OBJECTIVES: To explore the key role of myeloid-derived suppressive cells (MDSCs) in pre-metastatic niche (PMN) and analyze their interrelationships with the main components in the microenvironment using a mathematical model. METHODS: Mathematical descriptions were used to systematically analyze the functions of MDSCs in tumor metastasis and elucidate their association with the major components (vascular endothelial cells, mesenchymal stromal cells, and cancer-associated macrophages) contributing to the formation of the pre-metastatic microenvironment. Based on the formation principle of the pre-metastatic microenvironment of tumors, the key biological processes were assumed to construct a coupled partial differential diffusion equation model. The existence and uniqueness of the model solutions were investigated using approximation methods, the qualitative theory of partial differential equations and Banach's immovable point theorem, and numerical simulations were carried out by differential numerical methods to verify the reliability and accuracy of the model. RESULTS: The existence and uniqueness of the local and overall solutions of the model were proved using the approximation method, the qualitative theory of partial differential equations and Banach's immovable point theorem in combination with the regularity estimation of the local solutions and the embedding inequality. Numerical simulation results further validated the reliability of the model and demonstrated the important role of MDSCs in the pre-metastatic microenvironment of tumors, especially in angiogenesis and immunosuppression. CONCLUSIONS This study reveals the important functions of MDSCs in the pre-metastatic microenvironment of tumors through mathematical modeling and numerical simulation, which provides an important theoretical basis for understanding the mechanism of tumor metastasis and devising cancer treatment strategies.
Tumor Microenvironment ; Myeloid-Derived Suppressor Cells ; Neoplasm Metastasis ; Humans ; Models, Biological ; Models, Theoretical ; Neoplasms/pathology*

OBJECTIVES: To construct a nomogram for predicting the efficacy of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (aNSCLC) by integrating chest CT radiomics signature that reflects the tumor microenvironment (TME) and clinical parameters of the patients. METHODS: Transcriptomic and CT imaging data from TCGA, GEO and TCIA databases were integrated for weighted gene co-expression network analysis (WGCNA) of the GEO cohort to identify the immunotherapy-related genes (IRGs) associated with ICIs response. A prognostic model was built using these IRGs in the TCGA cohort to assess immune microenvironment features across different risk groups. Radiomics features were extracted from TCIA lung_3 cohort using PyRadiomics, and 94 features showing strong association with IRGs (|r|>0.4) were selected. A retrospective cohort consisting of 210 aNSCLC patients receiving first-line ICIs at Guangdong Provincial People's Hospital was analyzed and divided into training (n=147) and validation (n=63) groups. Least absolute shrinkage and selection operator was used for radiomic features selection, and logistic regression was applied to construct a combined clinical-radiomic model and nomogram for predicting ICIs therapy response. The performance of the model was evaluated using ROC curve, calibration curve, and decision curve analysis. RESULTS: WGCNA identified 84 IRGs enriched in immune activation pathways. The combined model outperformed individual models in both the training (AUC=0.725, 95% CI: 0.644-0.807) and validation cohorts (AUC=0.706, 95% CI: 0.577-0.836). Calibration curve and decision curve analyses confirmed the clinical efficacy of the nomogram for predicting ICIs therapy response in aNSCLC patients. CONCLUSIONS The genomic-radiomic-clinical multidimensional predictive framework established in this study provides an interpretable biomarker combination and clinical decision-making tool for evaluating ICIs efficacy in aNSCLC, potentially facilitating personalized immunotherapy decision-making.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; Tumor Microenvironment ; Lung Neoplasms/therapy* ; Immunotherapy ; Tomography, X-Ray Computed ; Nomograms ; Retrospective Studies ; Immune Checkpoint Inhibitors/therapeutic use* ; Prognosis ; Male ; Female ; Radiomics

OBJECTIVES: To establish a prognostic model for primary liver cancer (PLC) using bioinformatics methods. METHODS: Based on the data from 404 patients in the Cancer Genome Atlas (TCGA) database, we constructed a prognostic model integrating the differentially expressed genes, anoikis, and immune-related genes (DAIs) using univariate Cox regression and the LASSO-Cox approach. The predictive ability of the model was evaluated using Kaplan-Meier method and receiver-operating characteristic curves, and a nomogram was developed to facilitate its clinical applications. Gene set enrichment analysis (GSEA) was performed to explore the associated pathways and relationship between the DAIs and the tumor immune microenvironment, and the half-maximal inhibitory concentration (IC₅₀) of liver cancer drugs was calculated using the "pRRophetic" R package. We also detected the expression of SEMA7A in paired tumor and adjacent tissues from liver cancer patients. RESULTS: We constructed and validated a prognostic model based on 7 DAIs (NR4A3, SEMA7A, IL11, AR, BIRC5, EGF, and SPP1), and obtained consistent results in both the TCGA training cohort and GEO validation cohort (GSE14520), where the patients in the low-risk group were characterized by more favorable clinical outcomes and immune status. By integrating this prognostic signature with clinical information, a composite nomogram was generated. Somatic mutation analysis showed that TTN, TP53, and CTNNB1 mutations accounted for the largest proportion of total mutations, and the patients in the low-risk-low-TMB group had higher survival rate. Drug sensitivity analysis revealed differences in sensitivity to chemotherapeutic agents between high- and low-risk groups and between TP53 mutations and non-mutations. In clinical tissue specimens, SEMA7A expression was significantly higher in liver cancer tissues than in the adjacent tissues. CONCLUSIONS We established a new prognostic model based on DAIs for predicting clinical outcomes and therapeutic response of patients with primary liver cancer.
Humans ; Liver Neoplasms/diagnosis* ; Prognosis ; Anoikis ; Nomograms ; Computational Biology ; Tumor Microenvironment ; Semaphorins/metabolism*

OBJECTIVES: To investigate the expression levels of marginal zone B and B1-cell-specific protein (MZB1) in pan-cancer and its association with patient prognosis and tumor microenvironment (TME). METHODS: MZB1 expression data, clinicopathological parameters, and survival data from 33 cancer types were extracted from the UCSC database for analyzing the correlations of MZB1 with clinical stage, patient prognosis, immunomodulatory genes, immune checkpoint genes, tumor stemness, immune cell infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI). MZB1 gene mutations in pan-cancer were assessed using cBioPortal online database, and the value of MZB1 for cancer diagnosis was evaluated using ROC curve analysis. MZB1 expression levels in myeloid leukemia and renal carcinoma cells were detected using RT-qPCR and Western blotting, and the effect of MZB1 knockdown on cell proliferation was examined using EdU assay. RESULTS: MZB1 was significantly overexpressed in 20 cancer types, including kidney renal clear cell carcinoma (KIRC), breast invasive carcinoma, and acute myeloid leukemia. Its expression was associated with TNM stage, clinical stage, overall survival, and progression-free survival in multiple cancers. In most tumors, MZB1 expression was correlated significantly with immunomodulatory genes, immune checkpoint genes, tumor stemness, immune cell infiltration, TMB, and microsatellite instability. Gene amplification was the predominant mutation type of MZB1 in pan-cancer, and MZB1 showed high diagnostic value for skin cutaneous melanoma, KIRC, and head and neck squamous cell carcinoma. MZB1 was highly expressed in different myeloid leukemia cell lines and renal carcinoma cell lines, and MZB1 knockdown significantly suppressed the proliferation of HL60 and 769-P cells. CONCLUSIONS MZB1 is highly expressed in a variety of tumors, and its aberrant expression affects the occurrence and prognosis of many tumors, suggesting its potential as a novel tumor biomarker and immunomodulatory target.
Humans ; Prognosis ; Tumor Microenvironment ; Neoplasms/pathology* ; Cell Line, Tumor ; Mutation ; Kidney Neoplasms ; Microsatellite Instability ; Cell Proliferation ; Carcinoma, Renal Cell

OBJECTIVES: To investigate the prognostic significance of PDZ-binding kinase (PBK) in pan-cancer and its potential as a therapeutic target for pancreatic cancer. METHODS: PBK expression levels were investigated in 33 cancer types based on data from TCGA, GEO and CPTAC databases. RT-PCR and Western blotting were employed to examine PBK expression in clinical pancreatic cancer specimens and cell lines. The diagnostic and prognostic value of PBK in pancreatic cancer was evaluated using survival analysis, Cox regression analysis, ROC curve analysis, and clinical correlation studies. Gene enrichment and immune correlation analyses were conducted to explore the potential role of PBK in tumor microenvironment, and its correlation with drug sensitivity was investigated using GDSC and CTRP datasets. In pancreatic cancer BXPC-3 cells, the effects of lentivirus-mediated PBK knockdown on cell proliferation, migration, and invasion were examined using CCK-8, colony formation, and Transwell assays. The interaction between PBK and non-SMC condensin II complex subunit G2 (NCAPG2) was analyzed using co-immunoprecipitation and Western blotting. RESULTS: PBK was overexpressed in multiple cancer types, including pancreatic cancer. A high PBK expression was associated with a poor prognosis of the patients and correlated with immune infiltration and alterations in the tumor microenvironment. Elevated PBK expression was positively correlated with the sensitivity to MEK inhibitors (Trametinib) and EGFR inhibitors (Afatinib) but negatively with the sensitivity to Bcl-2 inhibitors (TW37) and niclosamide. In BXPC-3 cells, PBK knockdown significantly suppressed NCAPG2 expression and inhibited cell proliferation, migration, and invasion. Co-immunoprecipitation confirmed a direct binding between PBK and NCAPG2. CONCLUSIONS PBK is a key regulator of pancreatic cancer and interacts with NCAPG2 to promote tumor progression, suggesting its value as a potential biomarker and therapeutic target for pancreatic cancer.
Humans ; Pancreatic Neoplasms/genetics* ; Prognosis ; Biomarkers, Tumor/genetics* ; Cell Line, Tumor ; Cell Proliferation ; Adenocarcinoma/metabolism* ; Tumor Microenvironment ; Cell Movement ; Mitogen-Activated Protein Kinase Kinases

Immune suppression in the tumor microenvironment (TME) is closely related to abnormal glycolysis. Tumor cells gain metabolic advantages and suppress immune responses through the "Warburg effect". Traditional Chinese medicine (TCM) has been shown to regulate key glycolysis enzymes (such as HK2 and PKM2), metabolic signaling pathways (such as PI3K/AKT/mTOR, HIF-1α) and non-coding RNAs at multiple targets, thus synergistically inhibiting lactate accumulation, improving vascular abnormalities, and relieving metabolic inhibition of immune cells. Studies have shown that TCM monomers and formulas can promote immune cell infiltration and functions, improve metabolic microenvironment, and with the assistance by the nano-delivery system, enhance the precision of treatment. However, the dynamic mechanism of the interaction between TCM-regulated glycolysis and TME has not been fully elucidated, for which single-cell sequencing and other technologies provide important technical support to facilitate in-depth analysis and clinical translational research. Future studies should be focused on the synergistic strategy of "metabolic reprogramming-immune activation" to provide new insights into the mechanisms of tumor immunotherapy.
Humans ; Tumor Microenvironment/immunology* ; Glycolysis/drug effects* ; Neoplasms/drug therapy* ; Medicine, Chinese Traditional ; Signal Transduction ; Drugs, Chinese Herbal/pharmacology*

Microwave thermochemotherapy (MTC) has been applied to treat lip squamous cell carcinoma (LSCC), but a deeper understanding of its therapeutic mechanisms and molecular biology is needed. To address this, we used single-cell transcriptomics (scRNA-seq) and spatial transcriptomics (ST) to highlight the pivotal role of tumor-associated neutrophils (TANs) among tumor-infiltrating immune cells and their therapeutic response to MTC. MNDA⁺ TANs with anti-tumor activity (N1-phenotype) are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion, and these TANs are characterized by enhanced cytotoxicity, ameliorated hypoxia, and upregulated IL1B, activating T&NK cells and fibroblasts via IL1B-IL1R. In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC, fibroblasts accumulated in the tumor front (TF) can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs (pro-tumor phenotype) via CXCL12-CXCR4, which results in the aggregation of N1-TANs and extracellular matrix (ECM) deposition. In addition, we construct an N1-TANs marker, MX2, which positively correlates with better prognosis in LSCC patients, and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin (H&E)-stained images so as to conveniently guide decision making in clinical practice. Collectively, our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.
Humans ; Neutrophils/metabolism* ; Single-Cell Analysis ; Lip Neoplasms/genetics* ; Hyperthermia, Induced/methods* ; Microwaves/therapeutic use* ; Transcriptome ; Carcinoma, Squamous Cell/immunology* ; Tumor Microenvironment

In the ever-evolving landscape of cancer therapy, while cancer treatments such as chemotherapy, radiotherapy, and targeted therapy aim to eradicate malignant cells, they also inadvertently trigger cellular senescence in both cancerous and microenvironmental tissues. Therapy-induced senescence (TIS) can act as a barrier against tumor growth by halting cell proliferation in the short term, but the long-term persistence of therapy-induced senescent (TISnt) cells may pose a significant challenge in cancer management. Their distinct characteristics, like senescence-associated secretory phenotype (SASP), metabolic dysregulation, and immune evasion, make them exhibit remarkable heterogeneity to orchestrate the tumor microenvironment (TME), resulting in therapy resistance. However, how these TISnt cells functioning differently in cancer progression, and the intricate mechanisms by which they remodel the senescence-associated immunosuppressive microenvironment present challenges for improving anticancer therapy. Therefore, this review summarizes the heterogeneous TISnt cell phenotypes contributing to an accumulated senescent state, outlines their multidimensional interactions in the senescent microenvironment, and discusses current senescence-targeting strategies. Building on the current understanding of TIS, we propose potential avenues for improving TIS-targeting methodologies in the context of head and neck cancer, a representative heterogeneous malignancy, which can substantially enhance the efficacy of the "one-two punch" sequential treatment approach for head and neck cancer.
Humans ; Cellular Senescence/drug effects* ; Tumor Microenvironment ; Neoplasms/pathology* ; Senescence-Associated Secretory Phenotype

Metal ion-promoted chemodynamic therapy(CDT) combined with photodynamic therapy(PDT) offers broad application prospects for enhancing anti-tumor effects. In this study, glycyrrhizic acid(GA), copper ions(Cu~(2+)), and norcantharidin(NCTD) were co-assembled to successfully prepare a natural small-molecule, carrier-free hydrogel(NCTD Gel) with excellent material properties. Under 808 nm laser irradiation, NCTD Gel responded to the tumor microenvironment(TME) and acted as an efficient Fenton reagent and photosensitizer, catalyzing the conversion of endogenous hydrogen peroxide(H_2O_2) within the tumor into oxygen(O_2), and hydroxyl radicals(·OH, type Ⅰ reactive oxygen species) and singlet oxygen(~1O_2, type Ⅱ reactive oxygen species), while depleting glutathione(GSH) to stabilize reactive oxygen species and alleviate tumor hypoxia. In vitro and in vivo experiments demonstrated that NCTD Gel exhibited significant CDT/PDT synergistic therapeutic effects. Further safety evaluation and metabolic testing confirmed its good biocompatibility and safety. This novel hydrogel is not only simple to prepare, safe, and cost-effective but also holds great potential for clinical transformation, providing insights and references for the research and development of metal ion-mediated hydrogel-based anti-tumor therapies.
Hydrogels/chemistry* ; Animals ; Photochemotherapy ; Humans ; Mice ; Antineoplastic Agents/administration & dosage* ; Photosensitizing Agents/chemistry* ; Neoplasms/metabolism* ; Female ; Copper/chemistry* ; Reactive Oxygen Species/metabolism* ; Tumor Microenvironment/drug effects* ; Cell Line, Tumor ; Male

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal