The intratumoral microbiota plays a critical role in lung cancer development, metastasis, and treatment response, offering valuable insights into the tumor microenvironment (TME) and revealing new therapeutic opportunities. Lung cancer remains the leading cause of cancer-related deaths worldwide, with the intratumoral microbiota exhibiting unique characteristics and functions within this disease. In this review, we summarized the origin of the intratumoral microbiota, its entry into the tumor, its detailed composition, functions, and its potential clinical applications in lung cancer. For the first time, we estimate the absolute abundance of different microbes in lung cancer, highlight the specific differences in microorganisms, and track their dynamic changes from health to disease. We also describe the overall landscape of intratumoral microbiota. Finally, we discuss the challenges and implications of this emerging field, offering insights for future research and therapeutic strategies.

Colorectal cancer liver metastasis (CRLM) represents one of the most severe complications of colorectal cancer (CRC), often associated with unfavorable prognosis. The herbal formulation Kang-Ai-Jing-Fang (KAJF) has been employed clinically against CRC for several decades, although its precise mechanism of action remains elusive.

This study investigates the anti-metastatic potential of KAJF in CRLM, focusing on its modulatory effects on gut microbiota and inhibition of M2-like macrophage activation.

KAJF was administered orally to CRLM model mice established through intrasplenic injection of murine CRC cells. To elucidate the role of gut microbiota reshaped by KAJF, fecal microbiota transplantation (FMT) was utilized to assess its impact on CRLM inhibition. Core targets and active compounds were identified through network pharmacology and molecular docking. To characterize microbiota composition, metabolite profiles, and gene expression variations, 16S rRNA sequencing, untargeted liquid chromatography-mass spectrometry (LC-MS/MS) metabolomics, and transcriptomics analyses were performed.

KAJF demonstrated significant inhibitory effects on CRLM and ameliorated gut microbiota dysbiosis by enhancing the abundance of butyrate-producing bacteria (Lactobacillus, Bacteroides, Bifidobacterium). The therapeutic efficacy of KAJF-induced bacterial alterations in delaying CRLM and promoting butyrate-producing microbiota enrichment was further substantiated by FMT. Network pharmacology identified active ingredients in KAJF, including asperulosidic acid, polyphyllin II, ganoderenic acid B, calycosin, and ganoderic acid C, which exhibit substantial interactions with TLR4, PPARγ, SIRT1, PTGS2, and TNF. Molecular dynamics simulations and surface plasmon resonance (SPR) analysis demonstrated that ganoderic acid C2 exhibits a strong binding affinity for PPARγ. Moreover, KAJF administration led to a marked reduction in F4/80+ CD206+ macrophages and their associated cytokines (CCL17, CCL22, IL10, IL4, TGF), accompanied by a decrease in CD4+ T cells and myeloid-derived suppressor cells (MDSCs), while increasing CD8+ T cell populations.

This study demonstrates that KAJF mitigates CRLM, primarily through the regulation of gut microbiota and microbial metabolites, alongside inhibition of M2-like macrophage polarization. By integrating metabolomics, transcriptomics, and network pharmacology, this research elucidates the molecular mechanisms underpinning KAJF's therapeutic effects against CRLM, offering a promising approach for clinical intervention.

Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide, causing a serious threat to global health and social burden. Clostridioides difficile infection (CDI) is one of the most important nosocomial infections and has a higher incidence in cancerous population compared with non-cancerous cases. Different risk factors, including gut microbiota dysbiosis, extensive surgery, chemotherapy, prolonged hospitalization, and antimicrobial therapy, compromise host defenses against CDI and contribute to cancer patients' susceptibility to this infection. The emergence of CDI in patients with CRC creates conditions for therapy escalation and prolonged hospitalization, highlighting the need for correct and effective CDI management in these patients. Here, common risk factors associated with CDI in patients with CRC are discussed. In addition, different available techniques for the prevention, detection, and treatment of CDI with the lowest impact on gut microbiota diversity are summarized. This review aims to improve the understanding of the interplay between CDI and CRC and provide new insights into restoring and maintaining gut microbiota balance during CDI management in patients with CRC.

Intratumoral bacteria have been identified as prevalent in various solid tumors, playing a significant role in tumor progression. Lymph node metastasis is a major clinical feature and the primary cause of mortality in cervical cancer (CC). However, the effect of intratumoral bacteria on lymphatic node metastasis in CC remains unclear.

This study employed 16S rDNA sequencing and targeted bacterial culture to investigate the distribution of intratumoral bacteria in human CC tissues. The identified Gram-negative bacteria, including Escherichia coli (E. coli), Prevotella bivia (P. bivia), and Fusobacterium nucleatum (F. nucleatum), were isolated and their roles in metastasis were examined using in vitro transwell and capillary tube formation assays on human lymphatic endothelial cells (HLEC). The signaling pathways involved in metastasis were assessed by examining TLR4/MAPK activation and the expression of prometastatic factors EFNA1 and EDN2. In vivo studies using a mouse footpad tumorigenesis model were also conducted to observe the effect of LPS which extracted from these three gram-negative intratumoral bacteria and E. coli on lymph node metastasis.

A higher abundance of Gram-negative bacteria, especially in metastatic CC tissues, was observed. E. coli, P. bivia, and F. nucleatum enhanced capillary tube formation in lymphatic endothelial cells and facilitated metastasis of uninfected tumor cells through paracrine signaling. These bacteria activated the TLR4/MAPK signaling pathway via lipopolysaccharide (LPS), leading to the upregulation of prometastatic factors EFNA1 and EDN2. Knockdown of EFNA1 and EDN2 attenuated the bacteria-induced metastasis, whereas overexpression of these factors mimicked the effects of bacterial infection. In vivo, LPS which extracted from E. coli, P. bivia, and F. nucleatum and live E. coli promoted lymph node metastasis, with elevated LPS levels and MAPK-EFNA1/EDN2 expression observed in infected mice compared to controls.

The study suggests that Gram-negative bacteria, particularly E. coli, P. bivia, and F. nucleatum, play a causal role in exacerbating lymph node metastasis in CC. These findings highlight the potential of targeting these bacteria and their associated signaling pathways as therapeutic strategies to improve clinical outcomes in CC patients.

Epithelial-to-mesenchymal transition (EMT) is a crucial cellular process for embryogenesis, wound healing, and cancer progression. It involves a shift in cell interactions, leading to the detachment of epithelial cells and activation of gene programs promoting a mesenchymal state. EMT plays a significant role in cancer metastasis triggering tumor initiation and stemness, and activates metastatic cascades resulting in resistance to therapy. Moreover, reversal of EMT contributes to the formation of metastatic lesions. Metastasis still needs to be better understood functionally in its major but complex steps of migration, invasion, intravasation, dissemination, which contributes to the establishment of minimal residual disease (MRD), extravasation, and successful seeding and growth of metastatic lesions at microenvironmentally heterogeneous sites. Therefore, the current review article intends to present, and discuss comprehensively, the status quo of experimental models able to investigate EMT and metastasis in vitro and in vivo, for researchers planning to enter the field. We emphasize various methods to understand EMT function and the major steps of metastasis, including diverse migration, invasion and matrix degradation assays, microfluidics, 3D co-culture models, spheroids, organoids, or latest spatial and imaging methods to analyze complex compartments. In vivo models such as the chorionallantoic membrane (CAM) assay, cell line-derived and patient-derived xenografts, syngeneic, genetically modified, and humanized mice, are presented as a promising arsenal of tools to analyze intravasation, site specific metastasis, and treatment response. Furthermore, we give a brief overview on methods detecting dissemination and MRD in carcinomas, highlighting its significance in tracking the course of disease and response to treatment. Enhanced lineage tracking tools, dynamic in vivo imaging, and therapeutically useful in vivo models as powerful preclinical tools may still better reveal functional interdependencies between metastasis and EMT. Future directions are discussed in light of emerging views on the biology, diagnosis, and treatment of EMT and metastasis.

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, highlighting the urgent need for novel preventive and therapeutic strategies. Emerging research highlights the crucial role of the gut microbiota, including bacteria, fungi, viruses, and their metabolites, in the pathogenesis of CRC. Dysbiosis, characterized by an imbalance in microbial composition, contributes to tumorigenesis through immune modulation, metabolic reprogramming, and genotoxicity. Specific bacterial species, such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis , along with fungal agents like Candida species, have been implicated in CRC progression. Moreover, viral factors, including Epstein-Barr virus and human cytomegalovirus, are increasingly recognized for their roles in promoting inflammation and immune evasion. This review synthesizes the latest evidence on host-microbiome interactions in CRC, emphasizing microbial metabolites, such as short-chain fatty acids and bile acids, which may act as both risk factors and therapeutic agents. We further discuss the latest advances in microbiota-targeted clinical applications, including biomarker-assisted diagnosis, next-generation probiotics, and microbiome-based interventions. A deeper understanding of the role of gut microbiome in CRC pathogenesis could pave the way for diagnostic, preventive, and personalized therapeutic strategies.

Liver metastasis can occur in a wide range of cancers and have a significant impact on patient survival and prognosis. Once liver metastasis occurs, patients often lose the opportunity for surgery, and although a small percentage of patients can undergo hepatic resection to prolong survival, the benefit is not great. There were also many factors affecting liver metastasis, including reprogramming of the primary tumor metabolism, disturbances in the immune microenvironment and immune cells, alterations in the gut microbiota, and epigenetic changes. Interleukin-10 (IL-10) has a dual role as a cytokine that has been found in recent years to be pro-inflammatory as well as pro-liver metastasis. IL-10 exerts pro-metastatic effects mainly by regulating the polarization of tumor macrophages in the tumor microenvironment, especially by promoting the polarization of M2 macrophages. However, the role of IL-10 in tumorigenesis and progression remains controversial and the molecular mechanism involved in promoting liver metastasis is currently unclear. In view of the increasing role of IL-10 in promoting liver metastasis, this review summarizes the role of IL-10 in liver metastasis of colorectal cancer, breast cancer and other tumors in recent years, and provides ideas for subsequent clinical practice and basic research.

The intestinal barrier serves as a boundary between the mucosal immune system in the lamina propria and the external environment of the intestinal lumen, which contains a diverse array of microorganisms and ingested environmental factors, including pathogens, food antigens, toxins, and other foreign substances. This barrier has a central role in regulating the controlled interaction between luminal factors and the intestinal immune system. Disruptions of intestinal epithelial cells, which serve as a physical barrier, or the antimicrobial peptides and mucins they produce, which act as a chemical barrier, can lead to a leaky gut. In this state, the intestinal wall is unable to efficiently separate the intestinal flora and luminal contents from the intestinal immune system. The subsequent activation of the immune system has an important role in the pathogenesis of inflammatory bowel disease, as well as in metabolic dysfunction-associated steatohepatitis, primary sclerosing cholangitis, and colorectal cancer. Dysregulated intestinal barrier integrity has also been described in patients with chronic inflammatory diseases outside the gastrointestinal tract, including rheumatoid arthritis and neurodegenerative disorders. Mechanistic studies of barrier dysfunction have revealed that the subsequent local activation and systemic circulation of activated immune cells and the cytokines they secrete, as well as extracellular vesicles, promote proinflammatory processes within and outside the gastrointestinal tract. In this Review, we summarise these findings and highlight several new therapeutic concepts currently being developed that attempt to control inflammatory processes via direct or indirect modulation of intestinal barrier function.

The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with its distribution patterns influenced by factors such as tumor anatomy, local immune status, and therapeutic interventions. This spatial heterogeneity not only alters the interactions between microbes and the host immune system but may also reshape the immunogenic and immunosuppressive landscapes of tumors. The enrichment or depletion of microbiota in different tumor regions can influence immune cell infiltration patterns, metabolic pathway activities, and immune checkpoint molecule expression, thereby driving the development of resistance to immunotherapy. Moreover, certain bacterial metabolites form concentration gradients between the tumor core and margins, thereby regulating immune cell function. Therefore, understanding and manipulating the spatial distribution of intratumoral microbiota, particularly in resistant patients, holds promise for developing new strategies to overcome immunotherapy resistance. In the future, precise modulation strategies targeting microbial spatial heterogeneity, such as engineered bacterial vectors, probiotic combinations, and phage therapy, may open new avenues for immunotherapy.

Emerging evidence reveals that microbiota plays a crucial role in multiple cancers. Nasopharyngeal carcinoma (NPC) tissues harbour microbiota, highlighting the need to investigate the clinical implications of tissue-resident microbiota in the development of NPC. Here, we aim to clarify the specific profile of tissue-resident microbiota and its influence on NPC outcomes.

This retrospective study included 491 NPC patients from Sun Yat-sen University Cancer Center (Guangzhou, China) and the Affiliated Hospital of Guilin Medical College (Guilin, China). We profiled the microbial composition of 343 NPC and 36 normal nasopharyngeal tissues through sequencing of the genes encoding the 16S rRNA subunit of bacterial ribosomes. There were significant differences in microbial composition, alpha diversity (Shannon index, P = 0.007; Simpson index, P = 0.036), and beta diversity (Bray-Curtis distance: R2 = 0.016, F = 5.187, P = 0.001; unweighted UniFrac distance: R2 = 0.017, F = 5.373, P = 0.001) between NPC and normal nasopharyngeal tissues. A bacterial signature comprising four risk bacterial genera, including Bacteroides, Alloprevotella, Parvimonas, and Dialister, was constructed in the training cohort (n = 171). Patients in the high-risk group had shorter disease-free (HR 2.80, 95% CI 1.51-5.18, P < 0.001), distant metastasis-free (HR 4.00, 95% CI 1.77-9.01, P < 0.001), and overall survival (HR 3.45, 95% CI 1.77-6.72, P < 0.001) than those of patients in the low-risk group. Similar results were yielded in the internal validation (n = 172) and external validation (n = 148) cohorts. Integrated multi-omics analysis revealed that NPC tissues harbouring abundant risk bacteria were characterised by deficient immune infiltration, which was verified by multiplex immunohistochemistry.

This study developed and validated the applicability of a four-bacteria signature as a prognostic tool for NPC prognostication. Integrated multi-omics analysis further uncovered that the tumour immune microenvironment was perturbed by tissue-resident microbiota, which might pave the way towards the era of microbiota-targeted precision medicine for NPC. Video Abstract.

Colorectal cancer liver metastasis generally refers to the process where colorectal cancer cells enter the liver through the bloodstream and form new tumors within the liver. The roles of complexin 2 (CPLX2) and synaptosome-associated protein 25 (SNAP25) in the recovery from colorectal cancer liver metastasis are not yet clear. Data sets GSE147602 and GSE144259 for colorectal cancer liver metastasis were downloaded from the gene expression omnibus database generated from GPL21047 and GPL11154. Batch normalization, differentially expressed genes (DEGs) screening, weighted gene co-expression network analysis, construction and analysis of the protein-protein interaction network, functional enrichment analysis, and Gene Set Enrichment Analysis were conducted. Heatmaps of gene expression were plotted. Immune infiltration analysis and Comparative Toxicogenomics Database analysis were performed. TargetScan was used to screen for miRNAs regulating central DEGs. Through experimental verification, a total of 1215 DEGs were identified. According to gene ontology analysis, they were mainly enriched in cell signaling, G-protein-coupled receptor signaling pathway, signal transduction receptor binding, and cytokine binding. Kyoto Encyclopedia of Genes and Genomes analysis results showed that the target cells were mainly enriched in cholesterol metabolism olfactory transduction. In the enrichment projects of metascape, gene ontology enrichment items included regulation of circulation, muscle structure development, vascular process in the circulatory system, and extracellular matrix organization. The soft-thresholding power for weighted gene co-expression network analysis was set to 4. Four core genes were obtained by intersecting the central genes identified by 5 different algorithms, as shown in a Venn diagram. The heatmap of gene expression showed that the core genes (CPLX2, SNAP25, and Bassoon) were underexpressed in primary colorectal cancer and overexpressed in colorectal cancer liver metastasis. Comparative Toxicogenomics Database analysis showed that 3 genes (CPLX2, SNAP25, and Bassoon) were related to abdominal pain, jaundice, chemical and drug-induced liver injury, and necrosis. The related miRNAs for the CPLX2 gene were hsa-miR-1-3p, hsa-miR-206, hsa-miR-613; for the SNAP25 gene were hsa-miR-181d-5p, hsa-miR-181b-5p, hsa-miR-181c-5p. The results confirmed that CPLX2 and SNAP25 positively regulated the phosphatidylinositol 3 kinase-AKT signaling pathway and promoted the progression of liver metastasis of colorectal cancer. CPLX2 and SNAP25 genes are overexpressed in colorectal cancer liver metastasis and may serve as important molecular targets.

Intestinal injury is one of the most prevalent complications following heat stress (HS) in both humans and animals. Autophagy has been shown to maintain intestinal homeostasis, and modulation of autophagy may help alleviate intestinal injury caused by HS. Lonicerin (LN) are flavonoids known to have enhanced autophagy and anti-inflammatory effects. However, how LN prevent intestinal damage and regulate autophagy after HS remains unknown. The aim of this study was to elucidate the potential regulatory effects of LN on intestinal inflammation and intestinal barrier function in a HS model, and to elucidate the underlying molecular mechanisms. Firstly, we searched for the same inflammatory cytokines in the drug and disease targets through network pharmacology, and in vitro and in vivo experiments showed that LN significantly inhibited the production of pro-inflammatory cytokines. Then it was demonstrated that LN alleviates HS induced intestinal mucosal barrier damage by repairing tight junctions, goblet cells, and mucins in the colon of rats, consistent with the findings of in vitro experiments. In addition, LN reversed HS-induced reduced autophagic flux and maintained autophagic homeostasis via the AMP-activated protein kinase (AMPK)-Silent information regulator 1 (SIRT1) pathway in intestinal epithelial cells and intestinal system. In summary, this study demonstrated that LN exert intestinal protective and immunomodulatory effects by inhibiting the production of pro-inflammatory cytokines, maintaining the integrity of the intestinal mucosal barrier, and the level of AMPK-SIRT1 autophagy.

In recent years, lactylation, a novel post-translational modification, has demonstrated a unique role in bridging cellular metabolism and epigenetic regulation. This modification exerts a dual-edged effect in both cancer and non-cancer diseases by dynamically integrating the supply of metabolic substrates and the activity of modifying enzymes: on one hand, it promotes tissue homeostasis and repair through the activation of repair genes; on the other, it exacerbates pathological progression by driving malignant phenotypes. In the field of oncology, lactylation regulates key processes such as metabolic reprogramming, immune evasion, and therapeutic resistance, thereby shaping the heterogeneity of the tumor microenvironment. In non-cancerous diseases, including neurodegeneration and cardiovascular disorders, its aberrant activation can lead to mitochondrial dysfunction, fibrosis, and chronic inflammation. Existing studies have revealed a dynamic regulatory network formed by the cooperation of modifying and demodifying enzymes, and have identified mechanisms such as subcellular localization and RNA metabolism intervention that influence disease progression. Nevertheless, several challenges remain in the field. This article comprehensively summarizes the disease-specific regulatory mechanisms of lactylation, with the aim of providing a theoretical foundation for its targeted therapeutic application.

The tumour microenvironment (TME) exerts a profound influence on cancer progression and treatment outcomes. Recent investigations have elucidated the crucial role of intratumoural microbiota and their metabolites in shaping the TME and modulating anti-tumour immunity. This review critically assesses the influence of intratumoural microbial metabolites on the TME and cancer immunotherapy. We systematically analyse how microbial-derived glucose, amino acid, and lipid metabolites modulate immune cell function, cytokine secretion, and tumour growth. The roles of specific metabolites, including lactate, short-chain fatty acids, bile acids, and tryptophan derivatives, are comprehensively examined in regulating immune responses and tumour progression. Furthermore, we investigate the potential of these metabolites to augment the efficacy of cancer immunotherapies, with particular emphasis on immune checkpoint inhibitors. By delineating the mechanisms through which microbial metabolites influence the TME, this review provides insights into novel microbiome-based therapeutic strategies, thereby highlighting a promising frontier in personalised cancer medicine.

Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.

Cancer metastasis is the leading cause of death in patients. In recent years, there has been a growing recognition of the role of tumor-associated microflora in tumor metastasis. The connection between oral and gut microflora and the tumor microenvironment has also been extensively studied. The migration of oral and gut microflora is closely associated with tumor development. Although there is awareness regarding the significant impact of microbial communities on human health, the focus on their relationship with host organisms, particularly those related to tumor-associated microflora, remains inadequate. As an integral part of the body, the host microflora is crucial for regulating the cancer risk and preventing tumor recurrence. The oral-gut axis plays an indispensable role in human immunity, and many types of cancers, such as colorectal, pancreatic, and breast, are significantly influenced by their internal microbial communities. However, further exploration into the mechanisms underlying the role of the intratumoral microflora in cancer is necessary to achieve a comprehensive understanding. We have summarized and analyzed related articles in PubMed. This article reviews the impact of the oral-gut axis on the human immune system, explores the relationship between the translocation of the oral and intestinal flora and the tumor microenvironment, analyzes the specific mechanisms involved in the translocation of the oral and intestinal microflora during the evolution and progression of tumors, and elaborates on the correlations between the occurrence and development of tumors and the changes in the microflora. Finally, a summary of these abovementioned points is provided.

Fungi in tumors act as a double-edged sword, potentially worsening or alleviating malignancy based on the ecological balance within the tumor microenvironment (TME). Hydrogels, as innovative drug delivery systems, are poised to redefine treatment paradigms. As advanced biomaterials, they offer a versatile platform for encapsulating and releasing antifungal agents and immunomodulators, responding to the TME's unique demands.

We have conducted and collated numerous relevant reviews and studies in recent years from three aspects: Hydrogels, intra-tumoral fungi, and tumor microbe microenvironment, in the hope of identifying the connections between hydrogels and intra-tumoral microbes.

This review underscores the crucial role of intra-tumoral microbes, particularly fungi, in tumorigenesis, progression, and treatment efficacy. At the same time, we concentrated on the findings of hydrogels investigations, with their remarkable adaptability to the tumor microenvironment emerge as intelligent drug delivery systems.

Hydrogels unique ability to precisely target and modulate the tumor microflora, including fungi, endows them with a significant edge in enhancing treatment efficacy. This innovative approach not only holds great promise for improving cancer therapy outcomes but also paves the way for developing novel strategies to control metastasis and prevent cancer recurrence.

Intratumoral microbiota has been found to be a crucial component of hepatocellular carcinoma (HCC). Due to insufficient recognition, technical limitations, and low biomass of intratumoral microbiota, it is poorly understood. Intratumoral microbiota exhibit significant diversity in HCC tissues. It is involved in the development of HCC through several mechanisms, such as remodeling the immunosuppressive microenvironment, metabolic reprogramming, and genetic alterations. Moreover, intratumoral microbiota is associated with the metastasis of HCC cells. Herein, we reviewed the history of intratumoral microbiota, applied biotechnology to depict the signatures of intratumoral microbiota, investigated the potential sources of intratumoral microbiota, and assessed their functions, mechanisms, and heterogeneity. Furthermore, in this review, we summarized the development of therapeutics that can be used in the treatment of HCC and proposed future perspectives for research in this field.

Liver metastasis is the most common site of metastasis in colorectal cancer, and the prognosis of colorectal cancer patients with liver metastasis is extremely poor. Revealing the key genes of CLM and implementing targeted interventions is of great significance for colorectal cancer patients. By using the weighted gene co-expression network analysis (WGCNA) algorithm, key gene modules related to metastasis in colorectal cancer were identified. Subsequently, immune-regulating and prognostic-influencing key gene sets were identified from these modules to construct a prognostic model related to colorectal cancer metastasis. Genetic background differences underlying this model were analyzed using colorectal cancer methylation and mutation data, followed by Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) analysis of the relevant biological processes associated with the model. The value of predicting tumor drug response through the model was assessed using drug half maximal inhibitory concentration (IC50) data from colorectal cancer cell lines. Subsequently, utilizing single-cell sequencing data about liver metastasis, the colorectal cancer immune microenvironment reflected in the predictive model was analyzed, and a key gene set of the model was identified. Lastly, experimental validation was conducted to investigate the regulatory effects of photodynamic therapy (PDT) on the key genes of the model, and the cytotoxic effect of PDT on colorectal cancer was confirmed. An immune-related gene prognostic model regulating CLM was constructed, consisting of HSPA1A, ULBP2, RBP7, OXT, SLC11A1, INHBB, and ICOS. This model can predict the clinical response of colorectal cancer patients to Oxaliplatin, Cisplatin, Irinotecan, and 5-Fluorouracil. Single-cell sequencing results demonstrate that the model is associated with an immunosuppressive microenvironment in CLM. The higher the model's riskscore, the weaker the MHC-I, MHC-II, and various tumor immune signaling pathway networks in the colorectal cancer microenvironment. Causal analysis reveals that SLC11A1, ICOS, and HSPA1A play key roles in this model. PDT can kill colorectal cancer cells, inhibit colorectal cancer cell metastasis, significantly influence the expression of genes such as SLC11A1, ICOS, and HSPA1A in these processes, and suppress the infiltration of macrophages in the colorectal microenvironment, inhibiting the immune escape process of PD-1/PD-L1. A prognostic model based on immunity regulated by PDT has been established for assessing the prognosis of CLM patients, as well as clinical responses to chemotherapy drugs and immunotherapy.

This letter addresses the recently published manuscript by Darnindro et al, which investigates the diversity and composition of colonic mucosal microbiota in Indonesian patients with and without colorectal cancer (CRC). Although the analysis revealed no statistically significant differences in alpha diversity between the CRC and non-CRC groups, the authors identified notable distinctions in the composition and diversity of colonic mucosal microbiota among patients with CRC compared to those without. At the genus level, a statistically significant difference in microbiota composition was documented between the two cohorts. Specifically, the genera Bacteroides, Campylobacter, Peptostreptococcus, and Parvimonas were found to be elevated in individuals with CRC, while Faecalibacterium, Haemophilus, and Phocaeicola were more prevalent in the non- CRC group.

Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.

The tumor microenvironment (TME) is a complex ecosystem where malignant and non-malignant cells cooperate and interact determining cancer progression. Cell abundance, phenotype and localization within the TME vary over tumor development and in response to therapeutic interventions. Therefore, increasing our knowledge of the spatiotemporal changes in the tumor ecosystem architecture is of importance to better understand the etiologic development of the neoplastic diseases. Imaging Mass Cytometry (IMC) represents the elective multiplexed imaging technology enabling the in-situ analysis of up to 43 different protein markers for in-depth phenotypic and spatial investigation of cells in their preserved microenvironment. IMC is currently applied in cancer research to define the composition of the cellular landscape and to identify biomarkers of predictive and prognostic significance with relevance in mechanisms of drug resistance. Herein, we describe the general principles and experimental workflow of IMC raising the informative potential in preclinical and clinical cancer research.

Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.

Efforts to deconvolve the complex interactions of cancer cells with other components of the tumor micro- and macro-environment have exposed a common tendency for cancers to subvert systems physiology and exploit endogenous programs involved in homeostatic control of metabolism, immunity, regeneration, and repair. Many such programs are engaged in the healing response to surgery which, together with other abrupt biochemical changes in the perioperative period, provide an opportunity for the macroevolution of residual disease. This review relates contemporary perspectives of cancer as a systemic disease with the overlapping biology of host responses to surgery and events within the perioperative period. With a particular focus on examples of cancer cell plasticity and changes within the host, we explore how perioperative inflammation and acute metabolic, neuroendocrine, and immune dyshomeostasis might contribute to cancer evolution within this contextually short, yet crucially influential timeframe, and highlight potential therapeutic opportunities within to further optimize surgical cancer care and its long-term oncological outcomes.

The translocation of bacteria from intestinal tracts into blood vessels and distal organs plays pivotal roles in the pathogenesis of numerous severe diseases. Intravital monitoring of bacterial translocation, however, is not yet feasible, which greatly hinders us from comprehending this spatially and temporally dynamic process. Here we report an in vivo fluorogenic labeling method, which enables in situ imaging of mouse gut microbiota and real-time tracking of the translocated bacteria. By mimicking the peptidoglycan stem peptide in bacteria, a tetrapeptide probe composed of alternating D- and L-amino acids and separately equipped with a fluorophore and a quencher on the N- and C-terminal amino acid, is designed. Because of its resistance to host proteases, it can be directly used in gavage and achieves fluorogenic labeling of the microbiota in the gut via the functioning of the L,D-transpeptidases of the labeled bacteria. Using intravital two-photon microscopy, we then successfully visualize the translocation of gut bacteria into the bloodstream and liver in obesity mouse models. This technique can help further exploration into the spatiotemporal activities of gut microbiota in vivo, and be valuable in investigating the less understood pathogenicity of bacterial translocation in many severe diseases.

Intestinal barrier dysfunction is a prevalent and varied manifestation of acute pancreatitis (AP). Molecular mechanisms underlying the early intestinal barrier in AP remain poorly understood.

To explore the biological processes and mechanisms of intestinal injury associated with AP, and to find potential targets for early prevention or treatment of intestinal barrier injury.

This study utilized single-cell RNA sequencing of the small intestine, alongside in vitro and in vivo experiments, to examine intestinal barrier function homeostasis during the early stages of AP and explore involved biological processes and potential mechanisms.

Seventeen major cell types and 33232 cells were identified across all samples, including normal, AP1 (4x caerulein injections, animals sacrificed 2 h after the last injection), and AP2 (8x caerulein injections, animals sacrificed 4 h after the last injection). An average of 980 genes per cell was found in the normal intestine, compared to 927 in the AP1 intestine and 1382 in the AP2 intestine. B cells, dendritic cells, mast cells (MCs), and monocytes in AP1 and AP2 showed reduced numbers compared to the normal intestine. Enterocytes, brush cells, enteroendocrine cells, and goblet cells maintained numbers similar to the normal intestine, while cytotoxic T cells and natural killer (NK) cells increased. Enterocytes in early AP exhibited elevated programmed cell death and intestinal barrier dysfunction but retained absorption capabilities. Cytotoxic T cells and NK cells showed enhanced pathogen-fighting abilities. Activated MCs, secreted chemokine (C-C motif) ligand 5 (CCL5), promoted neutrophil and macrophage infiltration and contributed to barrier dysfunction.

These findings enrich our understanding of biological processes and mechanisms in AP-associated intestinal injury, suggesting that CCL5 from MCs is a potential target for addressing dysfunction.

Studies have shown that the colonisation of active microorganisms is more conducive to the development of tumour immunotherapy, but intuitive evidence regarding shaping of the tumour immune microenvironment is lacking. In this study, we used Bifidobacterium longum subsp. longum (XZ01) to intervene in a colon cancer mouse model and found that its mechanism may be related to the interaction between the spatial distribution of microorganisms and tumour immunity. Through the visualisation method we established, for the first time, we showed that harmful active bacteria such as Streptococcus and Rhodococcus specifically accumulate in the middle and upper layers of tumour tissue. These bacteria likely participate in signalling pathways that affect macrophages by directly contacting or invading the macrophages, leading to a nondifferentiated state in macrophages and the loss of some immune functions. Furthermore, the accumulation of Streptococcus and Rhodococcus fragments in the deep layer of tumour tissue likely upregulates the expression of IL-10 in tumour tissue and inhibits other immune cells, such as CD8+ T cells, DC and NK cells. In contrast, XZ01 can specifically compete for the growth sites of Streptococcus and Rhodococcus in the middle and upper layers of tumour tissue and probably protects macrophages from being invaded by harmful bacteria. XZ01 directly regulates the polarisation of M0 macrophages towards the M1 phenotype by upregulating IFN-γ, thus activating tumour immunity to inhibit the growth of tumour cells. This study revealed that the influence of active microorganisms on the tumour immune microenvironment is crucial for effective immunotherapy intervention, potentially offering new targets for improving patient prognosis.

The human microbiome, an intricate ecosystem of trillions of microbes residing across various body sites, significantly influences cancer, a leading cause of morbidity and mortality worldwide. Recent studies have illuminated the microbiome's pivotal role in cancer development, either through direct cellular interactions or by secreting bioactive compounds such as metabolites. Microbial metabolites contribute to cancer initiation through mechanisms such as DNA damage, epithelial barrier dysfunction, and chronic inflammation. Furthermore, microbial metabolites exert dual roles on cancer progression and response to therapy by modulating cellular metabolism, gene expression, and signaling pathways. Understanding these complex interactions is vital for devising new therapeutic strategies. This review highlights microbial metabolites as promising targets for cancer prevention and treatment, emphasizing their impact on therapy responses and underscoring the need for further research into their roles in metastasis and therapy resistance.

The liver is the most commonly metastasized organ in colorectal cancer (CRC), and distant metastasis is the primary cause of mortality from CRC. In recent years, researchers have discovered that tumor cells create a "pre-metastatic niche (PMN)" favorable to metastasis before reaching the metastatic location. This review discusses the many processes and mechanisms that lead to PMN formation in CRC, including gut microbiota, stem cell stimulation, immunocyte interactions, and the induction of extracellular vesicles that carry important information. It examines research methods and diagnostic and therapeutic approaches for treating metastatic CRC with PMN. The crucial significance of PMN formation in metastatic CRC is also highlighted.

Tryptophan (Trp) is an essential amino acid that must be acquired exclusively through dietary intake. The metabolism of tryptophan plays a critical role in maintaining immune homeostasis and tolerance, as well as in preventing excessive inflammatory responses. Tryptophan-2,3-dioxygenase (TDO2) is a tetrameric heme protein and serves as one of the pivotal rate-limiting enzymes in the first step of tryptophan metabolism. Dysregulation of TDO2 expression has been observed in various digestive system diseases, encompassing those related to the oral cavity, esophagus, liver, stomach, pancreas, and colon and rectum. Digestive system diseases are the most common clinical diseases, with complex clinical manifestations and interrelated symptoms, and have become a research hotspot in the field of medicine. Studies have demonstrated that aberrant TDO2 expression is closely associated with various clinical manifestations and disease outcomes in patients with digestive system disorders. Consequently, TDO2 has garnered increasing recognition as a promising therapeutic target for digestive system diseases in recent years, attracting growing attention. This article provides a brief overview of the role of TDO2 in the tryptophan pathway, emphasizing its significant involvement in diseases of the digestive system. Strategies targeting TDO2 through specific inhibitors suggest considerable promise in enhancing therapeutic outcomes for digestive diseases. Thus, this review concludes by discussing recent advancements in the development of TDO2 inhibitors. We believe that targeted inhibition of TDO2 combined with immunotherapy, the screening of a large number of natural products, and the assistance of artificial intelligence in drug design will be important directions for developing more effective TDO2 inhibitors and improving treatment outcomes in the future.

As cancer research advances, the intricate relationship between the microbiome and cancer is gaining heightened recognition, especially concerning tumor metastasis, where bacterial involvement becomes increasingly complex. This review seeks to systematically examine the dual roles of bacteria in the tumor metastasis process, encompassing both mechanisms that facilitate metastasis and the inhibitory effects exerted by specific microorganisms. We explore the mechanisms through which bacteria influence tumor cell migration by inducing chronic inflammation, evading host immune responses, and remodeling the ECM. Moreover, the immunomodulatory potential of probiotics and genetically engineered bacteria offers promising prospects for the prevention and treatment of tumor metastasis. This article elucidates the complexity and emerging frontiers of bacterial involvement in tumor metastasis by examining the clinical significance of bacteria as potential biomarkers and evaluating the effects of antibiotic usage on the metastatic process. We posit that comprehending the biological characteristics and clinical significance of bacteria, as a critical component of the tumor microenvironment, will offer innovative strategies and theoretical foundations for cancer treatment. Furthermore, this article explores future research directions, including the application of microbiome technologies and bacteria-based therapeutic strategies, thereby offering a valuable perspective for the development of novel anti-cancer approaches.

Colorectal liver metastasis (CRLM) represents a major therapeutic challenge in colorectal cancer (CRC), with complex interactions between the gut microbiota and the liver tumor microenvironment (TME) playing a crucial role in disease progression via the gut-liver axis. The gut barrier serves as a gatekeeper, regulating microbial translocation, which influences liver colonization and metastasis. Through the gut-liver axis, the microbiota actively shapes the TME, where specific microbial species and their metabolites exert dual roles in immune modulation. The immunologically "cold" nature of the liver, combined with the influence of the gut microbiota on liver immunity, complicates effective immunotherapy. However, microbiota-targeted interventions present promising strategies to enhance immunotherapy outcomes by modulating the gut-liver axis. Overall, this review highlights the emerging evidence on the role of the gut microbiota in CRLM and provides insights into the molecular mechanisms driving the dynamic interactions within the gut-liver axis.

Lymph node metastasis (LNM) is a key factor in the prognosis of papillary thyroid carcinoma (PTC). This study explores the effect of intratumoral bacteria on LNM in PTC. The intrathyroidal microbiome is analyzed in 55 PTC patients by 16S rRNA gene sequencing. The CCK8 and Transwell assays determine the impact of bacteria on the proliferation and migration abilities of PTC cells. Xenograft tumor and bacterial colonization experiments are carried out using nude mice. We show that Lactobacillus is significantly decreased in PTC lesions from patients with LNM. Lactobacillus johnsonii (L. johnsonii) suppresses the proliferation and migration capability of PTC cells in vitro and in vivo. Bacterial gut colonization of L. johnsonii increases its abundance in tumors and inhibits PTC growth and LNM. These findings suggest that L. johnsonii can be harnessed for the development of innovative therapeutic strategies for PTC.

Acetochlor is a widely used and highly effective herbicide. Its overuse poses significant threats to biosecurity and ecological integrity, particularly affecting free-ranging birds. Data on its impact, especially mechanisms of liver toxicity in chickens, are lacking. Thus, we established an animal-cell-animal model to explore intrinsic mechanisms at multiple levels. We found that acetochlor exposure caused liver cell swelling, inflammatory cell accumulation, and lipid deposition. Transcriptomic analyses revealed that differential gene were mainly enriched in hepatic immune, inflammatory, and programmed cell death pathways. We next focused on the gene GPR120, conducting transfection and agonism experiments in LMH, HD11, and co-cultured cells. Acetochlor significantly increased ROS accumulation, activated the NLRP3 inflammasome, and which induced PANoptosis. HD11 cells exhibited M1 polarization with upregulated pro-inflammatory factors. Silencing GPR120 exacerbated cellular damage and immune responses, whereas its agonist, GSK7A, dramatically reduced macrophage M1 polarization and mitigated immune damage to LMH cells. Finally, we returned to animal studies, adding Omega-3-a known GPR120 agonist-to the diet. Omega-3 effectively reversed acetochlor-induced hepatitis and PANoptosis. Given that acetochlor residues pose potential threats to ecosystems and avian health, it is crucial to strengthen residue control, conduct risk assessments, and explore targeted pathways and nutritional supplementation to counteract these negative impacts.

Symbiotic microbiota plays a crucial role in the education, development, and maintenance of the host immune system, significantly contributing to overall health. Through the gut-liver axis, the gut microbiota and liver have a bidirectional relationship that is becoming increasingly evident as more research highlights the translocation of the gut microbiota and its metabolites. The focus of this narrative review is to examine and discuss the importance of the gut-liver axis and the enterohepatic barrier in maintaining overall health. Additionally, we emphasize the crucial role of the gut microbiome in liver diseases and explore potential therapeutic strategies for liver diseases by manipulating the microbiota.

This study aims to compare intestinal mucosal damage and the expression levels of occludin, zonula occludens-1 (ZO-1), vascular endothelial (VE)-cadherin, β-catenin, and plasmalemma vesicle-associated protein (PLVAP) in the gut vascular barrier (GVB) among people living with HIV (PLWH), asymptomatic PLWH, and healthy volunteers (non-PLWH). Three groups were selected for the study: PLWH, asymptomatic PLWH, and healthy volunteers. Colonic mucosal tissue samples were collected via colonoscopy from all participants. Histological examination of the colonic mucosa was conducted using hematoxylin and eosin staining. The expression levels of occludin, ZO-1, VE-cadherin, β-catenin, and PLVAP were assessed using RT-qPCR, immunohistochemistry, and western blot analyses. Pathological scores of colonic mucosa in PLWH and asymptomatic PLWH were significantly higher than those in non-PLWH (p < .001 and p = .0056, respectively). CD4+ T cell counts in asymptomatic PLWH and non-PLWH were significantly higher than in PLWH (p < 0.05). The CD4+/CD8+ T cell ratio in non-PLWH significantly exceeded those in PLWH and asymptomatic PLWH (p < .05). Analysis of protein and mRNA expression revealed: (1) no statistically significant differences in PLVAP-mRNA expression across all groups (p > .05); (2) higher PLVAP protein levels in PLWH compared with asymptomatic PLWH and non-PLWH (p < .05), with no significant differences between asymptomatic PLWH and non-PLWH (p = .632); (3) significantly higher PLVAP expression in the colonic mucosa of PLWH and asymptomatic PLWH compared with non-PLWH (p = .034 and p = .011, respectively), with no significant differences between PLWH and asymptomatic PLWH (p > .999). ZO-1 expression was significantly lower in PLWH than in non-PLWH (p = .012), with no notable differences between asymptomatic PLWH and other groups. PLWH, compared with healthy controls, exhibit significant inflammatory changes in the intestinal mucosa. PLVAP expression serves as a potential indicator to assess the extent of GVB damage and disease progression in PLWH.

Neutrophils, the most abundant myeloid cells in human peripheral blood, serve as the first defense line against infection and are also significantly involved in the initiation and progression of cancer. In colorectal cancer (CRC), neutrophils exhibit a dual function by promoting tumor events and exerting antitumor activity, which is related to the heterogeneity of neutrophils. The neutrophil extracellular traps (NETs), gut microbiota, and various cells within the tumor microenvironment (TME) are involved in shaping the heterogeneous function of neutrophils. This article provides an updated overview of the complex functions and underlying mechanisms of neutrophils in CRC and their pivotal role in guiding prognosis assessment and therapeutic strategies, aiming to offer novel insights into neutrophil-associated treatment approaches for CRC.

Growing evidence reveals that the tumor microbiome-comprising distinct microbial communities within neoplastic tissues-exerts a profound influence on cancer initiation, progression, and therapeutic response. These microbes actively reshape the tumor microenvironment (TME) through metabolite secretion, the modulation of immune pathways, and direct interactions with host cells, thereby affecting tumor biology and therapeutic outcomes. Despite substantial heterogeneity among cancer types, recent insights underscore the tumor microbiome's potential as both a diagnostic/prognostic biomarker and a targetable component for innovative treatments. In this review, we synthesize emerging knowledge on the mechanistic roles of tumor-associated microbiota in shaping the TME, with a focus on how these discoveries can guide novel therapeutic strategies. We further explore interdisciplinary advances, including the convergence of microbiomics and nanotechnology, to enhance drug delivery, circumvent resistance, and foster TME remodeling. By highlighting these cutting-edge developments, our review underscores the transformative potential of integrating tumor microbiome research into precision oncology and advancing more personalized cancer therapies.

Microorganisms, including bacteria, viruses, and fungi, have been found to play critical roles in tumor microenvironments. Due to their low biomass and other obstacles, the presence of intratumor microbes has been challenging to definitively establish. However, advances in biotechnology have enabled researchers to reveal the association between intratumor microbiota and cancer. Recent studies have shown that tumor tissues, once thought to be sterile, actually contain various microorganisms. Disrupted mucosal barriers and adjacent normal tissues are important sources of intratumor microbiota. Additionally, microbes can invade tumors by traveling through the bloodstream to the tumor site and infiltrating through damaged blood vessels. These intratumor microbiota may promote the initiation and progression of cancers by inducing genomic instability and mutations, affecting epigenetic modifications, activating oncogenic pathways, and promoting inflammatory responses. This review summarizes the latest advancements in this field, including techniques and methods for identifying and culturing intratumor microbiota, their potential sources, functions, and roles in the efficacy of immunotherapy. It explores the relationship between gut microbiota and intratumor microbiota in cancer patients, and whether altering gut microbiota might influence the characteristics of intratumor microbiota and the host immune microenvironment. Additionally, the review discusses the prospects and limitations of utilizing intratumor microbiota in antitumor immunotherapy.

The gut microbiota is closely associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). Probiotics such as Clostridium butyricum (CB) or Akkermansia muciniphila (AKK) have the potential to treat inflammatory bowel disease (IBD) or colorectal cancer (CRC). However, research on the combined therapeutic effects and immunomodulatory mechanisms of CB and AKK in treating IBD or CRC has never been studied. This study evaluates the potential of co-administration of CB and AKK in treating DSS/AOM-induced IBD and colitis-associated CRC. Our results indicate that compared to mono-administration, the co-administration of CB and AKK not only significantly alleviates symptoms such as weight loss, colon shortening, and increased Disease Activity Index in IBD mice but also regulates the gut microbiota composition and effectively suppresses colonic inflammatory responses. In the colitis-associated CRC mice model, a combination of CB and AKK significantly alleviates weight loss and markedly reduces inflammatory infiltration of macrophages and cytotoxic T lymphocytes (CTLs) in the colon, thereby regulating anti-tumor immunity and inhibiting the occurrence of inflammation-induced CRC. In addition, we found that the combined probiotic therapy of CB and AKK can enhance the sensitivity of colitis-associated CRC mice to the immune checkpoint inhibitor anti-mouse PD-L1 (aPD-L1), significantly improving the anti-tumor efficacy of immunotherapy and the survival rate of colitis-associated CRC mice. Furthermore, fecal microbiota transplantation therapy showed that transplanting feces from CRC mice treated with the co-administration of CB and AKK into other CRC mice alleviated the tumor loads in the colon and significantly extended their survival rate. Our study suggests that the combined use of two probiotics, CB and AKK, can not only alleviate chronic intestinal inflammation but also inhibit the progression to CRC. This may be a natural and relatively safe method to support the gut microbiota and enhance the host's immunity against cancer.

Our study suggests that the combined administration of CB and AKK probiotics, as opposed to a single probiotic strain, holds considerable promise in preventing the advancement of IBD to CRC. This synergistic effect is attributed to the ability of this probiotic combination to more effectively modulate the gut microbiota, curb inflammatory reactions, bolster the efficacy of immunotherapeutic approaches, and optimize treatment results via fecal microbiota transplantation.