Nat Commun. 2026 Aug 7;17(1):9491. doi: 10.1038/s41467-026-76495-3.

ABSTRACT

Cancer-associated fibroblasts comprise diverse functionally distinct cellular subsets, with certain subpopulations exerting pivotal influence in shaping the pancreatic cancer immune microenvironment. Here we show that Lin28b⁺ cancer-associated fibroblasts contribute to establishing an immunologically cold tumor microenvironment in pancreatic ductal adenocarcinoma. Mechanistically, Lin28b directly binds to STING mRNA and promotes its degradation, thereby suppressing STING expression and downstream type I interferon signaling. Loss of Lin28b in cancer-associated fibroblasts activates the cGAS-STING-interferon signaling cascade, enhancing dendritic cell antigen presentation and CD8⁺ T cell cytotoxic function. Importantly, genetic inhibition of Lin28b in cancer-associated fibroblasts enhances sensitivity to anti-PD-L1 immune checkpoint blockade therapy. These findings reveal that targeting the Lin28b-STING axis represents a promising therapeutic strategy for overcoming the intrinsic resistance of pancreatic ductal adenocarcinoma to immunotherapy.

PMID:42693143 | PMC:PMC13542369 | DOI:10.1038/s41467-026-76495-3

J Thorac Dis. 2026 Apr 30;18(4):415. doi: 10.21037/jtd-2026-1-0025. Epub 2026 Apr 24.

ABSTRACT

BACKGROUND AND OBJECTIVE: Circulating tumor cells (CTCs) are malignant cells shed into blood that enable noninvasive, longitudinal assessment of lung cancer. Increasing evidence frames CTCs within a circulating tumor microenvironment (cTME) and broader circulating tumor-associated cell (CTAC) ecosystems that include multicellular clusters and circulating tumor endothelial cells (CTECs). We summarize definitions, detection approaches, and clinical applications of CTC-centered liquid biopsy in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

METHODS: A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and Google Scholar using the terms "non-small cell lung cancer", "small cell lung cancer", and "circulating tumor cells". Relevant clinical, basic, and translational studies were selected and synthesized to outline current knowledge and future directions.

KEY CONTENT AND FINDINGS: CTCs can be enriched by immunoaffinity, size, or microfluidic platforms, enabling enumeration and downstream profiling. In both NSCLC and SCLC, CTC positivity and higher burden are associated with worse survival, with the strongest effects in SCLC and with circulating tumor emboli (CTE). Serial monitoring provides early signals of response or failure; and post-treatment supports minimal residual disease (MRD) detection and relapse prediction. Molecular and phenotypic profiling enables driver and resistance tracking, including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), while CTECs may add vascular and immune-relevant information.

CONCLUSIONS: CTC-based assays have the potential to complement imaging and tissue biopsy across screening research, prognostication, therapeutic monitoring, MRD assessment, and personalized care. Clinical translation requires standardized preanalytical workflows, harmonized thresholds, and prospective trials testing CTC-guided management.

PMID:42182710 | PMC:PMC13190041 | DOI:10.21037/jtd-2026-1-0025

Front Immunol. 2026 May 8;17:1762222. doi: 10.3389/fimmu.2026.1762222. eCollection 2026.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) exhibits profound molecular heterogeneity and aberrant cellular senescence. This study systematically dissects the senescence-associated molecular landscape to identify key regulators driving HCC progression and immune evasion.

METHODS: Integrating multi-cohort transcriptomic datasets, we developed a robust prognostic signature using 101 machine-learning models, identifying prognostic signature. We employed preliminary proteomic, exploratory metabolomic, and single-cell RNA sequencing (scRNA-seq) analyses to explore multi-omics alterations. The functional senescence status and MCM7 were validated in a clinical HCC cohort by RT-qPCR, Western blotting, immunohistochemistry, and multiplex immunofluorescence (mIF). Causality was established using in vitro functional assays in HepG2 cells.

RESULTS: A 12-gene random survival forest (RSF) signature accurately predicted patient survival across independent cohorts. MCM7 emerged as a central senescence-associated driver. ScRNA-seq and mIF confirmed MCM7 characterizes a highly proliferative, clonally expanding subset of CD8⁺ T cells within the tumor microenvironment. In vitro, MCM7 knockdown significantly inhibited HepG2 cell proliferation and upregulated senescence enforcers p16 and p21, whereas overexpression facilitated evasion. Additionally, TIDE analysis revealed that high-risk patients exhibited elevated immune evasion potential, predicting poor immunotherapy response.

CONCLUSION: This integrative multi-omics framework uncovers an MCM7 MCM7-driven senescence-associated axis promising HCC progression and immune dysfunction, offering a robust tool for prognostic stratification and novel therapeutic insights.

PMID:42183188 | PMC:PMC13195000 | DOI:10.3389/fimmu.2026.1762222

Front Immunol. 2026 May 8;17:1762222. doi: 10.3389/fimmu.2026.1762222. eCollection 2026.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) exhibits profound molecular heterogeneity and aberrant cellular senescence. This study systematically dissects the senescence-associated molecular landscape to identify key regulators driving HCC progression and immune evasion.

METHODS: Integrating multi-cohort transcriptomic datasets, we developed a robust prognostic signature using 101 machine-learning models, identifying prognostic signature. We employed preliminary proteomic, exploratory metabolomic, and single-cell RNA sequencing (scRNA-seq) analyses to explore multi-omics alterations. The functional senescence status and MCM7 were validated in a clinical HCC cohort by RT-qPCR, Western blotting, immunohistochemistry, and multiplex immunofluorescence (mIF). Causality was established using in vitro functional assays in HepG2 cells.

RESULTS: A 12-gene random survival forest (RSF) signature accurately predicted patient survival across independent cohorts. MCM7 emerged as a central senescence-associated driver. ScRNA-seq and mIF confirmed MCM7 characterizes a highly proliferative, clonally expanding subset of CD8⁺ T cells within the tumor microenvironment. In vitro, MCM7 knockdown significantly inhibited HepG2 cell proliferation and upregulated senescence enforcers p16 and p21, whereas overexpression facilitated evasion. Additionally, TIDE analysis revealed that high-risk patients exhibited elevated immune evasion potential, predicting poor immunotherapy response.

CONCLUSION: This integrative multi-omics framework uncovers an MCM7 MCM7-driven senescence-associated axis promising HCC progression and immune dysfunction, offering a robust tool for prognostic stratification and novel therapeutic insights.

PMID:42183188 | PMC:PMC13195000 | DOI:10.3389/fimmu.2026.1762222

Biosci Trends. 2026 May 21. doi: 10.5582/bst.2026.01000. Online ahead of print.

ABSTRACT

Oncolytic adenovirus H101 has shown antitumor activity in hepatocellular carcinoma (HCC), but the molecular determinants of treatment response remain unclear. In this study, a Hepa1-6 subcutaneous tumor model was established in C57BL/6 mice and treated with intratumoral H101, followed by integrated transcriptomic and proteomic analyses to identify candidate genes associated with H101 response. PRXL2B was selected for further investigation using public multi-omics datasets, tissue microarray-based immunohistochemistry, in vitro functional assays, mechanistic analyses, and in vivo validation experiments. Integrated multi-omics analyses identified PRXL2B as a candidate gene downregulated after H101 treatment. Public datasets and tissue-based validation further showed that PRXL2B was upregulated in HCC tissues. In MHCC97H and HCCLM3 cells, PRXL2B knockdown inhibited proliferation, migration, and invasion, promoted apoptosis and cell-cycle arrest, and enhanced the antitumor effect of H101. Mechanistically, PRXL2B silencing reduced AKT phosphorylation and PD-L1 expression. In vivo, PRXL2B knockdown suppressed tumor growth, and the combination of PRXL2B knockdown and H101 produced the strongest antitumor effect. These findings indicate that PRXL2B promotes malignant phenotypes in HCC and may modulate H101 efficacy through the PI3K/AKT/PD-L1 axis. Targeting PRXL2B may therefore represent a potential strategy to enhance the therapeutic efficacy of oncolytic virus therapy in HCC.

PMID:42161529 | DOI:10.5582/bst.2026.01000

Chin Med J (Engl). 2026 May 19. doi: 10.1097/CM9.0000000000004098. Online ahead of print.

ABSTRACT

High-salt diet (HSD) has emerged as a prevalent environmental factor that exacerbates chronic inflammation and insulin resistance in obesity-associated type 2 diabetes (T2D) by modulating macrophage polarization, metabolic reprogramming, and epigenetic imprinting. Current evidence demonstrates that HSD activates p38/mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways, by which it drives macrophage polarization toward a proinflammatory M1 phenotype while inducing a glycolysis-dominant metabolic shift, thereby establishing a persistent "metabolic memory". Moreover, HSD orchestrates metabolic memory in macrophages through coordinated epigenetic machinery, including histone modifications (Trimethylation of histone H3 at lysine 4 [H3K4me3] and Acetylation of histone H3 at lysine 27 [H3K27ac]), DNA methylation, and noncoding RNAs (e.g., long non-coding RNA MALAT1 and miR-155), leading to sustained inflammatory phenotypes. In multiple metabolic organs (e.g., adipose tissue, liver, pancreas, and gut), the HSD-macrophage axis aggravates systemic insulin resistance through shared proinflammatory signaling and other tissue-specific mechanisms. Most importantly, therapeutic strategies targeting the NLRP3 inflammasome, metabolic pathways, and epigenetic alterations offer novel approaches for managing metabolic inflammation. Future investigations are encouraged to leverage lineage tracing, single-cell sequencing, and spatial multi-omics technologies to advance the development of precision medicine for macrophage-associated metabolic disorders.

PMID:42156155 | DOI:10.1097/CM9.0000000000004098

J Multidiscip Healthc. 2026 Mar 11;19:584071. doi: 10.2147/JMDH.S584071. eCollection 2026.

ABSTRACT

Non-small cell lung cancer (NSCLC) is one of the malignant tumors with the highest incidence and mortality rates. Zeqi Decoction has the functions of "promoting diuresis and reducing swelling, resolving phlegm and dispersing nodules", embodying the unique approach of traditional Chinese medicine in treating lung cancer by "strengthening the body's resistance and eliminating pathogenic factors". Modern research shows that Zeqi Decoction exerts anti-NSCLC effects through multiple pathways and targets. In terms of the material basis of its efficacy, its active ingredients (such as diterpene esters and flavonoids contained in Zeqi) have the ability to directly inhibit the proliferation, invasion and migration of tumor cells and induce apoptosis. In terms of the mechanism of action, basic experiments have revealed that Zeqi Decoction can down-regulate the S100A9/STAT3 signaling pathway, inhibit the immunosuppressive activity of myelium-derived suppressor cells (MDSCs), reshape the tumor microenvironment, thereby enhancing the cytotoxic function of CD8⁺T cells, and can also regulate the EGFR/PI3K/Akt pathway to affect PD-L1 expression. Intervene in tumor immune escape; In terms of clinical transformation, the combination of Zexi Decoction with chemotherapy and targeted therapy can improve patients' symptoms such as cough and pleural effusion, prolong progression-free survival, and alleviate the toxic and side effects of Western medical treatment. In addition, Zexi Decoction also shows potential value in reversing drug resistance such as gemcitabine. At present, there are still problems such as the lack of standardized protocols and unclear molecular mechanisms in the research. In the future, it is necessary to combine new technologies such as network pharmacology and multi-omics analysis to deepen the research on the pharmacological material basis, dose-effect relationship and evidence-based medicine of Zeqi Decoction, so as to promote the clinical application and transformation of the combination of traditional Chinese and Western medicine in the treatment of NSCLC.

PMID:41847115 | PMC:PMC12991379 | DOI:10.2147/JMDH.S584071