Qing Wei

Cancer-associated fibroblasts (CAFs) exhibit remarkable functional heterogeneity, with conserved subtypes observed across diverse malignancies. However, their shared roles in shaping the tumor microenvironment (TME) and their dynamic plasticity remain incompletely understood. In this study, through integrated single-cell and spatial transcriptomic profiling across four cancer types, we identified two distinct immunomodulatory CAF states, termed antigen-presenting CAFs (apCAFs) and matrix-producing CAFs (mCAFs). Across multiple solid tumors, apCAFs were associated with enhanced anti-tumor immune features and favorable prognosis, whereas mCAFs were associated with immunosuppressive characteristics and poorer clinical outcomes. Spatial analyses revealed distinct localization patterns of apCAFs and mCAFs within the TME. Functionally, patient-derived apCAFs promoted T-cell migration, proliferation, and activation, whereas mCAFs suppressed these responses in vitro. Pan-cancer analyses further revealed a strong inverse correlation between apCAF and mCAF abundance across tumor tissues. Mechanistically, IFN-γ and TGF-β–associated signaling contexts were linked to distinct CAF transcriptional programs, with IFN-γ promoting apCAF-associated features and TGF-β favoring mCAF-associated features, suggesting a potential role of cytokine context in shaping CAF state heterogeneity. Clinically, apCAFs correlated with favorable immunotherapy response, whereas mCAFs predicted poor therapeutic outcomes. Collectively, these findings identify conserved immunomodulatory CAF subtypes across cancers, reveal distinct cytokine-associated CAF programs, and support stromal reprogramming as a promising strategy to enhance immunotherapy efficacy.

The genus Fusobacterium encompasses significant pathogens implicated in diseases spanning from infections to cancer. However, taxonomic ambiguities persist within the genus, particularly concerning Fusobacterium nucleatum (sensu lato). Through genus-wide average nucleotide identity (ANI) and phylogenetic analyses of 540 Fusobacterium genomes, we identify an ANI gap (93.38%−93.89%) for species delineation, leading to comprehensive taxonomic revisions that resolve these ambiguities. We further establish gyrB and rpoB as high-resolution taxonomic markers with phylogenies consistently supporting the revised taxonomy. Leveraging these markers, we develop B&B, a general strategy for precise species identification without whole-genome sequencing, and validate its accuracy in clinically relevant strains. Integrating the revised taxonomy with genomic/metagenomic toolkits demonstrate broad utilities, reinterpreting key colorectal cancer-associated species. This work establishes a unified taxonomic framework and enables standardised species classification for Fusobacterium isolates and microbiomes, highlighting the genetic divergence among Fusobacterium species and providing the taxonomic precision essential for advancing Fusobacterium-related research.

Dysregulation of complement factor D (CFD) has been associated with various diseases, such as metabolic, cardiovascular, and renal disorders. However, its role in intestinal function has been less studied. Our research found that CFD-deficient (Cfd^–/–) mice exhibited spontaneous slow transit constipation (STC) compared to wild-type (WT) mice. Moreover, the fecal weight and water content in Cfd^–/– mice were significantly reduced, despite no specific changes in feeding behavior. Reduced C-kit protein expression, colon injury, complement dysfunction and dysbiosis of the fecal microbiota are also observed in Cfd^–/– mice. After microbiota transplantation from WT mice into Cfd^–/– mice, reduced stool output, water content, decreased C-kit protein expression and colon injury were significantly improved. These results indicate that CFD is critical for controlling microbial homeostasis in the colon and, in its absence, leads to colon injury and promotes slow transit constipation.

Accumulating evidence indicates that the occurrence, development, and treatment of inflammatory bowel disease (IBD) are closely related to the intestinal microecology. However, whether Crohn’s disease (CD) and Ulcerative colitis (UC) are characterized by distinct gut microbial signatures and associated disease phenotypes remains to be determined. The present study investigates the correlation between potential pathogenic or protective intestinal bacteria and the clinical pathological characteristics of patients with IBD. A total of 274 tissue samples from patients with IBD, including 237 formalin-fixed paraffin-embedded (FFPE) samples and 37 fresh samples, were detected by qPCR for Enterotoxigenic Bacteroides fragilis, Klebsiella pneumoniae, Listeria monocytogenes, Akkermansia muciniphila, and Mycobacterium avium subspecies paratuberculosis. The study identified significant correlations between specific bacteria and clinical features such as age, disease location, disease behavior, and immunohistochemical markers. Among patients with CD, Enterotoxigenic Bacteroides fragilis colonization was associated with Epstein-Barr virus (EBV) infection, Ki-67 expression, disease behavior, and prognosis. Klebsiella pneumoniae colonization showed a significant association with EBV infection and lesion location. Listeria monocytogenes colonization was correlated with IgG4 levels and disease location. Moreover, as a potential probiotic, the colonization rate of Akkermansia muciniphila is significantly higher during the remission phase than in the active phase of CD. Notably, among patients with UC, these bacteria did not correlate well with clinical pathological characteristics. In addition, compared with healthy people, these bacteria in the feces of patients with CD and UC also exhibit different characteristics. These findings suggest that, compared with UC, certain specific gut bacteria, such as Enterotoxigenic Bacteroides fragilis, may play a more important role in the occurrence, development and prognosis of CD. In addition, different intestinal microbiota-based therapeutic strategies should be developed for CD and UC.

Non-nucleatum Fusobacterium may play a nonnegligible role in colorectal cancer (CRC) and certain Fusobacterium lineages (namely, L1 and L5) have shown specific associations with CRC. We aim to clarify the complex connections between Fusobacterium and CRC. We found that the widely adopted quantitative PCR (qPCR) method could overestimate F. nucleatum abundance and, in fact, reflect L1 levels in clinical samples. A lineage-specific qPCR assay targeting L1/L5 was developed and validated using mock and clinical samples. Its application in independent cohorts confirmed that L1 was overabundant in CRC, whereas L5 correlated with lymphovascular invasion. Importantly, faecal L1 abundance was more predictive of CRC than F. nucleatum, supported also by cross-population metagenomic data. CRC-associated virulence and colonisation genes were found in various L1 species other than F. nucleatum. Our results highlight the clinical importance of L1/L5 in CRC with high-diversity Fusobacterium contexts and suggest that non-nucleatum Fusobacterium may also contribute to CRC.

Background: Malignant luminal alimentary tract tumor chemotherapy remains a great challenge at present due to risks and toxicities associated with current chemodrugs, as well as the potential for treatment resistance. Layered double hydroxide (LDH)/ethylenediamine tetraacetic acid (EDTA), such a tumor disaggregation-based treatment reagent for alimentary tract cancers was assessed in six patients bearing luminal tumors. The aim of this study was to evaluate the bio-safety and efficacy of LDH/EDTA for treating luminal alimentary tract tumors with high malignance. Methods: Two patients with colorectal cancer received intestinal perfusion of LDH/EDTA by colonoscopy every week for 6 weeks, and four patients with esophagus tumors received oral administration of LDH/EDTA for at least 1 month. The efficacy of LDH/EDTA were evaluated by determining tumor size reductions through contrast-enhanced CT imaging. Tumor cell dissociation was evaluated by flow cytometry to validate the tumor disaggregation. Results: The colorectal cancer patients presented 33.3% and 16.7% reductions in tumor size after LDH/EDTA treatment. Additionally, symptoms of intestinal obstruction were largely alleviated. Four esophagus cancer patients experienced 6.7%, 26.7%, 16.7% and 15.4% reductions in tumor size, respectively, and symptoms of dysphagia were largely alleviated. All enrolled patients had normal physical condition based on blood routine examinations and hepatic and renal function examinations. Conclusions: Tumor disaggregation strategy for luminal alimentary tract tumor removal is a highly promising, mild, noninvasive modality, which offers an unprecedented paradigm for highly effective and safe treatment for patients with luminal alimentary tract tumors. This study is registered with www.chictr.org.cn (ChiCTR2200061587, ChiCTR2200065010).

Colorectal cancer (CRC) is the third most common cancer worldwide, and its high incidence, mortality, and treatment resistance highlight the urgency of exploring new therapeutic targets. As research into cancer metabolic reprogramming deepens, the central role of lipid metabolism abnormalities in CRC progression has gradually become apparent. In the tumor microenvironment (TME), conditions such as hypoxia, glucose deprivation, and lactic acid accumulation alter the energy demands of tumor cells, driving metabolic reprogramming in lipid uptake, synthesis, and oxidation. This reprogramming helps maintain high energy needs and supports the malignant growth of tumor cells. This lipid metabolic reprogramming provides tumor cells with the necessary energy and enhances their proliferation, invasion, immune evasion, and resistance characteristics. Moreover, the lipid metabolic reprogramming of tumor cells is closely related to various cells within the TME, and these interactions promote, to some extent, the remodeling of the tumor microenvironment, further driving tumor development. Emerging lipid detection technologies position specific lipid molecules as promising biomarkers for auxiliary diagnosis and prognostic evaluation. Concurrently, targeting key lipid metabolic pathways offers innovative strategies to optimize existing therapies and overcome drug resistance. This review summarizes the basic and abnormal mechanisms of lipid metabolism in CRC, lipid metabolic interactions in the tumor microenvironment, the regulatory network between the gut microbiota and lipid metabolism, and the progress in therapeutic strategies targeting lipid metabolism. By exploring the interaction between CRC and lipid metabolism in depth, this review aims to provide new ideas and theoretical support for the treatment, early intervention, and prognosis evaluation of CRC.

Backgrounds: Fusobacterium nucleatum (F. nucleatum) has been shown to be associated with immunotherapy in colorectal cancer (CRC), but its exact mechanism needs to be further explored.Methods: We first analyzed the correlation between F. nucleatum abundance and mismatch repair (MMR) protein deficiency in CRC tissues from 567 patients. We then treated CRC cells and tissues with F. nucleatum and its metabolites. RNA sequencing was used to evaluate the involved pathways, and non-targeted metabolomics was employed to analyze the metabolites regulating MLH1. CRC cells were treated with butyrate, a metabolite of F. nucleatum, with or without the autophagy-lysosome pathway inhibitor chloroquine or mTOR activator MHY1485. Finally, subcutaneous tumors of BALB/C mice were treated with PD-L1 blockade, butyrate, or their combination.Results: The results showed that the abundance of F. nucleatum in CRC tissues is correlated with MSI and MLH1 deficiency. F. nucleatum, its culture supernatant, and its metabolite butyrate cause the downregulation of MLH1 protein via autophagy-lysosome pathway. Subcutaneous tumors in mice received the combined treatment of PD-L1 blockade and butyrate shrink more evidently than those disposed by single therapy.Conclusions: F. nucleatum reduces MLH1 expression via the lysosomal pathway by butyrate, leading to deficient mismatch repair (dMMR), which may yield therapeutic benefits in CRC patients with microsatellite stability (MSS).