Gut. 2026 Jan 13:gutjnl-2025-335683. doi: 10.1136/gutjnl-2025-335683. Online ahead of print.

ABSTRACT

BACKGROUND: Accumulating evidence has demonstrated that distinct tumour-promoting and tumour-restraining cancer-associated fibroblast (CAF) subtypes coexist in pancreatic ductal adenocarcinoma.

OBJECTIVE: To develop targeted CAF therapeutic strategies by reprogramming tumour-promoting CAF subtypes.

DESIGN: We leveraged multiomics technologies to systematically identify and characterise CAF subtypes transcriptionally, epigenetically and spatially and correlate them with clinicopathological features.

RESULTS: We found that complement-secreting CAFs (csCAFs), initially identified by our group and inflammatory CAFs (iCAFs) share significant overlap in their transcriptional profiles and chromatin accessibility. iCAFs specifically express transcription factors from the heme and oxidative homeostasis pathway and the activator protein 1 family, which are both involved in cellular response to oxidative stress. Notably, the composition of csCAFs among all CAFs declined during pancreatic carcinogenesis, while trajectory analysis showed that csCAFs could potentially differentiate into iCAFs. Spatially resolved analysis indicated that tumour regions with a higher csCAF composition were associated with lower levels of TGF-β ligands, fewer M2 tumour-associated macrophages and increased levels of lipid mediators. Additionally, we identified a spatially defined CXCL12-CXCR4 ligand-receptor interaction between csCAFs and T cells, but in distinct patterns between different metastatic organs. Patients with a higher composition of csCAFs have significantly longer overall survival and recurrence-free survival through multiplex immunohistochemistry and bulk RNA-seq deconvolution.

CONCLUSION: Our study demonstrates that csCAFs may represent an early-stage iCAF subtype and suggests a promising strategy for reprogramming iCAFs into csCAFs.

PMID:41534892 | DOI:10.1136/gutjnl-2025-335683

Discov Oncol. 2026 Jan 5. doi: 10.1007/s12672-025-04366-2. Online ahead of print.

ABSTRACT

BACKGROUND: Emerging evidence highlights the overexpression of Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) in multiple malignancies. However, its pan-cancer prognostic significance, tumor immune microenvironment (TIME) interactions, and therapeutic implications remain underexplored.

METHODS: Multi-omics data were integrated from UCSC Xena, GTEx, UALCAN, and published cohorts. PCMT1 expression patterns were systematically analyzed across 33 cancer types. Associations between PCMT1 and clinical outcomes, immune infiltration, immune checkpoint genes (ICGs), tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity were evaluated using bioinformatics pipelines.

RESULTS: Our pan-cancer analysis revealed differential expression patterns of PCMT1 across various malignancies, with significant upregulation in 20 cancer types and downregulation in 3 cancer types. Notably, PCMT1 overexpression was predominantly observed in epithelial-origin tumors, such as ACC (adrenocortical carcinoma), BRCA (breast invasive carcinoma), COAD (colon adenocarcinoma), and LUAD (lung adenocarcinoma). Survival analysis demonstrated that elevated PCMT1 expression was significantly correlated with unfavorable prognosis in multiple epithelial tumors, particularly in BRCA, esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and mesothelioma (MESO). Furthermore, comprehensive analysis identified significant associations between PCMT1 expression and various tumor microenvironment features, including immune scores, six distinct immune cell types, four immunosuppressive cell populations, cancer-associated fibroblasts (CAFs)-related markers, and immunosuppressive factors. PCMT1 expression also showed significant correlations with tumor mutation burden (TMB), microsatellite instability (MSI), DNA stemness score (DNAss), and RNA stemness score (RNAss). Particularly noteworthy was the strong positive correlation between PCMT1 expression and CAFs infiltration, along with their associated factors. These findings were further validated in independent immunotherapy cohorts, where PCMT1 consistently demonstrated immunosuppressive characteristics.

CONCLUSION: Multi-omics analysis suggests that PCMT1 may serve as a potential prognostic biomarker and a novel immunotherapy target for pan-cancer.

PMID:41491065 | DOI:10.1007/s12672-025-04366-2

J Int Med Res. 2025 Dec;53(12):3000605251403252. doi: 10.1177/03000605251403252. Epub 2025 Dec 11.

ABSTRACT

BackgroundGastric cancer remains a major global health challenge due to its high mortality rate and complex pathophysiological mechanisms. Emerging evidence highlights that dysregulated lipid metabolism contributes to gastric cancer progression and prognosis, but the associations between lipid metabolism-associated genes, gastric cancer patient survival, and tumor immune microenvironment remodeling are not fully elucidated.MethodsWe analyzed publicly available omics and clinical data, including RNA sequencing data from 371 gastric cancer samples in The Cancer Genome Atlas database and 433 gastric cancer samples in the Gene Expression Omnibus database. We first curated the top 100 lipid metabolism-associated genes based on relevance scores. Then, univariate Cox regression was used to identify genes significantly associated with overall survival. Consensus clustering was applied to these survival-related genes to define gastric cancer molecular subtypes. Copy number variation analysis was performed to assess genomic alterations of these genes in tumor samples. A prognostic risk model was constructed using least absolute shrinkage and selection operator regression and validated via multivariate Cox regression. Immune infiltration analysis using CIBERSORT and ESTIMATE algorithms was conducted to explore associations between lipid metabolism-associated genes and tumor immune microenvironment characteristics.ResultsA total of 3911 differentially expressed genes were identified between gastric cancer and adjacent normal tissues. Among the top 100 lipid metabolism-associated genes, 43 were significantly linked to patient survival, most of which were considered as poor prognostic factors. Copy number variation analysis revealed frequent copy number gains of these genes in tumor samples. Consensus clustering stratified patients into two molecular subtypes (LMAGcluster A and LMAGcluster B), with LMAGcluster A showing significantly worse survival outcomes (median survival: 2.6 years vs. 8.3 years in LMAGcluster B, p < 0.001). LMAGcluster A was also characterized by elevated infiltration of pro-tumor immune cells, such as regulatory T cells and follicular helper T cells. The prognostic model based on 14 key lipid metabolism-associated genes exhibited robust predictive performance, with area under the receiver operating characteristic curve values of 0.702-0.761 in The Cancer Genome Atlas cohort and 0.621-0.638 in the Gene Expression Omnibus cohort for 1-, 3-, and 5-year survival.ConclusionLipid metabolism-associated genes are closely associated with gastric cancer prognosis and tumor immune microenvironment remodeling. The identified gene-based molecular subtypes and prognostic model provide novel insights into gastric cancer progression, and the 14 key genes may serve as potential biomarkers and therapeutic targets.

PMID:41381057 | DOI:10.1177/03000605251403252

Mol Cancer. 2025 Dec 3. doi: 10.1186/s12943-025-02521-5. Online ahead of print.

ABSTRACT

Gut microbiota-derived metabolites are emerging as systemic "remote immunoregulators" that shape tumor immunity across tissues. Integrating evidence across short-chain fatty acids, tryptophan derivatives, secondary bile acids, polyamines and other metabolites, we advance a metabolite-immune pathway-cancer framework that links receptor-mediated signaling, epigenetic remodeling and metabolic reprogramming to context-dependent, bidirectional immune effects. Importantly, in addition to the g protein-coupled receptor / aryl hydrocarbon receptor pathway, the selected microbial small molecule metabolites are the true T-cell receptor ligands of unconventional T cells, directly shaping the tissue resident immune and tumor microenvironment, supplementing the receptor signaling and epigenetic programs in our framework. We synthesize how these metabolites recalibrate the tumor immune microenvironment-modulating antigen presentation, T-cell effector fitness and exhaustion, regulatory T-cell activity, and myeloid polarization-and why the same metabolite can either potentiate immune surveillance or entrench immunosuppression depending on ligand-receptor pairing, dose and tissue niche. We compare tumor-type specific patterns (e.g., colorectal, liver, lung, breast and prostate cancers) to highlight common circuits and organ-restricted idiosyncrasies. Methodologically, we outline how single-cell and spatial multi-omics, imaging mass spectrometry and functional biosensors now enable co-registration of metabolite exposure with immune-cell states in human tumors, providing an actionable basis for biomarker discovery. Given ongoing debate about signals attributed to intratumoral microbiota in low-biomass tumor tissues, we foreground quantifiable, spatially mappable and pharmacologically tractable metabolite-receptor pathways, using microbe-associated molecular patterns / translocation as comparators to judge when chemical signals should be prioritized as intervention targets. Finally, we evaluate precision intervention avenues-including fecal microbiota transplantation, rational bacterial consortia, engineered microbes and nanoparticle-enabled metabolite delivery-and propose stratification rules that pair metabolite/receptor signatures with fit-for-purpose delivery. Together, mapping tissue-specific metabolite-immune circuits and embedding them in robust biomarker frameworks may convert microbial metabolites from correlative markers into therapeutic targets and tools, improving the efficacy and durability of cancer immunotherapy.

PMID:41339918 | DOI:10.1186/s12943-025-02521-5