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Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment.

Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSC). Pan-cancer analyses have revealed that ste … iptional upregulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK-BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its …

Identification of a novel monocytic phenotype in Classic Hodgkin Lymphoma tumor microenvironment.

Classic Hodgkin lymphoma (CHL) characteristically shows few malignant cells in a microenvironment comprised of mixed inflammatory cells. Although CHL is associated with a high cure rate, recent studies have associated poor prognosis with absolute monocyte count in peripheral blood and increased monocyte/macrophages in involved lymph nodes. Thus, the role of monocytic infiltration and macrophage differentiation in the tumor microenvironment of CHL may be more relevant than absolute macrophage numbers to defining prognosis in CHL patients and potentially have therapeutic implications. Most studi…

Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12.

Radiotherapy is a mainstay in glioblastoma therapy as it not only directly targets tumor cells but also depletes the tumor microvasculature. The resulting intra-tumoral hypoxia initiates a chain of events that ultimately leads to re-vascularization, immunosuppression and, ultimately, tumor-regrowth. The key component of this cascade is overexpression of the CXC-motive chemokine ligand 12 (CXCL12), formerly known as stromal-cell derived factor 1 (SDF-1). We here review the role of CXCL12 in recruitment of pro-vasculogenic and immunosuppressive cells and give an overview on future and current dr

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… It has been demonstrated that MDSCs play a critical role in the development of an immunosuppressive tumor microenvironment [ 31 , 32 , 33 ] ( Figure 1 ). … Therefore, CXCL12/CXCR4 interaction could be considered as an important driving force of MDSC recruitment into the tumor microenvironment. …

Reprogramming the Tumor Microenvironment to Improve Immunotherapy: Emerging Strategies and Combination Therapies.

Emerging immunotherapeutic approaches have revolutionized the treatment of multiple malignancies. Immune checkpoint blockers (ICBs) have ena … rapies and limit irAEs. In fact, preclinical and clinical data have identified abnormalities in the tumor microenvironment (TME) that can thwart the efficacy of immunotherapies such as ICBs. Here, we will discuss how reprogramming various facets of the TME (blood vessels, myeloid cells, and regulatory T cells [Tregs]) may overcome TME-instigated resistance mechanisms to …

Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.

Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral tra

Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment.

Cancer microenvironment is created not only by malignant epithelial cells, but also by several kinds of stromal cells. Since Paget proposed the "seed and soil" hypothesis, the biological importance of the cancer microenvironment has come to be widely accepted. The main compartment of host stromal cells are fibroblasts (Cancer-Associated Fibroblasts; CAFs), which are the main source of the collagen-producing cells. CAFs directly communicate with the cancer cells and other types of stromal cells to acquire a specific biological phenotype. CAFs play important roles in several aspects of the tumor

Mesenchymal stem cells in the colorectal tumor microenvironment: recent progress and implications.

Mesenchymal stem cells (MSCs) are nonhematopoietic multipotent adult stem cells. They have been shown to have a natural tropism for many tumors types, including colorectal, and are capable of escaping host immune surveillance. MSCs are known to engraft at tumors and integrate into their architecture, potentially as carcinoma-associated fibroblasts. In contrast with other malignancies, our understanding of the interactions between colorectal cancer cells and MSCs remains limited. Considering the established importance of inflammation in the colorectal cancer primary tumor microenvironment and t…

PD-L1 in Merkel Cell Carcinoma: From Tumor Microenvironment to Pathological Interpretation.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma in which Merkel cell polyomavirus (MCPyV) oncoproteins and ultraviolet-induced mutations provide distinct sources of tumor immunogenicity. This narrative review examines the biological determinants, immunohistochemical assessment, and prognostic and therapeutic relevance of programmed death ligand 1 (PD-L1) in MCC, linking tumor immunobiology to pathological interpretation. PD-L1 expression on tumor and immune cells is often concentrated at tumor-immune interfaces, consistent with interferon-γ-driven adaptive

Astragaloside IV in hepatocellular carcinoma: repolarizing macrophages to reprogram the tumor microenvironment.

The establishment of an immunosuppressive tumor microenvironment (TME) represents a central mechanism underlying the failure of conventional therapies and resistance to immunotherapy in hepatocellular carcinoma (HCC). Tumor-associated macrophages (TAMs), as the most abundant immune cell population within this microenvironment, play a pivotal role in establishing immunosuppression, promoting angiogenesis, and driving therapeutic resistance through their polarization toward the M2 phenotype. Astragaloside IV (AS-IV), the principal bioactive constituent of the traditional Chinese medicine Astraga…

Ferroptosis and tumor microenvironment: orchestrating therapy resistance, immune evasion, and metastatic events.

Ferroptosis, an iron-dependent form of regulated cell death characterized by accumulation of lethal lipid peroxides, has emerged as a critic … ing it an attractive therapeutic target. However, the complex interplay between ferroptosis and the tumor microenvironment (TME) creates a double-edged sword that can either suppress or promote tumor progression. Recent evidence demonstrates that distinct cell populations within the TME exhibit differential sensitivities to ferroptosis, with profound consequences for tu …

HBV reprograms the tumor microenvironment in hepatocellular carcinoma: mechanisms and therapeutic implications.

Hepatitis B virus (HBV) infection is an important worldwide health issue and attribute to hepatocellular carcinoma (HCC) via direct oncogenic and indirect mechanisms. HBV reprograms the tumor microenvironment (TME) through immunosuppression, metabolic adaptation, and stromal remodel, allowing tumor promotion and immune evasion. This review examines HBV-induced TME changes, including epigenetic dysregulation, immune cell dysfunction, and fibrosis, as well as new therapeutic options including immune checkpoint blockade, adoptive cell therapy, and metabolic targeting to improve outcomes in HBV-re…

Dental Pulp Stem Cell-Derived Secretome-Induced Reprogramming of Tongue Tumor Microenvironment.

Oral tongue cancer is among the most aggressive malignancies in the head and neck region, driven by a complex tumor microenvironment (TME) that fosters tumor progression, immune evasion, and therapy resistance. Conventional treatments often fail to address the stromal and immunological intricacies of the TME, highlighting the need for microenvironment-targeted therapies. One promising strategy involves the use of dental pulp stem cell-derived secretome (DPSC-Sec), which contains a broad range of bioactive molecules, cytokines, chemokines, growth factors, and extracellular vesicles enriched wit…

Targeting CCR1 Remodels the Tumor Microenvironment and Relieves Immunosuppression in Pancreatic Cancer.

A hallmark of pancreatic cancer is an extensive fibroinflammatory stroma. Myeloid cells, including abundant macrophages, are a prevalent cellular component of the pancreatic cancer microenvironment and a key driver of immunosuppression. Identifying mechanisms of myeloid cell-driven immunosuppression is thus key to developing therapeutic approaches. Harnessing single-cell RNA sequencing data from human and murine tumors, we determined that tumor-infiltrating myeloid cells (including macrophages and granulocytes) have elevated expression of C-C motif chemokine receptor 1 (CCR1). To determine the

Tumor microenvironment-induced epigenetic reprogramming of Tregs and its impact on immunotherapy.

The tumor microenvironment (TME) represents a complex system comprising various cells and extracellular matrix components that play a crucial role in tumor initiation and progression. While recent therapeutic strategies for predominantly focus on targeting tumor cells, their impact on other cellular components in the TME, such as regulatory T (Treg) cells, remains insufficiently understood. The cellular components of the TME include tumor cells, immune cells, tumor-associated stromal cells, and myeloid-derived suppressor cells. Notably, the role of Treg cells in tumor therapy has emerged as a …

Nanomedicine strategies targeting STAT3 in cancer: From tumor suppression to microenvironment modulation.

Signal transducer and activator of transcription 3 (STAT3) is a central oncogenic signaling hub that regulates tumor proliferation, survival, metastasis, angiogenesis, immune evasion, and therapeutic resistance across multiple cancer types. Persistent STAT3 activation, driven by aberrant cytokine signaling, growth factor receptors, and oncogenic kinases, promotes transcriptional programs that support malignant progression and suppress antitumor immunity. Despite its recognized role as an attractive therapeutic target, direct pharmacological inhibition of STAT3 has been challenging because of p

Regulation of PD-1 and PD-L1 expression in tumor immune microenvironment.

Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) constitute a core immune checkpoint axis that restrains T cell activation. Under physiological conditions, the interaction between PD-1 and PD-L1 maintains peripheral tolerance and prevents tissue damage from excessive immune responses. In tumor microenvironment, this axis is frequently activated through upregulation of PD-L1 on cancer cells, causing T cell dysfunction and tumor immune escape. PD-1/PD-L1 blockades reactivate exhausted T cells to kill cancer cells. However, some cancer patients fail to respond to PD-1/…

Cross-Cancer Perspectives on CD40 Agonist Therapy: Modulating the Tumor Immune Microenvironment.

The CD40 pathway has become one of the most promising immunologic axes in oncology. As a central intermediary between innate and adaptive immunity, CD40 activation engages dendritic cells (DCs), amplifies antigen presentation, and stimulates potent cytotoxic T-cell (CTL) activity. Therapeutic CD40 agonists have been studied in a broad range of cancers over the past decade to reconfigure the tumor's immune microenvironment (TIME) and overcome immune refractoriness to standard immunotherapies. Clinical development has been most significant in pancreatic cancer, an exemplar cold tumor resistant t

Tumor microenvironment evolution in lung cancer: Spatio-temporal dynamics and clinical implications.

The treatment of non-small cell lung cancer (NSCLC), a disease known for its aggressiveness and significant global impact, has substantially … yond genetic and epigenetic changes within malignant cells, as the bidirectional crosstalk with the tumor microenvironment (TME) also plays a crucial role. This complex ecosystem, consisting of various cellular components (e.g., fibroblasts, endothelial cells, immune cells), extracellular matrix elements, and soluble factors, significantly influences tumor progression, …

Single-cell and spatial transcriptomic technologies for lung cancer tumor microenvironment analysis.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide; beyond its rising incidence, its marked molecular heterogeneity and complex tumor microenvironment (TME) hinder treatment response and drive resistance, contributing directly to its high mortality rate. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) provide complementary approaches for dissecting these features. scRNA-seq enables high-resolution analysis of cellular diversity and transcriptional states but requires tissue dissociation and therefore loses spatial context. In contrast, S…