Search Results (179)

For decades, peritoneal metastases (PM) have been regarded as a terminal manifestation of advanced malignancies and managed primarily with palliative intent because of limited sensitivity to systemic therapies. Accumulating clinical, molecular, and immunological evidence now supports the view that PM is not merely an anatomic pattern of spread but a distinct metastatic niche with characteristic biological, microenvironmental, and therapeutic features. This review summarizes the major routes of PM development—transcoelomic, lymphatic, and hematologic dissemination—and emphasizes how these pathways converge through shared biological programs. Core mechanisms include epithelial–mesenchymal transition (EMT), adhesion signaling, extracellular matrix remodeling, and tumor–immune cell interactions. A central focus is the peritoneal tumor microenvironment: mesothelial-to-mesenchymal transition, cancer-associated fibroblast activity, adipocyte-derived metabolic support, macrophage polarization, and regulatory T-cell enrichment collectively shape an immunotolerant and treatment-resistant niche on the peritoneal surface. In addition, evidence from pre-metastatic niche biology suggests that primary tumor-derived exosomes and epitranscriptomic regulation can prime the peritoneal environment before overt implantation. These features provide a biological rationale for locoregional strategies such as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, as well as emerging intraperitoneal modalities and microenvironment-targeted approaches. Finally, organoid platforms, liquid biopsy-based minimal residual disease monitoring, and theranostic technologies may enable more personalized, biology-driven management of PM. Full article

Pancreatic ductal adenocarcinoma frequently metastasises to the liver, although the mechanisms underlying hepatic pre-metastatic niche formation remain unclear. Small extracellular vesicles mediate tumour–host communication and may drive hepatic microenvironment reprogramming. This study investigated the effects of pancreatic ductal adenocarcinoma-derived small extracellular vesicles on extracellular matrix remodelling and epithelial–mesenchymal transition-related plasticity in hepatic cells. Small extracellular vesicles were isolated from pancreatic ductal adenocarcinoma cell lines (MIAPaCa-2, PANC-1) and from the serum of 25 patients, characterized, and administered to hepatic stellate (LX-2) and hepatocyte-like (HEPA-RG) cells. Cell viability and migration were evaluated by functional assays, morphology by scanning electron microscopy, and molecular changes by RT-PCR, Western blotting, and immunofluorescence. In LX-2 cells, small extracellular vesicles exposure increased metabolic activity, adhesion, and migration, while inducing morphological and molecular changes associated with extracellular matrix remodelling, including reduced collagen type I alpha 2 chain, vimentin, and E-cadherin expression. In HEPA-RG cells, viability was minimally affected, whereas migration and EMT-related plasticity were enhanced. Patient-derived small extracellular vesicles induced similar but less pronounced effects. Overall, pancreatic ductal adenocarcinoma-derived small extracellular vesicles induced early hepatic microenvironmental remodelling, supporting a potential role for tumour–liver crosstalk in pre-metastatic niche-associated processes, highlighting tumour–liver crosstalk as a potential therapeutic target. 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

Breast cancer brain metastasis (BCBM) affects up to 30% of patients with metastatic disease and carries a median survival of only 4–18 months. Emerging evidence reveals that BCBM cells are not passive survivors, but active participants that hijack core neurotransmitter networks, GABA (gamma-aminobutyric acid) and glutamate, to fuel their growth. BCBM, particularly triple-negative breast cancer (TNBC), frequently switch to a GABAergic mode utilizing brain-derived GABA as an oncometabolite. In parallel, BCBM cells can also form direct synapses with neurons, tapping into excitatory input through glutamatergic receptors to drive tumor cell proliferation and survival. Concurrently, reprogrammed astrocytes establish gap junctions, secrete growth factors, and provide metabolic support. Together, tumor cells, neurons, and astrocytes form a pathological partnership locked in feedback loops sustaining metastatic progression. This review focuses on the unique mechanisms employed by distinct breast cancer subtypes and maps the metastatic progression from pre-metastatic to mature brain metastatic niche formation of BCBM. We highlight opportunities to repurpose neurological drugs to disrupt these communication axes. Full article

Retinoblastoma (Rb) is an intraocular tumor caused by genetic alterations in the RB1 and MYCN genes within developing retinal cells. Chemoresistance and metastasis are major challenges for treatment, with the bone marrow (BM) representing the most common metastatic site. We investigated the effect of tumor-derived sEVs (TDsEVs) on the crosstalk between metastatic site cells (BM-derived mesenchymal stem cells (BM-MSC)) and tumor cells, and characterized them according to MISEV guidelines. The uptake of sEVs and the associated phenotypic changes in the BM-MSCs were analyzed with confocal microcopy. The functional effects were assessed through MTT assays for viability, scratch and Transwell assays for migration, and colony- and sphere-formation assays to evaluate clonogenicity and self-renewal, while stemness marker expression was examined by immunoblotting. Secretome changes following sEV exposure were analyzed using dot blot assays. sEVs were taken up by both cells. TD-sEVs significantly enhanced BM-MSC migration and induced differentiation into a myofibroblast-like phenotype without affecting cell viability. Conversely, BM-MSC-derived sEVs promoted tumor cell viability, migration, and stemness marker expression. Both the BM-MSCs and tumor cells exhibited altered secretory profiles after sEV treatment. The in vitro findings provide cumulative evidence that sEV-mediated interactions contribute to a tumor-supportive milieu or premetastatic niche at the BM in Rb. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumours, driven by late diagnosis, early metastatic dissemination, and profound resistance to systemic therapies. Increasing evidence indicates that these hallmarks are not solely tumour cell intrinsic but are critically orchestrated by a complex and highly dynamic tumour microenvironment (TME) composed of pancreatic stellate cells (PSCs), cancer-associated fibroblast (CAF) subtypes, immune cells, endothelial and neuronal elements, and a dense extracellular matrix (ECM). This review provides an integrated overview of the cellular and acellular components of the PDAC TME and delineates how their reciprocal crosstalk drives desmoplasia, immune suppression, metabolic reprogramming, epithelial–mesenchymal transition (EMT), pre-metastatic niche formation, and metastatic outgrowth. Particular emphasis is placed on the context-dependent roles of stromal and immune niches in modulating drug delivery, chemoresistance, and failure of immunotherapy, highlighting why indiscriminate stromal depletion has yielded paradoxical outcomes. Building on these mechanistic insights, the review critically examines emerging therapeutic strategies targeting PSCs, CAF subsets, ECM components, myeloid and lymphoid populations, and key signalling pathways, including approaches that normalize stroma, reprogram immunity, or exploit nanocarrier-based delivery systems. Finally, a structured framework is proposed for rational TME-targeted combination regimens that integrate cytotoxic, targeted, and immunotherapeutic agents to overcome current therapeutic barriers in PDAC. Full article

Extracellular vesicles (EVs) have emerged as important messengers in cell-to-cell communication, carrying biologically active molecules such as lipids, nucleic acids, and proteins that influence both normal physiology and disease. In cancer, EVs play complex and context-dependent roles, contributing to tumor growth, angiogenesis, immune evasion, metastasis, and resistance to therapy, while in certain settings, they may also support antitumor immune responses. Increasing evidence shows that EVs released from tumor and stromal cells actively reshape the tumor microenvironment (TME) and participate in the formation of pre-metastatic niches, thereby facilitating cancer dissemination. Because EVs are stable, readily detectable in body fluids, and reflect the molecular characteristics of their cells of origin, they have attracted considerable interest as minimally invasive biomarkers for cancer diagnosis, prognosis, and treatment monitoring. In addition, their natural biocompatibility makes them attractive candidates for targeted drug delivery. This review summarizes current knowledge on EV biogenesis, cargo composition, and functional roles in cancer progression, with a particular focus on recent advances in their clinical applications. Key challenges related to EV isolation, characterization, and clinical translations are also discussed, highlighting future opportunities for integrating EV-based strategies into precision oncology. Full article

Background: Accurate detection of cervical lymph node metastases is a critical determinant of prognosis and treatment planning in head and neck squamous cell carcinoma (HNSCC). Although ultrasound-guided fine-needle aspiration biopsy (USgFNAB) is widely used as a minimally invasive diagnostic tool, its sensitivity for detecting occult metastases remains limited. Current preoperative staging modalities are further constrained by operator dependency and suboptimal specificity in early-stage disease. Integration of molecular diagnostics, particularly the analysis of long non-coding RNAs (lncRNAs), represents a promising strategy to enhance diagnostic accuracy. Objective: This review synthesizes the current evidence on lncRNA expression profiles in HNSCC, with an emphasis on their association with lymph node metastasis and potential application in FNAB-derived material for pre-treatment staging. Methods: A structured literature search was conducted, focusing on studies evaluating lncRNA expression profiles in HNSCC and their relevance to lymph node metastasis, with a particular focus on the feasibility of analysis of USgFNAB samples. Results: Multiple lncRNAs, including HOTAIR, MALAT1, UCA1, TUG1, AFAP1-AS1, H19, MEG3, and ADAMTS9-AS2, have been implicated in metastatic progression through their involvement in diverse mechanisms such as epithelial-to-mesenchymal transition, chromatin remodeling, angiogenesis, and pre-metastatic niche formation. Elevated expression of several of these transcripts correlates with adverse clinicopathological features, including advanced tumor stage, extranodal extension, and reduced survival. However, no studies have profiled lncRNA expression in matched primary tumors and metastatic lymph nodes, and transcriptomic analysis of FNAB samples remains largely unexplored in HNSCC. Conclusions: lncRNAs represent promising molecular biomarkers for enhancing the sensitivity and specificity of USgFNAB in detecting occult cervical metastases. Future research should prioritize paired tumor–node lncRNA profiling, validation of FNAB-based molecular assays, and integration of multi-omics data for predictive modeling. Overall, integrating lncRNA analysis into ultrasound-guided fine-needle aspiration biopsy may enhance the detection of occult nodal metastases in head and neck squamous cell carcinoma and support more accurate nodal staging in clinically node-negative patients. Full article

This review describes the immunosuppressive effect of secreted phosphoprotein 1 (SPP1)+ tumor-associated macrophages (TAMs) in coordinating the tumor microenvironment (TME) as a functionally unique myeloid cell subgroup. SPP1+ TAMs transcend the traditional M1/M2 paradigm and represent a group of cells that are widely found in various cancer types. SPP1+ TAMs have the characteristics of high expression of SPP1 and promoting immune escape, matrix remodeling and metastasis. We clarify the dual developmental source of SPP1+ TAMs, and introduce the activation process of SPP1+ TAMs through recruitment, polarization and epigenetic locking. After SPP1+ TAMs are activated, they are strategically enriched in the tumor core and tumor marginal area to play their functions. Functionally, SPP1+ TAMs mainly promote the progression of tumors through three mechanisms: (1) Interacting with cancer-associated fibroblasts (CAFs): constructing an immunoexcluded fibrotic niche; (2) Multiple regulation of immune cells; (3) Promoting tumor metastasis and the construction of pre-metastatic niche (PMN). Overall, this review aims to provide a comprehensive overview of the mechanisms mediated by SPP1+ TAMs in the TME, and emphasize their unique role in cancer progression. At the same time, the treatment strategies targeting them are further explored, highlighting their potential as precise therapeutic targets for tumor treatment. Full article

The landscape of first-line treatment for metastatic non-small cell lung cancer (NSCLC) without actionable driver mutations is rapidly evolving, currently dominated by pembrolizumab-based regimens. This review discusses the unique molecular characteristics of cemiplimab, a newer anti-PD-1 antibody, and defines its optimal positioning against established standards. Cemiplimab is a fully human IgG4 monoclonal antibody distinguished by two key features: an engineered hinge-region mutation that prevents Fab-arm exchange, ensuring exceptional molecular stability which minimizes anti-drug antibody (ADA) risks associated with unstable molecules; and a unique interaction with PD-1 glycosylation sites, potentially enhancing binding efficacy. These structural advantages may be particularly relevant in histologies like squamous NSCLC, where accumulating somatic mutations drive high neoantigen loads and heightened immune responses, creating an environment historically prone to ADA formation. Based on data from the pivotal EMPOWER-Lung program, we highlight cemiplimab’s exceptional promise in specific populations. Firstly, in the EMPOWER-Lung 1 trial, cemiplimab monotherapy demonstrated extraordinary survival benefits in a pre-specified analysis of the distinct “ultra-high” PD-L1 expression subgroup (TPS ≥90%), potentially surpassing historical benchmarks. Secondly, cemiplimab displays consistent, robust efficacy in challenging-to-treat squamous histology, both as monotherapy for patients with high PD-L1 expression and in combination with chemotherapy for patients with PD-L1 < 50%. In conclusion, cemiplimab establishes a unique therapeutic niche for patients with squamous histology and ultra-high PD-L1 expression, likely driven by its distinct structural stability and reduced immunogenicity. Full article

Tumor-draining lymph nodes function paradoxically not only as key sites for the priming and coordination of anti-tumor CD8+ T cell responses but also as regional hubs through which invading tumor cells can seed distant metastases. The quality of tumor-specific CD8+ T cells elicited at this site is therefore a critical determinant of the outcome of anti-tumor immunity and cancer progression. Recent studies have demonstrated the significance of CD8+ T cell dysfunction within tumor-draining lymph nodes, highlighting it as an important means of tumor immune escape that may arise early in the course of cancer progression. This review aims to bring attention to emerging data on this topic, with particular focus given to the implications that lymph-node-resident CD8+ T cell dysfunction has both for cancer immunotherapy and for pre-metastatic niche formation during early stages of cancer progression. Full article

The C-X-C motif chemokine ligand 10 (CXCL10) is implicated in the progression of osteosarcoma (OS), the most aggressive pediatric bone malignancy. However, its role often presents a profound clinical paradox: although high circulating levels are strongly linked to poor prognosis, its canonical function is to recruit anti-tumor immune cells. This review unravels these contrasting roles by proposing a novel spatiotemporal model. We argue that in the early stages, immune-evading OS cells initiate the formation of a pre-metastatic niche (PMN) in the lungs, creating a localized inflammatory environment that becomes the primary source of elevated circulating CXCL10. As the disease progresses, elevated systemic levels of CXCL10 overwhelm the localized chemokine gradient at the primary tumor site, creating a potent immune decoy that diverts anti-tumor CXCR3+ T cells away from the tumor. The resulting immune desertification permits unchecked tumor growth and an increased metastatic burden. We also discuss the therapeutic implications of this model, proposing that disrupting the chemokine axis offers a roadmap for developing rational, stage-specific therapies to effectively combat metastatic OS. Full article

Background: Colorectal cancer (CRC) frequently metastasizes to the liver (CRLM), where M2-polarized macrophages shape an immunosuppressive pre-metastatic niche. The molecular cues driving this polarization remain unclear. Methods and Results: Using integrated transcriptomics, patient cohorts, and mouse models, we investigated the role of tissue inhibitor of metalloproteinases-1 (TIMP1) in CRLM. TIMP1 was consistently overexpressed in CRC tissues and associated with poor overall survival. CRC cells secreted TIMP1 into the tumor microenvironment, where it induced M2-like macrophage polarization and increased the expression of immunosuppressive mediators such as CSF1 and IRF4. In vivo, TIMP1 overexpression enhanced, whereas its knockdown reduced, liver metastatic burden. Immune profiling and depletion experiments indicated that these pro-metastatic effects were largely macrophage-dependent. Mechanistically, TIMP1 engaged CD63/β1-integrin on macrophages, activating AKT/mTOR signaling and stabilizing the M2 phenotype. Conclusions: CRC-derived TIMP1 remodels liver macrophages via the CD63/β1-integrin–AKT/mTOR pathway to promote a hepatic pre-metastatic niche. Pharmacologic inhibition of this signaling axis with the integrin antagonist cilengitide suppressed macrophage M2 markers and liver colonization in mice, supporting TIMP1–integrin signaling as a potential therapeutic target. Full article

The premetastatic niche (PMN) represents a specialized microenvironment established in distant organs before the arrival of metastatic cells. This concept has fundamentally altered our understanding of cancer progression, shifting it from a random event-driven process to an orchestrated one. This review examines the critical role of extracellular proteases in PMN formation, focusing on matrix metalloproteinases (MMPs), serine proteases, and cysteine cathepsins that collectively orchestrate extracellular matrix remodeling, immune modulation, and vascular permeability changes essential for metastatic colonization. Key findings demonstrate that MMP9 and MMP2 facilitate basement membrane degradation and the recruitment of bone marrow-derived cells. At the same time, tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes organ-specific hepatic PMN recruitment through neutrophil recruitment mechanisms. The plasminogen–plasmin system emerges as a master regulator through its broad-spectrum proteolytic activity and ability to activate downstream proteases, with S100A10-mediated plasmin generation providing mechanistic pathways for remote PMN conditioning. Neutrophil elastase and cathepsin G contribute to the degradation of anti-angiogenic proteins, thereby creating pro-metastatic microenvironments. These protease-mediated mechanisms represent the earliest interventional window in metastatic progression, offering therapeutic potential to prevent niche formation rather than treat established metastases. However, significant methodological challenges remain, including the need for organ-specific biomarkers, improved in vivo methods for measuring protease activity, and a better understanding of temporal PMN dynamics across different target organs. Full article

Tissue-resident memory T (TRM) cells have emerged as critical sentinels in the control of cancer metastasis, yet their precise roles across different tumor types and tissues remain underappreciated. Here, we review current insights into the mechanisms governing TRM cell seeding and retention in pre-metastatic niches, their effector functions in eliminating disseminated tumor cells, and their dynamic crosstalk with local stromal and myeloid populations. Here, we highlight evidence for organ-specific variability in TRM cell-mediated immunity, discuss strategies for therapeutically harnessing these cells—ranging from vaccination and checkpoint modulation to chemokine axis manipulation—and explore their promise as prognostic biomarkers. Finally, we outline key knowledge gaps and future directions aimed at translating TRM cell biology into targeted interventions to prevent and treat metastatic disease. Full article