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Hypoxic Stress-Induced Tumor and Immune Plasticity, Suppression, and Impact on Tumor Heterogeneity.

The microenvironment of a developing tumor is composed of proliferating cancer cells, blood vessels, stromal cells, infiltrating inflammator … coordinated by various cellular pathways. Accumulating data also suggest that hypoxic stress in the tumor microenvironment promotes tumor escape mechanisms through the emergence of immune-resistant tumor variants and immune suppression. Thus, solid tumors seem to build up a hostile hypoxic microenvironment that hampers cell-mediated immunity and dampen the efficacy of t …

Molecular mechanisms and clinical management of cancer bone metastasis.

As one of the most common metastatic sites of malignancies, bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish. The fenestrated capillaries in the bone, bone matrix, and bone cells, including osteoblasts and osteoclasts, together maintain the homeostasis of the bone microenvironment. In contrast, tumor-derived factors act on bone components, leading to subsequent bone resorption or excessive bone formation. The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases. In this review, we summarize the curr

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… microenvironment and is mainly produced by tumor-associated macrophages and tumor cells. 118 – 120 TNF-α was reported to accelerate tumor cell apoptosis at a high dose. 121 However, when released into the tumor microenvironment, TNF-α also promotes cancer metastases at a low dose. 122 The proinflammatory … microenvironment. 236 However, previous studies have found that MMP-2 promotes the release of bioactive fragments of ECM, such as endostatin, 237 restin, 238 and arrestin, 239 which inhibits angiogenesis. …

Spatial Regulation of Cancer-Associated Fibroblasts and Tumor Cells via pH-Responsive Bispecific Antibody Delivery for Enhanced Chemo-Immunotherapy Synergy.

The effectiveness of chemotherapy is often compromised by physiological barriers and an immunosuppressive tumor microenvironment. Cancer-associated fibroblasts (CAFs) significantly contribute to the reconfiguration of the tumor extracellular matrix (ECM) and the suppression of immune responses, making them crucial targets for therapeutic intervention. Here, a tumor acidic microenvironment-responsive delivery system that utilizes tumor cell-derived microparticles (MPs) as carriers for the chemotherapeutic agent doxorubicin (DOX) and the bispecific antibody YM101 targeting both TGF-β and PD-L1 i…

The role of long non-coding RNAs in breast cancer microenvironment.

The tumor microenvironment (TME), which includes tumor cells, fibroblasts, endothelial cells, immune cells, and blood vessels, can affect tumor growth and metastasis. Studies have shown that tumor cells, fibroblasts, and macrophages can promote the development of tumors, while T and B cells can inhibit tumor progression. The crosstalk among different cells within the TME needs further study. Long non-coding RNAs (lncRNAs) are involved in biological processes, including cell proliferation, migration, and differentiation. The abnormal expression of certain lncRNAs is correlated with the progress…

Fibroblast heterogeneity and its impact on extracellular matrix and immune landscape remodeling in cancer.

Tumor progression is marked by dense collagenous matrix accumulations that dynamically reorganize to accommodate a growing and invasive tumor mass. Cancer-associated fibroblasts (CAFs) play an essential role in matrix remodeling and influence other processes in the tumor microenvironment, including angiogenesis, immunosuppression, and invasion. These findings have spawned efforts to elucidate CAF functionality at the single-cell level. Here, we will discuss how those efforts have impacted our understanding of the ways in which CAFs govern matrix remodeling and the influence of matrix remodelin…

Nanozyme-Assisted Engineered Oncolytic Adenovirus for Improving Intratumoral Immune Deficiency and Enhancing Cancer Immunotherapy.

Oncolytic adenovirus (OA) exhibit tumor-selective tropism, inducing direct oncolysis while simultaneously potentiating host immune responses … cell death and activating tumor-specific cytotoxic T cells to attack tumors, thereby reversing the tumor microenvironment. OA@AuA, as a potent immunomodulator, not only has good biocompatibility, but also breaks the immunosuppressive state in the tumor microenvironment, enhances immune infiltration in the tumor microenvironment, reverses immunosuppressive "cold" tumors …

O2-sensing and HIF regulation: from oxygen homeostasis to tumor-associated immune responses.

Oxygen is needed to generate adenosine triphosphate (ATP) via aerobic respiration in mitochondria. Hypoxia-when the tissue's oxygen demand e … t tissues. In addition, HIF activation in many tumors promotes the creation of an immunosuppressive tumor microenvironment that prevents immune cells from effectively fighting the tumor. Therefore, promising approaches have been made in the combination of immune therapies with HIF inhibition. In this review, we highlight that a better understanding of the role of hypoxi …

New Insights into Monocyte-Derived Macrophages in Glioblastoma.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by an immunosuppressive microenvironment that importantly contributes to … int inhibitors, the dynamic spatiotemporal heterogeneity and adaptability of macrophages within the tumor microenvironment remain substantial therapeutic challenges. Future development in combination therapies, integrating single-cell multi-omics, spatial metabolic profiling, and targeted interventions, will be critical to precisely modulate MDMs, overcome immune tolera …

Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis.

The matrix metalloproteinases MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 are highly expressed in the tumor-bone microenvironment, and, of these, MMP-7 and MMP-9 were found to be localized to bone-resorbing osteoclasts in human breast-to-bone metastases. In a bid to define the roles of host-derived MMP-7 and MMP-9 in the tumor-bone microenvironment, the tibias of MMP-7 and MMP-9 null mice were injected with osteolytic luciferase-tagged mammary tumor cell lines. Our data show that osteoclast-derived MMP-7 significantly contributes to tumor growth and tumor-induced osteolysis whereas osteoclast-deriv

Fibrinogen-like protein 1 induces the formation of an immunosuppressive microenvironment by upregulating fibronectin 1 to promote immune evasion in bladder cancer.

OBJECTIVES: The role of fibrinogen-like protein 1 (FGL1) in the immune microenvironment in bladder cancer has been extensively studied, but the specific regulatory pathways require further investigation. MATERIALS AND METHODS: The overexpression vector of FGL1 or small interfering RNA was transfected into RT4 cells, and cell growth was observed. Tumor cells with altered FGL1 expression were co-incubated with peripheral blood mononuclear cells to simulate the immune microenvironment of bladder cancer in vitro, and the number and function of immune cells were monitored. The potential interactin

In Vivo Multiparametric Ultrasound Imaging of Structural and Functional Tumor Modifications during Therapy.

Longitudinal imaging techniques are needed that can meaningfully probe the tumor microenvironment and its spatial heterogeneity. Contrast-enhanced ultrasound, shear wave elastography and quantitative ultrasound are ultrasound-based techniques that provide information on the vascular function and micro-/macroscopic tissue structure. Modifications of the tumor microenvironment induced by cytotoxic and anti-angiogenic molecules in ectopic murine Lewis lung carcinoma tumors were monitored. The most heterogenous structures were found in tumors treated with anti-angiogenic drug that simultaneously a…

Babaodan suppresses inflammatory and vascular microenvironment in triple-negative breast cancer by inhibiting the cGAS-STING/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine compound Babaodan (BBD), originating from Ming Dynasty in China, is known for its "clearing heat, removing toxins, circulating blood and transforming stasis" effects. Recent evidence increasingly highlights its potential in tumor treatment. However, its efficacy and underlying pharmacological mechanisms in triple-negative breast cancer (TNBC) remain underexplored. AIM OF THE STUDY: This study aimed to investigate the therapeutic potential of the traditional Chinese medicine Babaodan (BBD) on the inflammatory and vascular microen

Phenotypic Diversity of Immunosuppressive B Cells Associated in Urothelial Carcinoma of the Bladder.

BACKGROUND: Urothelial carcinoma of the bladder presents a complex tumor microenvironment, with tumor-infiltrating B cells (TIL-Bs) playing a significant role in disease progression. Although their presence is acknowledged, the phenotypic diversity of regulatory TIL-Bs in bladder cancer remain underexplored. MATERIALS AND METHODS: In this study, we evaluated core B cell subsets and their immunosuppressive phenotypes in both peripheral blood (n=40) and bladder tumor tissues (n=40) to evaluate their relationship with disease severity. RESULTS: Our findings revealed that high-grade bladder tumo…

Spatial multiplexed immunofluorescence analysis reveals coordinated cellular networks associated with overall survival in metastatic osteosarcoma.

Patients diagnosed with advanced osteosarcoma, often in the form of lung metastases, have abysmal five-year overall survival rates. The complexity of the osteosarcoma immune tumor microenvironment has been implicated in clinical trial failures of various immunotherapies. The purpose of this exploratory study was to spatially characterize the immune tumor microenvironment of metastatic osteosarcoma lung specimens. Knowledge of the coordinating cellular networks within these tissues could then lead to improved outcomes when utilizing immunotherapy for treatment of this disease. Importantly, vari…

The yin-yang effects of immunity: From monoclonal gammopathy of undetermined significance to multiple myeloma.

Multiple myeloma (MM) is the third most common malignant neoplasm of the hematological system. It often develops from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) precursor states. In this process, the immune microenvironment interacts with the MM cells to exert yin and yang effects, promoting tumor progression on the one hand and inhibiting it on the other. Despite significant therapeutic advances, MM remains incurable, and the main reason for this may be related to the complex and variable immune microenvironment. Therefore, it is crucial to

Integrating antigen capturing nanoparticles and type 1 conventional dendritic cell therapy for in situ cancer immunization.

Eliciting a robust immune response against tumors is often hampered by the inadequate presence of effective antigen presenting cells and their suboptimal ability to present antigens within the immunosuppressive tumor microenvironment. Here, we report a cascade antigen relay strategy integrating antigen capturing nanoparticles (AC-NPs) and migratory type 1 conventional dendritic cells (cDC1s), named Antigen Capturing nanoparticle Transformed Dendritic Cell therapy (ACT-DC), to facilitate in situ immunization. AC-NPs are engineered to capture antigens directly from the tumor and facilitate their…

ChREBP-Mediated Choline Deprivation and Chemokine Secretion Shape Tumor-Associated Macrophages to Promote Immune Evasion.

UNLABELLED: Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of cancer. In this study, we found that carbohydrate-responsive element-binding protein (ChREBP)-mediated choline deprivation induced tumor-associated macrophage (TAM) reprogramming and maintained an immunosuppressive tumor microenvironment. Mechanistically, ChREBP interacted with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CCL7 and choline transporter SLC44A1. A…

Intratumoral microbiota-driven macrophage reprogramming in pancreatic cancer via Blautia metabolite 6-hydroxyhexanoic acid.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a particularly immunosuppressive microenvironment, which contributes to its poor prognosis and resistance to conventional therapies. Recent studies have highlighted the microbiome as a dynamic regulator of anti-tumor immunity, ultimately contributing to tumor suppression. The tumor microenvironment is increasingly recognized as a dynamic ecosystem where the microbiome plays a pivotal role in shaping immune responses. Therefore, it is crucial to explore the specific biological processes by which intratumoral microbiome suppresses tumor growth and…

Single cell profiling of γδ hepatosplenic T-cell lymphoma unravels tumor cell heterogeneity associated with disease progression.

PURPOSE: Hepatosplenic T-cell lymphoma (HSTCL), mostly derived from γδ T cells, is a rare but very aggressive lymphoma with poor outcomes. I … of bioinformatics analysis, we investigated the gene expression profile of γδ HSTCS as well as its tumor microenvironment (TME). RESULTS: We characterized the unique gene expressing signatures of malignant γδ T cells with a set of marker genes were newly identified in HSTCL (AREG, PLEKHA5, VCAM1 etc.). Although the malignant γδ T cells were expanded from a single TCR …

Regulation of Ion Homeostasis for Enhanced Tumor Radio-Immunotherapy.

Intra/extracellular ion content affects the growth and metastasis of tumor cells, as well as the efficacy of various antitumor therapies. Herein, a carbonic anhydrase inhibitor (CAI) is loaded onto pH-responsive calcium carbonate (CaCO3 ) nanoparticles and then modify theses nanoparticles with liposomes to obtain biocompatible CaCO3 /CAI@Lipsome (CCL) for enhance tumor radio-immunotherapy. CCL can specially decompose in tumor microenvironment, releasing calcium ion (Ca2+ ) and CAI, as well as increasing the pH value of extracellular fluid. CAI restrains the flow of hydrogen ion (H+ ) inside an…