Search Results (148)

Inflammation can either encourage or suppress tumor growth, thus having a two-sided effect on cancer development. This depends on the balance between pro-tumor and anti-tumor immune responses within the tumor microenvironment (TME). Pro-tumor inflammation, driven by specific immune cells, enhances blood flow and nutrient supply to tumors, promoting the activation of dormant cancer cells (DCCs). Conversely, antitumor inflammation hinders blood flow and can force active cancer cells into a state of dormancy. Tumors actively shift this balance towards pro-tumor inflammation to create a favorable environment for growth. Therefore, anti-inflammatory therapy may be an integral part of comprehensive cancer immunotherapy. This review explores how different anti-inflammatory medications, such as glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines, anti-leukotrienes, statins, drugs that block pro-inflammatory cytokines, agents that inhibit oxidative phosphorylation, antioxidant vitamins, anti-angiogenic drugs, and low-dose chemotherapy, can be used to combat cancer. Granulocyte counts and erythrocyte sedimentation rate (ESR) can be used to assess inflammation levels and the effectiveness of anti-inflammatory treatments. We advocate for a paradigm shift in cancer treatment, moving away from aggressive tumor destruction, which triggers uncontrolled tumor regeneration, toward long-term immunological control of tumor growth while preserving the patient’s overall health. Full article

Bone metastasis is often treated clinically as a late complication of advanced cancer, yet accumulating evidence indicates that it is also a spatial evolutionary process shaped by clonal selection, niche adaptation, dormancy, and reseeding. This review examines BoM through a phylogeographic framework that links tumor ancestry with anatomical location and time. We discuss how heterogeneous primary tumors generate bone-tropic subclones, how circulating tumor cells pass through dissemination bottlenecks, and how disseminated tumor cells enter perivascular and endosteal niches that either maintain dormancy or support early micrometastatic outgrowth. We then compare clonal architectures across breast, prostate, lung, and renal cell carcinomas, emphasizing both lineage-specific programs and convergent bone-adaptive states, including osteomimicry, immune evasion, metabolic plasticity, and epigenetic remodeling. Methodological platforms such as multiregion sequencing, single-cell and spatial transcriptomics, lineage tracing, and liquid biopsy are evaluated with attention to the technical limitations imposed by mineralized tissue. Finally, we consider how bone lesions may function as reservoirs for secondary dissemination and how evolutionary thinking could improve biomarker development, dormancy prediction, trial design, and therapy selection. Viewing BoM as an evolving ecosystem may help shift the field from reactive skeletal management toward earlier, biology-informed intervention. Full article

Polyploid giant cancer cells (PGCCs) are increasingly recognized as major drivers of therapy resistance and tumor relapse, yet the conserved molecular programs underlying their persistence remain incompletely defined. To identify genes consistently deregulated across eight independent datasets, we performed an integrative transcriptomic analysis of PGCCs derived from prostate, ovarian, and breast cancers. By focusing on consistently up- or down-regulated genes that were expressed in at least five datasets and showed a concordant direction of expression across more than 70% of datasets and met a significance threshold of adjusted p < 0.05, we defined the core regulatory architecture stabilizing the PGCC state under therapeutic stress. Our analysis reveals that PGCCs exhibit a paradoxical ranscriptomic signature consistent with cytolytic activity alongside reduced immune detection. These cells activated pro-inflammatory cytokine and chemokine signaling while simultaneously engaging immune-evasion mechanisms, including PD-L1-associated and virus-like escape programs. Concurrently, PGCCs displayed transcriptional features characteristic of immune-privileged cellular states, including embryonic development, reproductive programs, senescence-associated survival, apoptosis resistance, and deep dormancy marked by coordinated suppression of major housekeeping processes. Notably, PGCCs also activated neuronal differentiation and neurodegeneration-associated pathways, including axon guidance, neurogenesis, and calcium signaling. This neuron-like, calcium-dependent stress adaptation program may further enhance immune privilege and long-term survival capacity. We propose that PGCCs represent an immune-adaptive polyploid survival state in which inflammatory and ontogenetic pathways are repurposed to support immune evasion and tumor persistence. By identifying actionable vulnerabilities within calcium signaling, neuronal mimicry, and checkpoint-associated pathways, this study provides a framework for therapeutic strategies aimed at dismantling the PGCC reservoir and preventing tumor relapse. Full article

Neoadjuvant immunochemotherapy (NICT), mainly anti-PD-1/PD-L1 therapy combined with cytotoxic chemotherapy, significantly improved perioperative outcomes for resectable solid tumors such as lung cancer and breast cancer. But a large number of patients still had residual lesions and eventually relapsed. Residual tumor cells are not simply unremoved cellular debris, but represent a therapy-selected and therapy-amplified subset of a pre-existing heterogeneous and plastic tumor ecosystem. To avoid implying that therapy generates a new form of tumor plasticity de novo, we use the term “plasticity of non-apoptotic residual tumor cells” to describe the plastic behavior of viable malignant cells that survive treatment-induced cytotoxicity rather than entering apoptosis. In this review, we define the plasticity of non-apoptotic residual tumor cells as the capacity of residual malignant cells to preserve, switch, or re-enter phenotypic states such as dormancy, hybrid EMT, stem-like regeneration, and immune evasion under the combined influence of intrinsic tumor heterogeneity, systemic therapy pressure, and microenvironmental protection. Before the NICT-specific discussion, we outline general theoretical frameworks including therapeutic stress response, apoptosis-induced regeneration, genetic and non-genetic heterogeneity, as well as spatial heterogeneity of involved lymph nodes, so as to provide a more robust interpretation of residual lesion biology under NICT. Also, this review proposes that residual disease may be reconceptualized as a treatment-shaped plastic niche, whose biological behavior is jointly shaped by clonal selection, reversible phenotypic transformation, and microenvironmental ecological protection. We summarize several key states of residual tumor cells: persistent-like/resting state, hybrid EMT/invasive plasticity state, stem-like/regenerative state, and immune escape state, and elucidate the underlying epigenetic basis, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA network reprogramming. Meanwhile, niche factors such as immune stress, CAF/TAM enrichment, fibrotic matrix, hypoxia, and metabolic stress can further stabilize these states and promote the survival of relapse seeds. Based on this, we propose that future postoperative assessments should be upgraded from residual volume to a stratified residual state, and dynamically identified by combining single-cell omics, spatial pathology, and ctDNA/MRD monitoring. Furthermore, treatment strategies should shift from simply shrinking tumors to plasticity-locking therapy, that is, identifying, classifying, and blocking the plasticity escape pathways of residual lesions before they evolve into recurrence. Full article

Background: Bone metastasis is a frequent and debilitating complication of advanced cancer, particularly in breast and prostate cancer, and is driven by complex interactions among tumor cells, bone-resident cells, immune populations, vascular components, and the extracellular matrix. Within this specialized microenvironment, proteoglycans have emerged as key molecular regulators of tumor–bone crosstalk, matrix remodeling, metastatic niche formation, dormancy, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published through 31 May 2026. Search terms included combinations of proteoglycan- and glycosaminoglycan-related concepts, including “proteoglycans,” “glycosaminoglycans,” “heparan sulfate proteoglycans,” “hyaluronan,” “heparanase,” “syndecans,” “glypicans,” “perlecan/HSPG2,” “versican,” and “decorin,” with disease- and process-related terms such as “bone metastasis,” “extracellular matrix,” “tumor–bone crosstalk,” “breast cancer,” “prostate cancer,” “metastatic niche,” “osteolytic metastasis,” “osteoblastic metastasis,” “dormancy,” “reactivation,” “immune regulation,” and “therapy resistance.” Original studies, reviews, and translational reports were selected according to their relevance to cell-surface, pericellular, and extracellular proteoglycans in bone metastatic progression. Results: Proteoglycans and associated GAG/ECM axes are implicated in multiple processes involved in skeletal metastasis, including growth factor availability, extracellular matrix organization, osteolytic and osteoblastic niche formation, angiogenesis, immune evasion, metastatic dormancy, reactivation, and therapy resistance. These functions are highly context-dependent and are influenced by proteoglycan localization, core protein structure, glycosaminoglycan composition, sulfation patterns, proteolytic processing, and cellular source. Conclusions: Proteoglycans represent critical molecular nodes in the bone metastatic microenvironment and hold potential as biomarkers, therapeutic targets, and tools for stratifying metastatic niche heterogeneity. Their clinical translation will require validation in human bone metastasis samples, improved models that reproduce the mineralized and immune-rich bone niche, and a clearer distinction between causal mechanisms and correlative associations. Future studies should integrate matrisome profiling, spatial proteomics, single-cell and spatial transcriptomics, glycosaminoglycan omics, degradomics, and three-dimensional bone niche models to define actionable proteoglycan-dependent mechanisms and improve therapeutic targeting of metastatic bone disease. Full article

Background/Objectives: Cancer metastasis is responsible for most cancer-related deaths, yet the precise anatomical and physiological routes by which cancer cells disseminate remain incompletely defined. This review aims to present an integrated model of lymphatic and hematogenous dissemination that provides a unified framework for understanding metastatic progression. Methods: The published literature on lymphatic biology, microvascular physiology, tumor immunology, and cancer metastasis was critically reviewed and integrated to develop a comprehensive anatomical and physiological model of cancer dissemination. Results: The proposed model identifies lymphatic dissemination as the predominant metastatic route in many solid tumors. Cancer cells enter structurally permissive initial lymphatic capillaries and are transported to the sentinel lymph node (SLN), where interactions with the tumor microenvironment may eliminate disseminated cells, maintain dormancy, or facilitate immune escape and further dissemination. Cancer cells that survive within or escape beyond the SLN subsequently travel through collecting lymphatics and the thoracic or right lymphatic duct to enter the systemic venous circulation. Following cardiopulmonary transit, surviving cells may be redistributed through the systemic arterial circulation to distant organs. A secondary pathway involves direct hematogenous intravasation through post-capillary venules, where reduced shear stress, increased endothelial permeability, and permissive endothelial biology facilitate entry into the venous circulation. Thus, lymphatic and direct venular pathways ultimately converge in the venous circulation before systemic arterial dissemination. Conclusions: This unified model integrates lymphatic and hematogenous dissemination into a coherent anatomical and physiological framework. By emphasizing the SLN as an early immunologic checkpoint and the arterial circulation as the final distribution network for disseminated cancer cells, this review provides a conceptual basis for understanding metastatic patterns and identifying biomarkers and therapeutic vulnerabilities. Full article

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases. Full article

Cancer stem cells (CSCs) are a highly influential population of tumor cells involved in tumor initiation, progression, metastasis, recurrence, and resistance to therapy. Although CSCs have been widely investigated, their behavior cannot be understood solely through intrinsic cellular features, as these cells strongly depend on a specialized supportive microenvironment known as the CSC niche. In this review, we discuss the CSC niche as a dynamic and therapeutically relevant ecosystem that is distinct from, but closely connected with, the broader tumor microenvironment. Particular attention is given to stromal cells, immune cells, endothelial cells, extracellular matrix components, hypoxia, cytokines, chemokines, and metabolic stress as regulators of CSC self-renewal, plasticity, dormancy, immune escape, epithelial–mesenchymal transition, metastatic dissemination, and survival under therapeutic pressure. We further consider how CSC–niche interactions contribute to pre-metastatic niche formation and tumor relapse. Finally, we outline emerging therapeutic strategies aimed at disrupting CSC-supportive signals, including approaches targeting developmental pathways, angiogenesis, hypoxia, extracellular matrix remodeling, immunosuppressive networks, and cytokine-mediated communication. Overall, this review emphasizes that targeting the CSC-supportive microenvironment is essential for limiting metastasis, recurrence, and long-term treatment failure. Full article

Cellular senescence and polyploidy are fundamental stress responses that shape cancer progression and therapeutic outcomes. While senescence initially suppresses tumor growth, senescent cells accumulate in aging and therapy-exposed tissues and actively remodel the tumor microenvironment through the senescence-associated secretory phenotype (SASP) and extracellular matrix (ECM) reorganization. Senescent stromal cells increase collagen deposition and generate disordered matrix architectures, as evidenced by enhanced second harmonic generation (SHG) signal and increased anisotropic variation across in vitro systems, 3D co-culture models, and fibrotic lung tissues. These biochemical and mechanical alterations promote cancer cell plasticity and create conditions permissive for disease progression. Polyploid giant cancer cells (PGCCs) are a rare but highly resilient cancer cell population enriched under genotoxic stress. PGCCs arise through mitotic failure, including mitotic slippage and cytokinesis defects, and can survive chemotherapy and radiation due to their altered cell-cycle regulation. Emerging evidence indicates that senescence-driven microenvironments promote the formation of PGCCs and multinucleated cells, linking ECM remodeling and mechanical stress to polyploidization. Functionally, PGCCs exhibit abnormal cytoskeletal and nuclear mechanics that support migratory persistence and enable survival within hostile tumor environments. In addition, PGCCs can promote the survival of neighboring cancer cells during treatment, suggesting a stromal-like role in establishing therapy-resistant niches. These cells can persist in a dormant state and later generate proliferative progeny, contributing to tumor recurrence and metastasis. Together, these findings support a model in which senescent niches may promote PGCC formation, persistence, and tumor repopulation. Targeting both senescence-associated microenvironments and PGCC-specific survival mechanisms may improve long-term therapeutic outcomes. Full article

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat, defined by its molecular heterogeneity, absence of hormone receptors, and poor clinical outcomes. While this difficulty with cancer cells persists even in the presence of chemotherapy and immune checkpoint inhibitors (ICIs), one critical factor linked to both chemoresistance and immune escape is autophagy. Autophagy is a cellular process with lysosomal recycling function. In TNBC, autophagy paradoxically shifts from tumor-suppressive to a tumor-promoting role. Autophagy was initially known to maintain genomic stability and alleviate oxidative damage. In TNBC, cancer cells use autophagy to detoxify platinum-induced DNA. damage, clear damaged mitochondria via mitophagy, recycle critical macromolecules, and sustain dormancy in cancer stem-like cells (CSCs). At the same time, the process of autophagic flux facilitates immune evasion, including PD-L1 expression stabilization, MHC-I degradation, and the establishment of an immunosuppressive tumor microenvironment (TME). The review encapsulates the progressive concepts of molecular regulation of autophagy, which involve key factors such as ULK1, VPS34, and non-coding RNAs (ncRNAs). These factors play a significant role in chemoresistance, taxanes, anthracyclines, and platinum compounds. The review also discusses various strategies for translation that aim to circumvent or suppress autophagy-mediated chemoresistance, including autophagy inhibitors, natural compounds, and nanoparticle-based formulations, with a focus on their synergistic potential with ICIs and chemotherapeutic agents. Targeting autophagy has shown considerable potential for effectively addressing chemoresistance in TNBC. Future studies should focus on addressing chemoresistance and immunoresistance through autophagy-based therapies. Full article

Metastasis is a complex, multistep process in which cancer spreads from its original tumor to other sites in the body. During metastasis, tumor cells move away from the primary tumor and intravasate into the lymphatics or circulation. Surviving tumor cells can then extravasate into and remain in distant tissues until they once again begin to proliferate, forming secondary tumors. An excess of reactive oxygen species (ROS) can promote metastasis, dependent on the ROS molecule, its level of excess, and the examined step within the metastatic cascade. Here, we highlight recent studies where ROS promote epithelial-to-mesenchymal transition, cell migration and invasion, circulating tumor cell survival and disseminated tumor cell dormancy. Additionally discussed are novel in vivo ROS detection methods, FDA-approved therapies and clinical trials that manipulate ROS to improve cancer patient survival. Since metastasis is the major cause of cancer-related death, a better understanding of this process and ROS as a contributing factor will help to identify novel targets for inhibition or prevention. Full article

Osteocytes, once viewed mainly as passive bone-embedded cells, are now recognized as active regulators of the metastatic bone niche. Emerging evidence indicates that these cells integrate mechanical, inflammatory, and tumor-derived cues to influence metastatic seeding, dormancy, reactivation, and lesion progression in bone. This review synthesizes current understanding of osteocyte contributions to skeletal metastasis. We discuss core signaling axes, including osteocyte-derived RANKL/OPG balance, Wnt antagonists (sclerostin/DKK1), mechanotransduction pathways (Piezo1 signaling and connexin-43 hemichannels), and osteocyte paracrine mediators (extracellular vesicles and senescence-associated factors), and examine how each axis modulates tumor cell dormancy, osteolysis, or osteoblastic progression. We then review translational strategies targeting osteocytes, recent preclinical and clinical insights. Emerging biomarkers (e.g., serum sclerostin, DKK1, bone turnover markers) and immune–skeletal imaging approaches are also considered. Controversies, including the paradoxical effects of sclerostin blockade and the identity of in vivo RANKL sources, are discussed. Finally, we outline key knowledge gaps and propose endpoints for future trials. In summary, an osteocyte-centric perspective reveals novel targets and strategies for managing bone metastases, guiding future translational research. Full article

Targeted therapies and chemoimmunotherapy have transformed outcomes for non–small cell lung cancer (NSCLC), yet relapse remains common. Resistance is increasingly recognized to include an early, largely reversible phase in which a minor subpopulation survives lethal therapy through non-genetic adaptation. These drug-tolerant persister (DTP) cells may be quiescent or cycling, and provide a reservoir from which stable, genetically resistant clones can later emerge. In parallel, late recurrence may reflect tumor dormancy, in which disseminated or residual cells persist for prolonged periods under microenvironmental constraint and/or immune surveillance. This review integrates DTP and dormancy frameworks in NSCLC, summarizes mechanisms that sustain persistence (chromatin and transcriptional plasticity, stress signaling, metabolic rewiring, and stromal/immune protection), and highlights experimental models and translational readouts, including circulating tumor DNA (ctDNA)–based minimal residual disease (MRD) monitoring. We also discuss potential therapeutic concepts to prevent DTP formation, exploit persister liabilities, or enforce dormancy in minimal-disease settings. A mechanistically grounded understanding of these survival programs is essential for rational combinations and biomarker-guided trials aimed at durable remission. Full article

Late metastatic relapses still represent a major clinical challenge in breast cancer, particularly in hormone receptor-positive (HR+) disease, with dormant disseminated tumor cells (DTCs) playing a critical role in driving late metastatic relapses. In fact, these cells can persist in a quiescent, non-proliferative state in metabolically hostile microenvironments such as the bone marrow, where they can resist conventional therapies, driving metastatic relapses even years after primary tumor removal. Recent advances highlight the crucial role of lipid metabolism in protecting dormant DTCs from ferroptosis—a form of regulated cell death characterized by iron-dependent lipid peroxidation. Dormant DTCs can avoid lipid peroxidation by incorporating monounsaturated fatty acids (MUFAs) into membrane phospholipids through ACSL3 and SCD1 activity, while accumulating lipid droplets (LDs) that sequester oxidizable polyunsaturated fatty acids (PUFAs), thus limiting the substrates available for ferroptosis. In parallel, antioxidant systems such as the GPX4–glutathione axis further prevent lethal lipid-derived reactive oxidative species (ROS) accumulation. This review highlights the central role of lipid metabolism, redox regulation and ferroptosis resistance in dormant DTCs; it also explores emerging therapeutic opportunities to overcome dormancy-associated resistance and reduce late relapse risk in breast cancer. Full article

This study investigates the nonlinear dynamics that emerge from the interactions between cancer cells and immune cells within a predator–prey model, wherein cancer cell growth obeys the Gompertz law. A bifurcation analysis allows for the identification of states of dormancy, uncontrolled growth, and multistability with and without chemotherapy. In the absence of chemotherapy, a Gompertz model predicts bistability with low (dormant) and high (active) tumor levels. However, unlike models based on the logistic equation, it shows that a stable tumor-free solution does not exist, consistent with the medical understanding about the risk of remaining disease even with successful treatment. Under chemotherapy, the model demonstrates highly complex dynamics with up to four coexisting stable steady states, stable tumor levels, and chemotherapy-induced oscillations. Parameter continuation studies show that the potency of immune recruitment, rate of cell inactivation, and drug saturation are essential in characterizing transitions among these dynamical regions. The analysis indicates that the choice of growth rate plays a significant role in determining the physiological implications for therapy, suggesting a cure for a model with a logistic growth rate, but merely tumor control for a Gompertzian scenario. Moreover, these results provide insights into optimal chemotherapy dosage to prevent problems associated with bistability and to capitalize on stable dormancy. Full article