi-omics analysis revealed that SKM primarily modulated the Ras signaling pathway, reducing the protein expression of Phospho- MEK1/2, Raf1, Phospho-ERK1/2, and RASH/RASK/RASN, thereby contributing to the treatment of ALI.

DISCUSSION: SKM alleviated LPS-induced ALI in mice by inhibiting the Ras pathway, highlighting the pathway's role in ALI pathogenesis. However, due to limitations of the animal model and incomplete validation, further studies combining clinical research and in vitro experiments are needed to confirm its efficacy and mechanism.

CONCLUSIONS: SKM shows potential to ameliorate ALI by suppressing inflammatory responses and reducing local tissue fibrosis. The combination of metabolomics, transcriptomics, and network pharmacology elucidated its mechanism, while Western blot analysis suggested that its therapeutic effect is associated with downregulation of the Ras signaling pathway.

PMID:41830142 | DOI:10.2174/0113862073398293251205055042