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A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer.

Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis in several cancers. Here, we have determined that CCR4 was highly expressed in human renal cell carcinoma (RCC) biopsies and observed abnormal levels of CCR4 ligands in RCC patient plasma. An antagonistic anti-CCR4 antibody had antitumor activity in the RENCA mouse model of RCC. CCR4 inhibition did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cell and Th1 cytokine levels, and reduced immature myeloid cell i…

Peptide ligand-modified nanomedicines for targeting cells at the tumor microenvironment.

Since their initial discovery more than 30years ago, tumor-homing peptides have become an increasingly useful tool for targeted delivery of therapeutic and diagnostic agents into tumors. Today, it is well accepted that cells at the tumor microenvironment (TME) contribute in many ways to cancer development and progression. Tumor-homing peptide-decorated nanomedicines can interact specifically with surface receptors expressed on cells in the TME, improve cellular uptake of nanomedicines by target cells, and impair tumor growth and progression. Moreover, peptide ligand-modified nanomedicines can …

Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype.

UNLABELLED: The majority of hepatocellular carcinoma develops in the background of chronic liver inflammation caused by viral hepatitis and alcoholic or nonalcoholic steatohepatitis. However, the impact of different types of chronic inflammatory microenvironments on the phenotypes of tumors generated by distinct oncogenes is largely unresolved. To address this issue, we generated murine liver tumors by constitutively active AKT-1 (AKT) and β-catenin (CAT), followed by induction of chronic liver inflammation by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride. Also, the

Dysfunctional Antibodies in the Tumor Microenvironment Associate with Impaired Anticancer Immunity.

PURPOSE: Studies have demonstrated that cancer-associated matrix metalloproteinases (MMP) can generate single peptide bond cleavages in the hinge region of immunoglobulin G1 (IgG1). This study investigated the cleavage of endogenous IgGs by MMPs in the tumor microenvironment and the consequences of the IgG hinge cleavage for humoral immunity. EXPERIMENTAL DESIGN: We investigated the occurrence of single peptide bond cleaved IgGs (scIgG) in tumor tissues and plasma samples collected from a cohort of breast cancer patients (n = 60). Samples from healthy people (n = 20) were used as the control.…

Targeting mast cells tryptase in tumor microenvironment: a potential antiangiogenetic strategy.

Angiogenesis is a complex process finely regulated by the balance between angiogenesis stimulators and inhibitors. As a result of proangiogenic factors overexpression, it plays a crucial role in cancer development. Although initially mast cells (MCs) role has been defined in hypersensitivity reactions and in immunity, it has been discovered that MCs have a crucial interplay on the regulatory function between inflammatory and tumor cells through the release of classical proangiogenic factors (e.g., vascular endothelial growth factor) and nonclassical proangiogenic mediators granule-associated (

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… As above described, indeed, in the tumor microenvironment, tryptase may upregulate uPA levels, [ 25 , 26 , 75 ] thereby activating latent TGF- β which, in turn, upregulates the production of uPA, MMP-2, and VEGF. … SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood. 2008;112(4):1269–1279. doi: 10.1182/blood-2008-03-147033. 80. Ribatti D, Vacca A, Ria R, et al. …

Tumor microenvironment-responsive injectable hydrogels for localized therapy of pancreatic cancer.

To address the clinical need for localized therapy for pancreatic cancer, an injectable, self-healing nanocomposite hydrogel (GPPA-Mn@DOX) was rationally designed and developed. The hydrogel consists of phenylboronic acid-modified gelatin (Gel-PBA) and polyvinyl alcohol (PVA), which are crosslinked through dynamic boronate ester bonds and loaded with doxorubicin (DOX)-containing hollow mesoporous MnO2 (H-MnO2) nanocarriers. This integrated design enables tumor microenvironment (TME)-responsive drug release while facilitating in situ O2 generation. The resulting network exhibits a three-dimensi…

Cancer heterogeneity explored through immune cell deconvolution of the tumor microenvironment.

Cancer is a highly heterogeneous disease, characterized by significant variability across multiple dimensions. This diversity has been extensively studied from various perspectives. In this study, we aim to examine cancer heterogeneity through the lens of immune cell composition within the tumor microenvironment. Transcriptome profiles of 11,274 subjects from 33 cancer types were deconvoluted to infer the composition of 22 immune cell types. A deep learning-based model was adapted to model a binary outcome for cancer type, tumor versus normal. The Shannon index was used to represent immune cel…

STING-mediated tumor microenvironment remodeling: turning adaptive resistance into therapeutic vulnerability.

Resistance to cancer immunotherapy is frequently sustained by immune exclusion, suppressive myeloid and stromal programs, abnormal tumor vasculature, and inhibitory checkpoint-ligand expression within the tumor microenvironment. Activation of the cGAS-STING (cyclic GMP-AMP Synthase)- (Stimulator of Interferon Genes) pathway has emerged as a context-dependent strategy to modulate the cancer immunity cycle and remodel resistant tumor ecosystems, with the potential to convert selected poorly inflamed immune-excluded tumors into immune-reactive lesions. However, STING activation does not simply "t…

TiRank prioritizes phenotypic niches in tumor microenvironment for clinical biomarker discovery.

BACKGROUND: Tumor microenvironment (TME) plays a crucial role in cancer progression, metastasis, and treatment response. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have provided valuable insights into the cellular diversity and spatial organization of the TME. However, prioritizing clinically relevant cellular subpopulations in spatial contexts using high-dimensional and sparse data remains a challenge. METHODS: We introduce TiRank, a novel framework designed to prioritize clinically relevant spatial niches. TiRank incorporates a relative express…

Unraveling the glioblastoma (GBM) tumor microenvironment: future perspective on targeted immunotherapy.

Glioblastoma (GBM) is one of the most aggressive, fast-growing, and therapeutically challenging brain tumors. The difficulty in managing GBM stems from its genetic instability and the intricately complex tumor microenvironment (TME). Within the TME, intricate interactions between neoplastic cells and signaling mediators drive tumor progression. Despite advances in current treatments, obstacles such as the blood-brain barrier (BBB) and pronounced inter- and intratumoral heterogeneity continue to hinder therapeutic success. Consequently, research efforts have increasingly focused on immunotherap…

DJ-1 inhibition reshapes tumor microenvironment and potentiates immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) can essentially treat cancer but only in a small subset of patients. Treatment strategies capable of eff … ile reducing immune-suppressive Spp1+ macrophages. Notably, this reprogramming may be stable across tumor microenvironments because the transplanted DJ-1-deficient macrophages maintain T cell-activating capacity. Pharmacological inhibition of DJ-1 by disulfiram markedly potentiated antitumor efficacy of PD-1 blockade. This designates DJ-1 as a promising target for overc …

TMEM201 regulates tumor malignancy and immune microenvironment in lower-grade glioma.

BACKGROUND: TMEM201, a nuclear membrane protein, is thought to play an important role in tumor progression, but its involvement in lower-grade glioma (LGG) remains unclear. This study aims to investigate the impact of TMEM201 expression on the prognosis, clinical characteristics, and biological behaviors of LGG. METHODS: RNA expression data from the TCGA, CGGA, and GEO databases were analyzed to explore the correlation between TMEM201 expression and clinical features of LGG. In vitro and in vivo experiments were conducted to assess the effects of TMEM201 knockdown on cell proliferation, migrat

MCT1 Inhibition Remodels the Tumor Immune Microenvironment for Enhanced Cancer Immunotherapy.

Despite advances in cancer immunotherapies such as immune checkpoint blockade (ICB), durable patient responses remain constrained, which is largely due to the highly suppressive tumor immune microenvironment (TIME). In this study, by analyzing cohorts of patients with pan-cancer and experimental validation, we found that monocarboxylate transporter 1 (MCT1) expression is broadly upregulated in malignant and myeloid compartments within the TIME. MCT1 expression is also associated with worse survival, a suppressive TIME state, and poor treatment response to ICB therapy. Functionally, MCT1-mediat

A malignant symbiosis: The neuro-metabolic symphony rewires the tumor microenvironment.

Emerging evidence in cancer neuroscience has established a reciprocal bidirectional loop between neural signaling and tumor metabolism as a central driver of malignant progression. This review critically evaluates bidirectional neuro-metabolic symbiosis and its profound implications for overcoming treatment refractoriness. We first analyzed the anterograde mechanism, in which peripheral nerve terminals and systemic endocrine factors impose distinct metabolic dependencies on malignant and stromal cell populations. By forcing alterations in nutrient utilization pathways, these neural cues create

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… The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374–403. doi: 10.1016/j.ccell.2023.02.016. 2. Sharma P., Aaroe A., Liang J., Puduvalli V.K. Tumor microenvironment in glioblastoma: current and emerging concepts. Neurooncol. … Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment. J. Exp. Clin. Cancer Res. 2023;42(1):59. doi: 10.1186/s13046-023-02634-z. 4. Yang K., Wang X., Song C., He Z., Wang R., Xu Y., et al. The role of lipid metabolic reprogramming in tumor microenvironment. …

PINCH-1-dependent regulation on tumor matrix microenvironment in pancreatic cancer.

Cancer-associated fibroblasts (CAFs) are vital in advancing pancreatic ductal adenocarcinoma (PDAC) cancer growth and fibrosis. Although the … NCH-1/Notch1/AKT axis presents a novel theragnostic strategy to simultaneously disrupt the fibrotic tumor microenvironment and inhibit tumor growth in PDAC. (188 words).

Spatial transcriptomics reveals tumor microenvironment-driven subtypes of invasive lobular carcinoma.

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and displays distinct clinical and biological behavior compared to breast cancer of no special type. However, current molecular classifications largely overlook its complex spatial organization and tumor microenvironment (TME). Here, we performed spatial transcriptomics on 43 hormone receptor-positive, HER2-negative (HR+/HER2-) ILC tumors with detailed morphological annotation and long-term clinical follow-up. By integrating spatial gene expression with histology and single-cell deconvolution, we c…

Mechanical Microenvironment-Dependent Tumor Growth Intervention: Recent Advances and Translational Outlook.

In recent years, increasing attention has been directed toward the mechanical microenvironment, which has become a major research focus in elucidating the mechanisms underlying tumor progression. On one hand, endogenous mechanical cues, such as matrix stiffness, fluid shear stress(FSS), and mechanical strain, have been shown to promote tumor cell malignant phenotypes, including proliferation, migration, 4 invasion, and drug resistance. These activities are primarily through mechano-transduction pathways involving integrin-FAK and YAP/TAZ. Meanwhile, mechanical microenvironment was also found t

Hierarchical Collagen Nanofiber Gels Recapitulate a Physiologically Relevant Tumor Stromal Microenvironment.

Cancer tissue forms cancer stroma with a high elastic modulus due to increased type I collagen (Col I) production from fibroblasts and cross-linking of Col I fibers. Stiffened cancer stroma acts on cancer cells as a mechanical stress and promotes cancer progression. This highlights the need for culture scaffolds that recapitulate the structural, mechanical, and biological characteristics of the tumor stromal microenvironment. In this study, we attempted to create a scaffold material that mimics the fibrous structure and elastic modulus of in vivo cancer tissue using Col I. By gelation with col

Nanosensitizer for enhanced radiotherapy via tumor microenvironment reshaping and ROS amplification.

Rationale: Radiotherapy is a principal modality in cancer treatment, effectively controlling local tumor growth and possessing the potential to enhance the immunogenicity of tumor cells, thereby improving the antitumor immunity. However, its efficacy is often limited by insufficient production of reactive oxygen species (ROS), tumor hypoxia, and the immunosuppressive tumor microenvironment (TME). Therefore, developing strategies to amplify ROS and reshaping the hypoxic, immunosuppressive TME is crucial for advancing radiotherapy. Methods: In this study, we designed a polyethylene glycol (PEG)-…

Bifunctional Phagocytic Synapse Enhancers Remodel the Tumor Microenvironment to Overcome Immunosuppression.

Current immunotherapies often fail in immunologically "cold", macrophage-rich tumor microenvironments (TMEs). Multi-targeting approaches that modulate innate-adaptive immune activation represent a promising frontier in cancer immunotherapy. Here, we developed phagocytic synapse enhancers (PSEs), a class of modular immune engagers comprising a high-affinity PD-L1 binder coupled to a macrophage-stimulating peptide, tuftsin. PSEs strengthened effector-target cell interactions and enhanced tumor phagocytosis by bridging tumor PD-L1 to macrophage neuropilin-1 (NRP1), bypassing the classical FcγR-de…