Search Results (112)

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal effects (AEs), radiation-induced genomic instability (RIGI), and adaptive responses, which collectively influence the behavior of cancer cells and the tumor microenvironment (TME). TRT also modulates immune responses, promoting immune-mediated cell death and enhancing the efficacy of combination therapies, such as the use of immune checkpoint inhibitors. The molecular mechanisms underlying TRT involve DNA damage, oxidative stress, and apoptosis, with repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) playing critical roles. However, challenges such as tumor heterogeneity, hypoxia, and radioresistance limit the effectiveness of this approach. Advances in theranostics, which integrate diagnostic imaging with TRT, have enabled personalized treatment approaches, while artificial intelligence and improved dosimetry offer potential for treatment optimization. Despite the significant survival benefits of TRT in prostate cancer and neuroendocrine tumors, 30–40% of patients remain unresponsive, which highlights the need for further research into molecular pathways, long-term effects, and combined therapies. This review outlines the dual mechanisms of TRT, direct toxicity and NTEs, and discusses strategies to enhance its efficacy and expand its use in oncology. Full article

Radiotherapy (RT) continues to be a fundamental component in the management of non-small cell lung cancer (NSCLC). Nevertheless, some NSCLC patients do not attain optimal therapeutic outcomes due to the emergence of radioresistance. Improving the effectiveness of RT in NSCLC necessitates a thorough comprehension of the mechanisms that lead to radioresistance. This review delineates various potential mechanisms of radioresistance in NSCLC, encompassing augmented DNA damage repair, cell cycle dysregulation, cancer stem cells (CSCs), epithelial–mesenchymal transition (EMT), tumor hypoxia, an immunosuppressive tumor microenvironment (TME), dysregulation of cell death pathways, metabolic reprogramming, exosome-mediated signaling, genetic mutations, aberrant activation of signaling pathways, and epigenetic modifications. In addition, this study explores various novel strategies aimed at enhancing the radiosensitivity of NSCLC and provides a concise overview of potential biomarkers predictive of RT response, which may contribute to the development of innovative combination therapies to address radioresistance and improve patient outcomes. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy characterized by a complex tumor microenvironment (TME) that plays a critical role in disease progression and therapeutic resistance. Tumor-infiltrating immune cells, including T lymphocytes, macrophages, dendritic cells, and myeloid-derived suppressor cells, exhibit dual functions, either promoting or suppressing tumor growth depending on their phenotype and interactions within the TME. The presence of immune evasion mechanisms, such as the loss of human leukocyte antigen (HLA) expression, upregulation of immune checkpoint molecules, and metabolic reprogramming (hypoxia-induced glycolysis and lactate accumulation), further contributes to immune suppression and poor treatment responses. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent/metastatic HNSCC, response rates remain highly variable, underscoring the need for biomarker-driven patient selection and combinatorial therapeutic strategies. This review provides a comprehensive analysis of the role of immune cells in the TME of HNSCC, discusses the mechanisms underlying immune escape, and explores emerging immunotherapeutic and epigenetic-targeting approaches aimed at enhancing antitumor immune responses and improving clinical outcomes. Full article

The tumor microenvironment (TME) is crucial for the onset, development, and resistance to treatment of lung cancer. The tumor microenvironment consisting of a complex array of immune cells, fibroblasts, endothelial cells, extracellular matrix elements, and signaling molecules, facilitates tumor growth and spread while inhibiting the body’s antitumor immune response. In lung cancer, tumor-associated macrophages, cancer-associated fibroblasts, mast cells, and dendritic cells interact through cytokines, chemokines, growth factors, and matrix metalloproteinases to create an immunosuppressive and proangiogenic milieu. Hypoxic conditions within the TME further enhance cancer cell adaptability through hypoxia-inducible factors (HIFs), promoting epithelial–mesenchymal transition, immune evasion, and metastasis. Moreover, miRNAs have emerged as key regulators of gene expression within the TME, offering novel insights into tumor behavior and potential therapeutic targets. Targeting dynamic interactions within the TME, particularly through the modulation of immune responses, angiogenesis, and stromal remodeling, offers promising avenues for precision pharmacological approaches. This review covers the current understanding of the lung TME, highlighting its impact on cancer pathophysiology and treatment strategies. Understanding and therapeutically reprogramming the TME may pave the way for personalized and more effective interventions for lung cancer treatment. Full article

The tumor microenvironment (TME) plays a pivotal role in shaping immunometabolism in prostate cancer, influencing disease progression and therapeutic response. This review examines the dynamic interactions between tumor cells and immune cells within the prostate cancer TME, focusing on how metabolic reprogramming of both tumor and immune cells drives immunosuppression. Key immune players, including T-cells, macrophages, and myeloid-derived suppressor cells, undergo metabolic adaptations influenced by hypoxia, nutrient deprivation, and signaling from tumor cells. Additionally, we discuss the metabolic pathways involved, such as glycolysis and oxidative phosphorylation, and how these processes are exploited by cancer cells to evade immune surveillance. Furthermore, this review highlights potential therapeutic strategies targeting immunometabolism, including metabolic inhibitors and their combination with immunotherapies. A deeper understanding of the complex role of immunometabolism in prostate cancer will not only provide insights into the tumor’s immune evasion mechanisms but also facilitate the development of novel treatment approaches that enhance the efficacy of current therapies. Full article

Gallbladder cancer (GBC) is a highly aggressive malignancy with a propensity for lymph node metastasis (LNM), which significantly worsens prognosis. This review explores the molecular mechanisms underlying LNM in GBC, focusing on the roles of vascular endothelial growth factors (VEGFs), chemokines, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), hypoxia-inducible factors (HIFs), and non-coding RNAs (ncRNAs) in shaping the tumor microenvironment (TME). Unique features of GBC, such as its bile-rich microenvironment and hypoxia-driven lymphangiogenesis, are highlighted. We discuss how these factors promote lymphangiogenesis, immune evasion, and extracellular matrix (ECM) remodeling, collectively facilitating LNM. Potential therapeutic targets, including VEGF-C/D pathways, matrix metalloproteinase (MMP) inhibitors, and immune-modulating therapies, are also reviewed. Future research integrating single-cell omics and patient-derived organoid models is essential for advancing precision medicine in GBC. Full article

Hypoxia is a critical factor affecting tissue homeostasis that dramatically alters the tumor microenvironment (TME) through genetic, metabolic, and structural changes, promoting tumor survival and proliferation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in this process by regulating hundreds of genes involved in the processes of tumorigenesis, angiogenesis, metabolic reprogramming, and immune evasion. This review provides a comprehensive examination of the role of HIF-1α in hypoxia and how hypoxia weakens intercellular junctions—including gap junctions, adherens junctions, tight junctions, and desmosomes. The disruption of gap junctions decreases intercellular communication, which alters signal transduction cascades and tumor suppressive properties. Adherens junctions are comprised of proteins that characterize the tissues and link cells to the actin cytoskeleton, whereby their disruption promotes the epithelial-to-mesenchymal transition (EMT). Under hypoxic conditions, the tight junction proteins are dysregulated, altering paracellular transport and cell polarity. In addition, desmosomes provide linkage to intermediate filaments, and hypoxia compromises tissue integrity. Collectively, the influence of hypoxia on cellular junctions promotes tumorigenesis through reducing cell communication, cytoskeletal interactions, and altering signaling pathways. Activation of matrix metalloproteinases (MMPs) further degrades the extracellular matrix and enhances tumor invasion and metastasis. This process also involves hypoxia-induced angiogenesis, regulated by HIF-1α. A comprehensive understanding of the mechanisms of hypoxia-driven tumor adaptation is essential for developing effective therapeutic strategies. Furthermore, this review examines current treatments aimed at targeting HIF-1α and explores future directions to enhance treatment efficacy and improve patient outcomes. Full article

Cancer invasion and metastasis are critical factors that influence patient prognosis. Carbonic anhydrase IX (CA IX) and carbonic anhydrase XII (CA XII) are key regulators of hypoxia and pH homeostasis in the tumor microenvironment (TME). It has been verified that both CA IX and CA XII play significant roles in promoting tumor metastasis in recent years, but most of the literature tends to treat them as separate entities rather than exploring their synergistic effects. This review provides a comprehensive overview of the roles of CA IX and CA XII in tumor invasion and metastasis, along with their clinical applications, including their spatial distribution characteristics, molecular mechanisms that facilitate tumor metastasis, and their potential for clinical translation. Moreover, this review incorporates the classical tumor core–invasive front model to propose a metabolic coupling model of CA IX and CA XII, offering a fresh perspective on precision therapies that target tumor metabolism. By emphasizing the metabolic coupling between these two molecules, this review offers new insights distinct from previous studies and highlights the clinical therapeutic potential of simultaneously targeting both during treatment. It sheds new light on future research and clinical applications, aiming to enhance the prognosis of cancer patients through innovative therapeutic strategies. Full article

Reactive oxygen species (ROS) play a dual role in cancer progression, acting as both signaling molecules and drivers of oxidative damage. Emerging evidence highlights the intricate interplay between ROS, microRNAs (miRNAs), and exosomes within the tumor microenvironment (TME), forming a regulatory axis that modulates immune responses, angiogenesis, and therapeutic resistance. In particular, oxidative stress not only stimulates exosome biogenesis but also influences the selective packaging of redox-sensitive miRNAs (miR-21, miR-155, and miR-210) via RNA-binding proteins such as hnRNPA2B1 and SYNCRIP. These miRNAs, delivered through exosomes, alter gene expression in recipient cells and promote tumor-supportive phenotypes such as M2 macrophage polarization, CD8⁺ T-cell suppression, and endothelial remodeling. This review systematically explores how this ROS–miRNA–exosome axis orchestrates communication across immune and stromal cell populations under hypoxic and inflammatory conditions. Particular emphasis is placed on the role of NADPH oxidases, hypoxia-inducible factors, and autophagy-related mechanisms in regulating exosomal output. In addition, we analyze the therapeutic relevance of natural products and herbal compounds—such as curcumin, resveratrol, and ginsenosides—which have demonstrated promising capabilities to modulate ROS levels, miRNA expression, and exosome dynamics. We further discuss the clinical potential of leveraging this axis for cancer therapy, including strategies involving mesenchymal stem cell-derived exosomes, ferroptosis regulation, and miRNA-based immune modulation. Incorporating insights from spatial transcriptomics and single-cell analysis, this review provides a mechanistic foundation for the development of exosome-centered, redox-modulating therapeutics. Ultimately, this work aims to guide future research and drug discovery efforts toward integrating herbal medicine and redox biology in the fight against cancer. Full article

Glioblastoma multiforme remains one of the most aggressive and treatment-resistant brain tumors that necessitate innovative therapeutic approaches. Nanomedicine has emerged as a promising strategy to enhance radiation therapy by improving drug delivery, radiosensitization, and real-time treatment monitoring. Stimuli-responsive nanoparticles can overcome limitations of the blood–brain barrier, modulate tumor microenvironment, and facilitate targeted therapeutic interventions. The integration of nanotechnology with proton and X-ray radiotherapy offers improved dose precision, enhanced radiosensitization, and adaptive treatment strategies. Furthermore, Artificial Intelligence-driven nanoparticle designs are optimizing therapeutic outcomes by tailoring formulations to tumor-specific characteristics. While promising, clinical translation remains a challenge that requires rigorous validation to ensure safety and efficacy. This review highlights advancements in nanomedicine-enhanced radiotherapy and future directions for glioblastoma multiforme treatment. Full article

Photodynamic therapy (PDT) is an innovative treatment that has recently been approved for clinical use and holds promise for cancer patients. It offers several benefits, such as low systemic toxicity, minimal invasiveness, and the ability to stimulate antitumor immune responses. For certain types of cancer, it has shown positive results with few side effects. However, PDT still faces some challenges, including limited light penetration into deeper tumor tissues, uneven distribution of the photosensitizer (PS) that can also affect healthy cells, and the difficulties posed by the hypoxic tumor microenvironment (TME). In hypoxic conditions, PDT’s effectiveness is reduced due to insufficient production of reactive oxygen species, which limits tumor destruction and can lead to relapse. This review highlights recent advances in photosensitizers and nanotechnologies that are being developed to improve PDT. It focuses on multifunctional nanoplatforms and nanoshuttles that have shown promise in preclinical studies, especially for treating solid tumors. One of the key areas of focus is the development of PSs that specifically target mitochondria to treat deep-seated malignant tumors. New mitochondria-targeting nano-PSs are designed with better water solubility and extended wavelength ranges, allowing them to target tumors more effectively, even in challenging, hypoxic environments. These advancements in PDT are opening new doors for cancer treatment, especially when combined with other therapeutic strategies. Moving forward, research should focus on optimizing PDT, creating more efficient drug delivery systems, and developing smarter PDT platforms. Ultimately, these efforts aim to make PDT a first-choice treatment option for cancer patients. Full article

Malignant glioma is a highly aggressive, therapeutically non-responsive, and deadly disease with a unique tumor microenvironment (TME). Of the 14 currently recognized and described cancer hallmarks, five are especially implicated in malignant glioma and targetable with repurposed drugs: cancer stem-like cells, in general, and glioma stem-like cells in particular (GSCs), vascularization and hypoxia, metabolic reprogramming, tumor-promoting inflammation and sustained proliferative signaling. Each hallmark drives malignant glioma development, both individually and through interactions with other hallmarks, in which the TME plays a critical role. To combat the aggressive malignant glioma spatio-temporal heterogeneity driven by TME interactions, and to overcome its therapeutic challenges, a combined treatment strategy including anticancer therapies, repurposed drugs and multimodal immunotherapy should be the aim for future treatment approaches. Full article

Glioblastoma (GBM) is the most aggressive brain tumor, characterized by high recurrence rates and poor patient outcomes. Treatment failure is driven by multiple factors, including complex tumor heterogeneity, the presence of cancer stem cells, the immunosuppressive tumor microenvironment (TME), and many others. GBM’s heterogeneity underlines its ability to resist therapies and adapt to the TME. The TME, which is highly immunosuppressive and shaped by hypoxia, impairs anti-tumor immunity and limits the efficacy of immunotherapy. The blood–brain barrier (BBB) remains a major obstacle to delivering sufficient drug concentrations to the tumor by restricting the penetration of therapeutic agents. Another problem is the lack of reliable biomarkers to perform better patient stratification or even guide personalized treatments, resulting in generalized therapeutic approaches that do not adequately address GBM complexities. This review highlights the multifactorial nature of GBM treatment failure and highlights the need for a paradigm shift and innovative, personalized strategies. A deeper understanding of tumor biology and advances in translational research will be crucial to developing effective therapies and improving patient outcomes in this devastating disease. Full article

Recent developments in single-cell multi-omics technologies have provided the ability to identify diverse cell types and decipher key components of the tumor microenvironment (TME), leading to important advancements toward a much deeper understanding of how tumor microenvironment heterogeneity contributes to cancer progression and therapeutic resistance. These technologies are able to integrate data from molecular genomic, transcriptomic, proteomics, and metabolomics studies of cells at a single-cell resolution scale that give rise to the full cellular and molecular complexity in the TME. Understanding the complex and sometimes reciprocal relationships among cancer cells, CAFs, immune cells, and ECs has led to novel insights into their immense heterogeneity in functions, which can have important consequences on tumor behavior. In-depth studies have uncovered immune evasion mechanisms, including the exhaustion of T cells and metabolic reprogramming in response to hypoxia from cancer cells. Single-cell multi-omics also revealed resistance mechanisms, such as stromal cell-secreted factors and physical barriers in the extracellular matrix. Future studies examining specific metabolic pathways and targeting approaches to reduce the heterogeneity in the TME will likely lead to better outcomes with immunotherapies, drug delivery, etc., for cancer treatments. Future studies will incorporate multi-omics data, spatial relationships in tumor micro-environments, and their translation into personalized cancer therapies. This review emphasizes how single-cell multi-omics can provide insights into the cellular and molecular heterogeneity of the TME, revealing immune evasion mechanisms, metabolic reprogramming, and stromal cell influences. These insights aim to guide the development of personalized and targeted cancer therapies, highlighting the role of TME diversity in shaping tumor behavior and treatment outcomes. Full article

Drug resistance is a significant challenge in pancreatic ductal adenocarcinoma (PDAC), where stromal elements such as adipose-derived mesenchymal stem cells (ASCs) contribute to a chemoresistant tumor microenvironment (TME). This study explored the effects of oxaliplatin (OXP) and 5-fluorouracil (5-FU) on PDAC cells (Capan-1) and ASCs to investigate the mechanisms of chemoresistance. While OXP and 5-FU reduced Capan-1 viability in a dose- and time-dependent manner, ASCs demonstrated high resistance, maintaining > 90% viability even at cytotoxic doses. Transcriptomic analyses revealed OXP-induced transcriptional reprogramming in ASCs, with over 7000 differentially expressed genes, highlighting the pathways related to DNA damage response, cell cycle regulation, and stress-related signaling. In contrast, 5-FU elicited limited transcriptional changes, affecting only 192 genes. Cytokine proteome profiling revealed that OXP-treated ASCs significantly influenced the tumor microenvironment by promoting immune evasion (via IL-4, GM-CSF, IP-10, and GROα) and driving extracellular matrix remodeling (through EMMPRIN and DPPIV). In contrast, 5-FU induced comparatively weaker effects, primarily limited to hypoxia-related pathways. Although OXP reduced angiogenic factors, it paradoxically activated pro-survival pathways, thereby enhancing ASC-mediated tumor support. These findings underscore ASCs as modulators of chemoresistance via secretome alterations and stress adaptation. Therefore, future strategies should prioritize the precise targeting of tumor cells while also focusing on the development of personalized treatments to achieve durable therapeutic responses in PDAC. Full article