Tumor Progression Research Articles

Spinal Intramedullary Tumors.

Intramedullary tumors are a subgroup of spinal tumors and are associated with high morbidity and mortality. The estimated incidence of spinal tumors in general is 0.74 to 1.6 per 100 000 persons per year, with intramedullary tumors making up 10% to 30% of the total. The diagnosis is often delayed because of the insidious onset of symptoms, which are often nonspecific at first. This review is based on pertinent publications about intramedullary tumors that were retrieved by a selective search in the PubMed database. Intramedullary tumors often cause diffuse neurologic symptoms of gradually increasing severity, progressing, in advanced cases, to a complete spinal cord transection syndrome. Magnetic resonance imaging of the spine without and with intravenous contrast is the standard diagnostic technique. The histopathological origin of most intramedullary tumors is from glial cells, but other types of intramedullary tumor exist as well. The primary treatment of all intramedullary tumors is surgical resection. 9% to 34% of patients may experience a worse neurological deficit after surgery than before, but such problems resolve completely in 25% to 41% of cases. The extent of resection is the main factor affecting the risk of tumor recurrence and progression. The extent of resection also determines the possible indication for adjuvant treatment, which is needed, in particular, for high-grade and subtotally resected tumors, and for those that display progression. The treatment of intramedullary tumors is based on case series, retrospective analyses, and case reports, as randomized trials are lacking. Patients with intramedullary tumors should be cared for, as much as possible, in the setting of prospective, uniform studies of their spontaneous course and the outcomes after treatment. This will yield better evidence on the treatment of these tumors in the future.

Teaching NeuroImage: Use of Arterial Spin Labeling to Differentiate Ictal Phenomenon From Tumor Progression in Grade 3 Astrocytoma.

Teaching NeuroImage: Use of Arterial Spin Labeling to Differentiate Ictal Phenomenon From Tumor Progression in Grade 3 Astrocytoma.

A trafficking regulatory subnetwork governs αVβ6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance.

HER2 and αVβ6 integrin are independent predictors of breast cancer survival and metastasis. We identify an αVβ6/HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound αVβ6 recruits HER2 and a trafficking subnetwork, comprising guanosine triphosphatases RAB5 and RAB7A and the Rab regulator guanine nucleotide dissociation inhibitor 2 (GDI2). The RAB5/RAB7A/GDI2 functional module mediates direct cross-talk between αVβ6 and HER2, affecting receptor trafficking and signaling. Acute exposure to trastuzumab increases recruitment of the subnetwork to αVβ6, but trastuzumab resistance decouples GDI2 recruitment. GDI2, RAB5, and RAB7A cooperate to regulate migration and transforming growth factor-β activation to promote invasion. However, these mechanisms are dysregulated in trastuzumab-resistant cells. In patients, RAB5A, RAB7A, and GDI2 expression correlates with patient survival and αVβ6 expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates αVβ6-HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive αVβ6-independent and HER2-independent tumor progression.

Expanding on roles of pleckstrin homology-like domain family A member 1 protein.

Pleckstrin homology-like domain, family A, member 1 (PHLDA1), one of the three members of PHLDA (1-3) family, has been reported to be expressed in mammalian cells and tissues and play diverse roles in various biological processes such as apoptosis, pyroptosis, and differentiation. Nevertheless, new roles and mechanisms of PHLDA1 action have come to light, with some needing further clarification. The major aim of the publication is to review proapoptotic or antiapoptotic roles of PHLDA1 in cancer, including ample evidence on PHLDA1 role as a tumor suppressor gene or oncogene and its influence on tumor progression. The role of PHLDA1 as a prognostic marker of cancer emerges, as well as its role in drug response and resistance. PHLDA1 involvement in autophagy, endoplasmic reticulum stress, pyroptosis, or differentiation is also scrutinized. It is also important to note that the association of PHLDA1 with miRNA regulation is described. Additionally, the emerging functions of PHLDA1 are indicated, specifically in inflammation and ischemia/reperfusion injury.

Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression

Extracellular vesicles (EVs) are known to mediate cell communications and shape tumor microenvironment. Compared to the well-studied small EVs, the function of large microvesicles (MVs) during tumorigenesis is poorly understood. Here we show the proteome of MVs in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), and identify olfactomedin 4 (OLFM4) is induced by EBV infection and secreted via MVs to promote tumor progression through Hippo signaling. Specifically, OLFM4 is a target gene of the cGAS-STING pathway, and EBV infection activates cGAS-STING pathway and increases OLFM4 expression. Moreover, MV-carried OLFM4 binds with the extracellular cadherin domain of FAT1, thereby impairing its intracellular interaction with MST1 and leading to YAP activation in recipient cells. Together, our study not only reveals a regulatory mechanism though which viral infection is coupled via MVs with intercellular control of the Hippo signaling, but also highlights the OLFM4-Hippo axis as a therapeutic target for EBV-associated cancers.

Do Pre-Treatment Biopsy Characteristics Predict Early Tumour Progression in Feline Diffuse Large B Cell Nasal Lymphoma Treated With Radiotherapy?

The standard of care treatment for localised feline nasal lymphoma (FeNL) is radiation therapy (RT). Early local or systemic failure occurs in 17%-45% of cats treated with RT with or without chemotherapy. The aim of this study was to determine if pre-treatment biopsy characteristics could predict early tumour progression in FeNL. Inclusion criteria consisted of histologically confirmed FeNL, available paraffin blocks of diagnostic quality, localised to the sinonasal cavity on staging pre-RT, treated with IMRT/IGRT (10 × 4.2 Gy) without chemotherapy and at least 1 year follow-up. All pre-RT biopsies were reviewed and evaluated with CD3, CD20, CD79a, pan-CK and Ki-67 immunohistochemistry and the mitotic activity index was determined. The primary endpoint was progression-free survival (PFS) at 1 year and hazard-ratios (HR) with confidence interval (CI) were calculated. Twenty-eight cats fit the inclusion criteria, and all had diffuse large B-cell lymphoma. Seventeen cats (61%) were progression free at 1 year. Of the 11 cats that progressed in the first year, two had local progression, two had both local and systemic progression and seven had systemic progression. The mitotic index (HR: 1.03, CI 0.9-1.19, p = 0.645), Ki-67 (HR: 1.00, CI 0.98-1.02, p = 0.845) and > 30% of tumour-infiltrating T cells (HR: 0.38, CI 0.09-1.56, p = 0.175) were not significantly associated with PFS. In this uniformly RT treated population of FeNL, none of the evaluated pre-RT histologic parameters could predict early treatment failure.

Oral squamous cell carcinoma in the Sudan: clinical behavior, DNA ploidy and S-phase fraction characteristics

BackgroundThe DNA ploidy and the S phase fraction (SPF) are associated with advanced tumors progression. The present study aimed to investigate the clinicopathological behavior of oral squamous cell carcinoma(OSCC) and the prognostication of the DNA ploidy and the SPF on its clinical outcomes.MethodsThis a prospective longitudinal study of 93 OSCC patients (186 specimens). Using high resolution flowcytometry, DNA analysis and SPF were performed for the primary tumor, field of cancerization and a control normal field. The patients were followed clinically for the development of recurrence or second primary tumor(SPT).ResultsAll the 93 patients are associated with wide field of cancerization. Out of the total number of cases, 28 (30%) patients developed recurrence. Of them 17 (18.3%) had regional recurrence, and eight (8.6%) had local recurrence. Second primary tumors were identified in 14 (15.1%) of the cases. Nodal metastasis, overall recurrence and SPTs were significantly associated with DNA aneuploidy and high SPF. High SPF and DNA hyperploidy showed a 28% increased risk of local recurrence (P.value = 0.032).ConclusionIn a series of 93 oral cancers who had wide field of cancerization, 30% of the patients developed recurrence, and 15% developed second primary tumors. The DNA ploidy and the SPF were independent prognosticators for the prediction of OSCC outcomes.

Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis

Advances in bladder cancer (BCa) treatment have been hampered by the lack of predictive biomarkers and targeted therapies. Here, we demonstrate that loss of the tumor suppressor NUMB promotes aggressive bladder tumorigenesis and worsens disease outcomes. Retrospective cohort studies show that NUMB-loss correlates with poor prognosis in post-cystectomy muscle-invasive BCa patients and increased risk of muscle invasion progression in non-muscle invasive BCa patients. In mouse models, targeted Numb ablation induces spontaneous tumorigenesis and sensitizes the urothelium to carcinogenic insults, accelerating tumor onset and progression. Integrative transcriptomic and functional analyses in mouse and human BCa models reveal that upregulation of YAP transcriptional activity via a RHOA/ROCK-dependent pathway is a hallmark of NUMB-deficient BCa. Pharmacological or genetic inhibition of this molecular pathway selectively inhibits proliferation and invasion of NUMB-deficient BCa cells in 3D-Matrigel organoids. Thus, NUMB-loss could serve as a biomarker for identifying high-risk patients who may benefit from targeted anti-RHOA/ROCK/YAP therapies.

Genomic Profiling in Glioma Patients to Explore Clinically Relevant Markers

Gliomas are a heterogeneous group of brain tumors, among which the most aggressive subtype is glioblastoma, accounting for 60% of cases in adults. Available systemic treatment options are few and ineffective, so new approaches to therapies for glioblastoma are in high demand. In total, 131 patients with diffuse glioma were studied. Paired tumor–normal samples were sequenced on the Illumina platform; the panel included 812 genes associated with cancer development. Molecular profiles in clinically distinct groups were investigated. In low-grade glioma (LGG) patients (n = 18), the most common mutations were IDH1/2 (78%), ATRX (33%), TP53 (33%), PIK3CA (17%), and co-deletion 1p/19q (22%). In high-grade glioma (HGG) patients (n = 113), more frequently affected genes were CDKN2A/B (33%), TERTp (71%), PTEN (60%), TP53 (27%), and EGFR (40%). The independent predictors of better prognosis were tumor grade and IDH1/2 mutations. In IDH—wildtype glioblastoma patients, a history of other precedent cancer was associated with worse overall survival (OS), while re-operation and bevacizumab therapy increased OS. Also, among genetic alterations, TERTp mutation and PTEN deletion were markers of poor prognosis. Nine patients received molecular targeted therapy, and the results were evaluated. The search for molecular changes associated with tumor growth and progression is important for diagnosis and choice of therapy.

FTO-mediated demethylation of MTUS1/ATIP1 promotes tumor progression in head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) has been recognized as the seventh most prevalent malignant tumor globally. It is a malignant neoplasm that arises from the mucosal epithelium of head and neck region. In our previous research, we have demonstrated that MTUS1/ATIP1 exhibits anti-cancer properties in HNSCC. Nevertheless, the underlying mechanism responsible for the reduction of MTUS1/ATIP1 expression has not been investigated.MethodsHNSCC and adjacent normal tissues were collected and examined using m6A MeRIP-seq, qRT-PCR, and IHC to investigate the relationship between MTUS1/ATIP1 and FTO. MeRIP-qPCR, m6A dot blot, RNA and protein stability assays, and RNC-qRT-PCR were employed to elucidate the mechanism by which FTO mediates demethylation of MTUS1/ATIP1 in HNSCC. Functional assays, subcutaneous tumorigenesis, and in situ tongue cancer models were conducted to assess the impact of the FTO-MTUS1/ATIP1 pathway on proliferative capacity of HNSCC tumors.ResultsFTO was observed to be markedly upregulated and showed a negative correlation with MTUS1/ATIP1 expression in HNSCC. FTO was responsible for mediating m6A demethylation in the 3’UTR of MTUS1/ATIP1, leading to its degradation. Additionally, silencing MTUS1/ATIP1 successfully reversed the tumor-promoting effects on HNSCC triggered by FTO in in vitro and in vivo.ConclusionsOur research elucidated the functional importance of FTO-mediated m6A demethylation of MTUS1/ATIP1, suggesting that targeting the FTO-MTUS1/ATIP1 axis could be a prospective novel approach for treating HNSCC.

FRK exerts oncogenic effects by targeting NQO2 via exosomal miR-9-3p to regulate mitochondrial function.

The role of Fyn-related kinase (FRK) in promoting tumor progression and metabolism in non-small cell lung cancer (NSCLC) has been demonstrated in our earlier study, and here we further explored whether exosome could serve as a key player in the relevant regulatory mechanism. Exosomes were isolated from the culture medium of FRK-knockout (KO) cells and co-cultured with NSCLC cells, showing negative effects on cell proliferation, metastasis, metabolism, and mitochondrial function. Exosomal miR-9-3p was selected as an intermediate messenger through microRNA (miRNA) sequencing. The miR-9-3p inhibitor and exosome inhibitor GW4869 were then applied in the co-culture system to verify the contribution of exosomal miR-9-3p to cell malignant phenotype and mitochondrial function. Moreover, NQO2, a potential target of exosomal miR-9-3p, was also suggested to be involved in the regulation of mitochondrial functional status. In brief, this study revealed a novel molecular mechanism by which FRK promotes the malignant progression of NSCLC by targeting NQO2 via exosomal miR-9-3p to strengthen mitochondrial function.

CRL3Keap1 E3 ligase facilitates ubiquitin-mediated degradation of oncogenic SRX to suppress colorectal cancer progression

The antioxidant protein sulfiredoxin-1 (SRX) is an oncogenic factor that promotes tumor progression, but the regulatory mechanism underlying SRX degradation remains to be understood. Herein, we report that Keap1, the substrate-specific adapter of CRL3 complex, specifically binds and promotes the ubiquitin-mediated degradation of SRX at residue K61. Keap1 knockdown accumulates SRX, which in turn facilitates colorectal cancer (CRC) metastasis by activating the activator protein-1/matrix metalloproteinase 9 (AP-1/MMP9) pathway. CRC-associated Keap1 mutants within the BACK domain lose the capability to ubiquitinate SRX and instead promote CRC metastasis. Moreover, inactivation of Keap1 facilitates CRC tumorigenesis and metastasis in mouse models of tumor xenograft due to SRX accumulation. Clinical sample analysis reveals that Keap1 is downregulated while SRX is overexpressed in CRC, which correlates with poor prognosis. Our findings elucidate a mechanism by which CRL3Keap1 ubiquitin ligase degrades SRX to suppress CRC progression, indicating that the Keap1-SRX axis will guide the targeted therapy towards CRC.

Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy.

This review examined the critical role of adenosine signaling in modulating the behavior of tumor-associated macrophages (TAMs), a key determinant of the tumor microenvironment (TME). Adenosine is an immunosuppressive metabolite that is highly enriched in the TME due to elevated expression of adenosine triphosphatase (ATPase). Adenosine influences polarization of TAMs through A2A and A2B receptors, which drives a phenotype that supports tumor progression and immune evasion. The adenosine-mediated regulation of TAMs significantly suppresses the TME, dampening the efficacy of current immunotherapies. Targeting the adenosine pathway has shown potential in preclinical studies through reversal of the immunosuppressive microenvironment and antitumor immune response enhancement. Clinical trials are currently underway to determine the impact of A2A receptor antagonists, and CD39 and CD73 inhibition, enzymes that are pivotal in adenosine production, in various cancers. The current understanding of the CD39-CD73-adenosine axis in TAM regulation and the emerging strategies targeting adenosine signaling pathway for therapeutic intervention are the subjects of this review. The current clinical trials focusing on adenosine pathway inhibitors in combination with existing therapies to improve clinical outcomes are summarized and the need for continued research to refine these approaches for cancer treatment is emphasized.

Identification and validation of cigarette smoking-related genes in predicting prostate cancer development through bioinformatic analysis and experiments

The morbidity and mortality rates of prostate cancer (PCa) are high among elderly men worldwide. Several factors, such as heredity, obesity, and environment are associated with the occurrence of PCa. Cigarette smoking, which is also an important factor in the development of PCa, can lead to genetic alterations and consequently promote PCa development. However, the smoking-induced genetic alterations in PCa are unclear. This study aimed to identify the potential smoking-related genes associated with PCa development. The smoking-related differentially expressed genes (DEGs) were identified using the Gene Expression Omnibus (GEO) which included lots of PCa datasets. DEGs were subjected to protein–protein interaction (PPI) network analysis to identify the hub genes. The pathways in which these hub genes were enriched were identified. The Cancer Genome Atlas (TCGA) dataset was used to examine the expression of smoking-related genes in PCa samples and estimate their value in predicting tumor progression and prognosis. In total, 110 smoking-related DEGs were got from GSE68135 dataset which included microarray data of PCa patients with smoking or not and 14 smoking-related key genes associated with PCa were identified from PPI network. The expression of the following seven key genes was altered in TCGA PCa patients: EWSR1, SRSF6, COL6A3, FBLN1, DCN, CYP2J2, and PLA2G2A. EWSR1, SRSF6, FBLN1, and CYP2J2 also influenced PCa progression. Additionally, EWSR1 influenced disease-free survival. In the logistic regression model, CYP2J2, which exhibited the highest risk scores, was identified as the risk gene for PCa. We also found one of the smoking-related genes: EWSR1 was truly upregulated in clinical PCa patients and influenced PCa cells invasion and proliferation. This study identified the function of smoking-related genes involved in the progression of PCa.

Epigenetic Modifiers: Exploring the Roles of Histone Methyltransferases and Demethylases in Cancer and Neurodegeneration

Histone methyltransferases (HMTs) and histone demethylases (HDMs) are critical enzymes that regulate chromatin dynamics and gene expression through the addition and removal of methyl groups on histone proteins. HMTs, such as PRC2 and SETD2, are involved in the trimethylation of histone H3 at lysine 27 and lysine 36, influencing gene silencing and activation. Dysregulation of these enzymes often leads to abnormal gene expression and contributes to tumorigenesis. In contrast, HDMs including KDM7A and KDM2A reverse these methylation marks, and their dysfunction can drive disease progression. In cancer, the aberrant activity of specific HMTs and HDMs can lead to the silencing of tumor suppressor genes or the activation of oncogenes, facilitating tumor progression and resistance to therapy. Conversely, in neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), disruptions in histone methylation dynamics are associated with neuronal loss, altered gene expression, and disease progression. We aimed to comprehend the odd activity of HMTs and HDMs and how they contribute to disease pathogenesis, highlighting their potential as therapeutic targets. By advancing our understanding of these epigenetic regulators, this review provides new insights into their roles in cancer and neurodegenerative diseases, offering a foundation for future research.

Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice

Cancer cells secrete extracellular vesicles (EV) encapsulating bioactive cargoes to facilitate inter-organ communication in vivo and are emerging as critical mediators of tumor progression and metastasis, a condition which is often accompanied by a dysregulated cholesterol metabolism. Whether EVs are involved in the control of cholesterol homeostasis during tumor metastasis is still undefined and warrant further investigation. Here, we find that breast cancer-derived exosomal miR-9-5p induces the expression of HMGCR and CH25H, two enzymes involved in cholesterol synthesis and the conversion of 25-hydroxycholesterol from cholesterol by targeting INSIG1, INSIG2 and ATF3 genes in the liver. Notably, in vivo miR-9-5p antagomir treatment and genetic CH25H ablation prevents tumor metastasis in a mouse model of breast cancer. Thus, our findings reveal the regulatory mechanism of tumor-derived miR-9-5p in liver metastasis by linking oxysterol metabolism and Kupffer cell polarization, shedding light on future applications for cancer diagnosis and treatment.

Regulation of Stromal Cells by Sex Steroid Hormones in the Breast Cancer Microenvironment

Breast cancer is a prevalent hormone-dependent malignancy, and estrogens/estrogen receptor (ER) signaling are pivotal therapeutic targets in ER-positive breast cancers, where endocrine therapy has significantly improved treatment efficacy. However, the emergence of both de novo and acquired resistance to these therapies continues to pose challenges. Additionally, androgens are produced locally in breast carcinoma tissues by androgen-producing enzymes, and the androgen receptor (AR) is commonly expressed in breast cancer cells. Intratumoral androgens play a significant role in breast cancer progression and are closely linked to resistance to endocrine treatments. The tumor microenvironment, consisting of tumor cells, immune cells, fibroblasts, extracellular matrix, and blood vessels, is crucial for tumor progression. Stromal cells influence tumor progression through direct interactions with cancer cells, the secretion of soluble factors, and modulation of tumor immunity. Estrogen and androgen signaling in breast cancer cells affects the tumor microenvironment, and the expression of hormone receptors correlates with the diversity of the stromal cell profile. Notably, various stromal cells also express ER or AR, which impacts breast cancer development. This review describes how sex steroid hormones, particularly estrogens and androgens, affect stromal cells in the breast cancer microenvironment. We summarize recent findings focusing on the effects of ER/AR signaling in breast cancer cells on stromal cells, as well as the direct effects of ER/AR signaling in stromal cells.

Single-nucleus CUT&RUN elucidates the function of intrinsic and genomics-driven epigenetic heterogeneity in head and neck cancer progression

Interrogating regulatory epigenetic alterations during tumor progression at the resolution of single cells has remained an understudied area of research. Here we developed a highly sensitive single-nucleus CUT&RUN (snCUT&RUN) assay to profile histone modifications in isogenic primary, metastatic, and cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) patient-derived tumor cell lines. We find that the epigenome can be involved in diverse modes to contribute towards HNSCC progression. First, we demonstrate that gene expression changes during HNSCC progression can be comodulated by alterations in both copy number and chromatin activity, driving epigenetic rewiring of cell states. Furthermore, intratumour epigenetic heterogeneity (ITeH) may predispose subclonal populations within the primary tumour to adapt to selective pressures and foster the acquisition of malignant characteristics. In conclusion, snCUT&RUN serves as a valuable addition to the existing toolkit of single-cell epigenomic assays and can be used to dissect the functionality of the epigenome during cancer progression.

Identification and validation of ATP6V1G1-regulated phosphorylated proteins in hepatocellular carcinoma.

V-ATPase Subunit G1 (ATP6V1G1) is one of the subunits of Vacuolar ATPases. Previous studies have indicated that ATP6V1G1 plays important roles in hepatocellular carcinoma (HCC) and is associated with HCC progression. However, the effect of ATP6V1G1 in HCC requires further elucidation. The aim of the present study was to explore the roles of ATP6V1G1 in HCC and further decipher the detailed mechanism. To identify the phosphorylated proteins regulated by ATP6V1G1 in HCC, phosphoproteomics and LC-MS/MS analysis were performed on HepG2 with overexpression of ATP6V1G1 and empty vector. Western blotting was applied to validate the differentially expressed phosphorylated proteins (DEPPs). As a result, 163 DEPPs were identified by proteomics; two up-regulated phosphorylated proteins (p-RPS6(Ser235)) and (p-SQSTM1(Ser272)) and two down-regulated phosphorylated proteins (p-PDPK1(Ser241)) and (p-EEF2 (Ser57)) were validated. Taken together, this study highlighted the potential impact of ATP6V1G1 on tumor progression, which may be beneficial to liver cancer related basic research.

Therapeutic potential of Xihuang Pill in colorectal cancer: Metabolomic and microbiome-driven approaches

IntroductionThe Xihuang Pill (XHP), a venerated traditional Chinese medicine, has demonstrated significant anti-cancer capabilities. Despite its proven efficacy, the scarcity of comprehensive pharmacological studies limits the widespread application of XHP. This research endeavor seeks to demystify the therapeutic underpinnings of XHP, particularly in the realm of colorectal cancer (CRC) therapy.MethodsIn this study, mice harboring CT26 tumors were divided into four groups, each administered with either XHP monotherapy, 5-fluorouracil (5-FU), or a combination of both. The tumor growth trajectory was closely monitored to evaluate the effectiveness of these anti-neoplastic interventions. Advanced techniques, including 16S-rDNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), were harnessed to scrutinize the gut microbiota and serum metabolite profiles. Immunohistochemical assays were employed to gauge the expression levels of CD4, CD8, and Foxp3, thereby providing insights into the dynamics of tumor-infiltrating lymphocytes within the tumor microenvironment.ResultsOur findings indicate that XHP effectively suppresses the initiation and progression of colorectal tumors. The combinatorial therapy of XHP with 5-FU exhibited an enhanced inhibitory effect on tumor growth. Metabolic profiling revealed that XHP induced notable metabolic shifts, particularly impacting pathways such as steroid hormone synthesis, arachidonic acid metabolism, purine biosynthesis, and renin secretion. Notably, 17α-ethinyl estradiol and α-ergocryptine were identified as serum metabolites with the most substantial increase following XHP administration. Analysis of the gut microbiome suggested that XHP promoted the expansion of specific bacterial taxa, including Lachnospiraceae_NK4A136_group, Clostridiales, Desulfovibrionaceae, and Anaerotignum_sp., while suppressing the proliferation of others such as Ligilactobacilus, Lactobacillus_taiwanensis, and Candidatus_saccharimonas. Immunohistochemical staining indicated an upregulation of CD4 and CD8 post-XHP treatment.ConclusionThis study delineates a potential mechanism by which XHP inhibits CRC tumorigenesis through modulating the gut microbiota, serum metabolites, and reshaping the tumor immune microenvironment in a murine CRC model. These findings contribute to a more profound understanding and potentially broaden the clinical utility of XHP in oncology.