Bone metastasis is common for breast cancer and associated with poor prognosis. Currently, radiotherapy (RT) serves as the standard treatment for patients exhibiting symptoms of bone metastasis to alleviate pain. Whether earlier application of RT will better control bone metastasis remains unclear.

We utilized a mouse model of breast cancer bone metastasis by intra-femoral injection of 4T1-luc breast tumor cells. The bone metastasis was treated by RT using various doses, timings, and modalities. Tumor growth was assessed through bioluminescence imaging, and lung metastases was quantified following lung tissue fixation. Flow cytometry was employed to analyze alterations in immune cell populations.

Single high-dose RT suppressed tumor growth of bone metastases, but caused severe side effects. Conversely, fractionated RT mitigated tumor growth in bone metastases with fewer adverse effects. Fractioned RT initiated at the early stage of bone metastasis effectively inhibited tumor growth in the bone, suppressed secondary lung metastases, and prolonged mouse survival. In line with the known pro- and anti-metastatic effects of neutrophils and T cells in breast cancer, respectively, earlier fractioned RT consistently decreased the proportions of neutrophils while increased the proportions of T cells in both the bone and the lung tissues.

The data suggest that fractionated RT can inhibit the progression of early stage of bone metastasis and reduce secondary lung metastasis, leading to favorable outcomes. Therefore, these findings provide preclinical evidence to support the application of fractionated RT to treat patients with bone metastasis as earlier as possible.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide, with Brain Metastases serving as a significant adverse prognostic factor. The blood-brain barrier poses a substantial challenge in the treatment of brain metastases, as it restricts the penetration of many anticancer agents. Novel immunotherapy, such as immune checkpoint inhibitors (ICIs) have emerged as promising treatment for NSCLC and its associated brain metastases. This review summarizes the biological mechanism underlying NSCLC brain metastases and provides an overview of the current landscape of immunotherapy, exploring the mechanism of action and clinical applications of these advanced treatments.

Cancer remains a significant global health burden due to its high morbidity and mortality. Oncogene-targeted therapy and immunotherapy have markedly improved the 5-year survival rate in the patients with advanced or metastatic tumors compared to outcomes in the era of chemotherapy/radiation. Nevertheless, the majority of patients remain incurable. Initial therapies eliminate the bulk of tumor cells, yet residual populations termed drug-tolerant persister cells (DTPs) survive, regenerate tumor and even drive distant metastases. Notably, DTPs frequently render tumor cross-resistance, a detrimental phenomenon observed in the patients with suboptimal responses to subsequent therapies. Analogous to species evolution, DTPs emerge as adaptative products at the cellular level, instigated by integrated intracellular stress responses to therapeutic pressures. These cells exhibit profound heterogeneity and adaptability shaped by the intricate feedforward loops among tumor cells, surrounding microenvironments and host ecology, which vary across tumor types and therapeutic regimens. In this review, we revisit the concept of DTPs, with a focus on their generation process upon targeted therapy or immunotherapy. We dissect the critical phenotypes and molecule mechanisms underlying DTPs to therapy from multiple aspects, including intracellular events, intercellular crosstalk and the distant ecologic pre-metastatic niches. We further spotlight therapeutic strategies to target DTP vulnerabilities, including synthetic lethality approaches, adaptive dosing regimens informed by mathematical modeling, and immune-mediated eradication. Additionally, we highlight synergistic interventions such as lifestyle modifications (e.g., exercise, stress reduction) to suppress pro-tumorigenic inflammation. By integrating mechanistic insights with translational perspectives, this work bridges the gap between DTP biology and clinical strategies, aiming for optimal efficacy and preventing relapse.

The liver is an important metastatic organ that contains many innate immune cells, yet little is known about their role in anti-metastatic defense. We investigated how invariant natural killer T (iNKT) cells influence colorectal cancer-derived liver metastasis using different models in immunocompetent mice. We found that hepatic iNKT cells promote metastasis by creating a supportive niche for disseminated cancer cells. Mechanistically, iNKT cells respond to disseminating cancer cells by producing the fibrogenic cytokines interleukin-4 (IL-4) and IL-13 in a T cell receptor-independent manner. Selective abrogation of IL-4 and IL-13 sensing in hepatic stellate cells prevented their transdifferentiation into extracellular matrix-producing myofibroblasts, which hindered metastatic outgrowth of disseminated cancer cells. This study highlights a novel tumor-promoting axis driven by iNKT cells in the initial stages of metastasis.

Gastric cancer peritoneal metastasis is clinically challenging, given the limited treatment options and poor prognosis. The molecular mechanisms that precede gastric cancer peritoneal metastasis, known as the pre-metastatic niche (PMN), and its relationship with N6-methyladenosine (m6A) modification remain unclear.

We used 87 resected gastric cancer tissues and 4 public datasets to explore the association between methyltransferase-like 3 (METTL3) expression and gastric cancer peritoneal metastasis. Roles of m6A, exosomes, or macrophages in PMN formation were explored in immunocompetent mouse models through exosome treatments or macrophage modifications. Key genes and regulatory mechanisms were uncovered using mass spectrometry, RNA/miRNA sequencing, RNA-immunoprecipitation, dual-luciferase assays, and point mutations in the ras-related protein Rab-27A (RAB27A) in cells. Macrophage and T-cell functions were assessed using enzyme-linked immunosorbent assay, flow cytometry, and cytotoxicity assays.

METTL3 overexpression in gastric cancer cells enhanced RAB27A translation by methylating its mRNA A502 base, facilitated by its m6A "reader" YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), and led to increased exosome biogenesis. The miRNA-17-92 cluster was enriched in METTL3-overexpressed cell-derived exosomes and targeted SRC kinase signaling inhibitor 1 (SRCIN1) to activate SRC proto-oncogene, non-receptor tyrosine kinase (SRC) signaling in peritoneal macrophages. Macrophage activation skewed cytokine production towards an immunosuppressive profile in the peritoneum, elevating the levels of interleukin (IL)-10 and tumor necrosis factor (TNF) and reducing the levels of IL-1 and IL-6. These cytokine shifts inhibited T cell proliferation and cytotoxic activities, which created an immunosuppressive PMN and led to peritoneal metastasis. The association between METTL3, macrophages, and peritoneal metastasis was verified in clinical samples.

Our study identified an intricate m6A-regulated mechanism of peritoneal PMN development that is mediated by exosome-promoted macrophages. These insights into gastric cancer peritoneal metastasis offer promising directions for translational research.

Neoadjuvant anti-PD-1 immunotherapy combined with chemotherapy has shown promising pathologic responses in various cancers, including oral squamous cell carcinoma (OSCC). However, the pathologic response of lymph node (LN) metastases remains poorly understood. This study aims to systematically evaluate the pathologic response rates (pRR) of LN metastases in patients with OSCC and identify potential targets to improve therapeutic outcomes.

We assessed the pRRs of LN metastases and matched primary tumors (PT) in patients with OSCC enrolled in a randomized, two-arm, phase II clinical trial (NCT04649476). Single-cell and spatial transcriptomics and multiplex IHC were performed to analyze the tumor microenvironment and identify potential therapeutic targets in LN metastases. A neoadjuvant orthotopic OSCC mouse model was established to evaluate the therapeutic potential of these targets.

We observed significant heterogeneity in pathologic regression of LN metastases, with lower pRRs compared with PTs. pRRs in LN metastases were correlated with overall and disease-free survival in patients with OSCC. We identified an abundance of macrophages in LN metastases exhibiting an unfolded protein response and activated protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling. These macrophages contributed to an extracellular matrix-enriched microenvironment through interactions with fibroblasts, which hindered T cell-mediated cytotoxicity. Pharmacologic inhibition of the PERK pathway significantly enhanced anti-PD-1 therapy in LN metastases and PTs in the mouse model.

Our study confirms that the pathologic response of LN metastases in patients with OSCC undergoing neoadjuvant immunotherapy or immunochemotherapy is inferior to that of PTs. It suggests that targeting the PERK pathway in macrophages could be a potential strategy to enhance treatment outcomes.

Triple-negative breast cancer cells must evade immune surveillance to metastasize to distant sites, yet this process is not well understood. The Eyes absent (EYA) family of proteins, which are crucial for embryonic development, become dysregulated in cancer, where they have been shown to mediate proliferation, migration, and invasion. Our study reveals an unusual mechanism by which EYA3 reduces the presence of cytotoxic natural killer (NK) cells in the premetastatic niche (PMN) to enhance metastasis, independent of its effects on the primary tumor. We find that EYA3 up-regulates nuclear factor κB signaling to enhance CCL2 expression, which, in contrast to previous findings, suppresses cytotoxic NK cell activation in vitro and their infiltration into the PMN in vivo. These findings uncover an unexpected role for CCL2 in inhibiting NK cell responses at the PMN and suggest that targeting EYA3 could be an effective strategy to reactivate antitumor immune responses to inhibit metastasis.

Osteosarcoma (OS) is the most common malignant tumor of bone in children and adolescents. Although lung metastasis is a major obstacle to improving the prognosis of OS patients, the underlying mechanism of lung metastasis of OS is poorly understood. Tumor-associated macrophages (TAMs) with M2-like characteristics are reportedly associated with lung metastasis and poor prognosis in OS patients. In this study, we investigated the metastasis-associated tumor microenvironment (TME) in orthotopic OS tumor models with non-metastatic and metastatic OS cells. Non-metastatic and metastatic tumor cells derived from mouse OS (Dunn and LM8) and human OS (HOS and 143B) were used to analyze the TME associated with lung metastasis in orthotopic OS tumor models. OS cell-derived secretion factors were identified by cytokine array and enzyme-linked immunosorbent assay (ELISA). Orthotopic tumor models with metastatic LM8 and 143B cells were analyzed to evaluate the therapeutic potential of a neutralizing antibody in the development of primary and metastatic tumors. Metastatic OS cells developed metastatic tumors with infiltration of M2-like TAMs in the lungs. Cytokine array and ELISA demonstrated that metastatic mouse and human OS cells commonly secreted CCL2, which was partially encapsulated in extracellular vesicles. In vivo experiments demonstrated that while primary tumor growth was unaffected, administration of CCL2-neutralizing antibody led to a significant suppression of lung metastasis and infiltration of M2-like TAMs in the lung tissue. Our results suggest that CCL2 plays a crucial role in promoting the lung metastasis of OS cells via accumulation of M2-like TAMs.

Despite the advances in cancer prevention, early detection, and treatments, all of which have led to improved cancer survival, globally, there is an increased incidence in cancer-related deaths. Although each patient and each tumor is wholly unique, the tipping point to incurable disease is common across all patients: the dual capacity for cancers to metastasize and resist systemic treatment. The discovery of genetic mutations and epigenetic variation that emerges during cancer progression highlights that evolutionary and ecology principles can be used to understand how cancer evolves to a lethal phenotype. By applying such an eco-evolutionary framework, the authors reinterpret our understanding of the metastatic process as one of an ecologic invasion and define the eco-evolutionary paths of evolving therapy resistance. With this understanding, the authors draw from successful strategies optimized in evolutionary ecology to define strategic interventions with the goal of altering the evolutionary trajectory of lethal cancer. Ultimately, studying, understanding, and treating cancer using evolutionary ecology principles provides an opportunity to improve the lives of patients with cancer.

Several types of cancer, including breast cancer, metastasize to the lung. However, before the disseminating tumor cells (DTCs) arrive there, the lung must be prepared as a hospitable environment for them, forming the pre-metastatic niche (PMN). It is now accepted that the primary tumor can release soluble mediators or extracellular vesicles that activate the PMN resident cells, recruit immune cells, promote angiogenesis, and remodel the extracellular matrix (ECM), even before the arrival of DTCs to the niche. However, not all the components of the tumor secretome are known. Here we demonstrate in a mouse model of breast cancer designed to generate lung PMN, that EMMPRIN, a multifunction protein and mediator of tumor-stroma cell interactions, is part of that secretome. To study the involvement of EMMPRIN in the generation of lung PMN, we knocked down its expression in D2A1 cells (D2A1-KD), treated the mice with the anti-EMMPRIN antibody developed in our lab (m161-pAb), or administered the recombinant EMMPRIN protein to healthy mice. We show that the primary tumor released elevated levels of EMMPRIN in mice implanted with paternal D2A1 cells (D2A1-WT), generating lung PMN by increasing VEGF, MMP-9 and TGFβ secretion, enhancing angiogenesis, activating fibroblasts, increasing neutrophils infiltration, and remodeling the ECM. These effects were inhibited in mice implanted with D2A1-KD cells or administered with m161-pAb. In healthy mice, the recombinant EMMRPIN recapitulated the effects of high EMMPRIN levels. Thus, EMMPRIN as part of the tumor secretome is sufficient to promote the lung PMN, and targeting it could potentially inhibit the metastatic cascade.

Renal cell carcinoma (RCC) is among the most frequently occurring types of cancer, and its metastasis is a major contributor to its elevated mortality. Before the primary tumor metastasizes to secondary or distant organs, it remodels the microenvironment of these sites, creating a pre-metastatic niche (PMN) conducive to the colonization and growth of metastatic tumors. RCC releases a variety of biomolecules that induce angiogenesis, alter vascular permeability, modulate immune cells to create an immunosuppressive microenvironment, affect extracellular matrix remodeling and metabolic reprogramming, and determine the organotropism of metastasis through different signaling pathways. This review summarizes the principal processes and mechanisms underlying the formation of the premetastatic niche in RCC. Additionally, we emphasize the significance and potential of targeting PMNs for the prevention and treatment of tumor metastasis in future therapeutic approaches. Finally, we summarized the currently potential targeted strategies for detecting and treating PMN in RCC and provide a roadmap for further in-depth studies on PMN in RCC.

Metastasis remains a major cause of morbidity and mortality in patients with malignant tumors. The pre-metastatic niche is a prerequisite for distant metastasis driven by primary tumors. Circular RNAs (circRNAs), a class of single-stranded closed non-coding RNAs, exhibit high stability, evolutionary conservation, and cell-type specificity. Exosomes, as natural carriers of circRNAs, mediate intercellular communication and contribute to the formation of the pre-metastatic niche; however, the mechanisms by which they do so remain incompletely understood. This review summarizes the biological characteristics and functions of exosomal circRNAs and outlines the molecular pathways through which they shape the tumor pre-metastatic microenvironment, with emphasis on immunosuppression, vascular permeability, extracellular matrix remodeling, and lymphangiogenesis. This is the first review to focus on the functional roles and molecular mechanisms of exosomal circRNAs in pre-metastatic niche regulation, providing a basis for the development of therapeutic strategies targeting metastatic progression.

The immunosuppressive microenvironment plays a crucial role in driving and accelerating tumor metastasis. S100A8/A9, produced by myeloid-derived suppressor cells, is a potential therapeutic target for metastatic cancer due to its role in promoting premetastatic niche formation. Previous studies have revealed that the S100A9-targeted peptide (H6, MEWSLEKGYTIK) fused to the Fc region of mouse IgG2b antibodies exhibits antitumor effects; however, the mechanism remains unclear. Here, dual-function peptide nanofibers (H6-Q11) were constructed, consisting of peptide H6 and self-assembly peptide (Q11, QQKFQFQFEQQ), which achieved high avidity for S100A9. In vivo studies showed that H6-Q11 nanofibers significantly prolonged lung retention and inhibited pulmonary metastasis from melanoma and breast cancer without obvious toxicity. Immunological analyses indicated that treatment with H6-Q11 nanofibers decreased the infiltration of immunosuppressive cells while promoting the recruitment of immune effector cells to the lungs, potentially correlated with disturbances of S100A8/A9-NCF1 signaling in the tumor microenvironment. Our findings support a potential clinical application of S100A9-targeted peptide nanofibers as candidate nanomedicine for inhibiting tumor metastasis.

Cancer-associated fibroblasts (CAFs) drive tumor progression through restructuring of the tumor microenvironment. This investigation aim to elucidate the function of molecular subtypes (MS) derived from cancer cells communication with CAFs, depicting the hallmarks of the tumor microenvironment and precise bladder cancer (BLCA) treatment. The BLCA data from TCGA and several external sources are utilized to generate a novel ligand, receptor, and transcription factor (LRT) associated molecular subtype and their corresponding score (LRT score). The LRT-mediated molecular subtype is identified via unsupervised clustering. LRT score is measured by principal component analysis. Then, the association of LRT clusters to established MS, immunophenotypes, and medical endpoints, together with BLCA treatment strategies is investigated. Two LRT clusters (A and B) are identified. LRT cluster (LRT score) can precisely propose immunophenotypes, classical MS, clinical outcomes, and BLCA therapeutic strategies. Cluster B (Low LRT score) represent a basal subtype and inflamed phenotype specified by high immunity against tumors and unfavorable clinical outcomes. Furthermore, it is highly sensitive to cancer immunotherapy; however, it has low sensitivity to antiangiogenic and targeted therapies. The novel LRT clusters with a strong association with biological characteristics and precise BLCA treatment strategies are derived from the communication between cancer cells and cancer-associated fibroblasts. The LRT may be a useful clinician tool for developing individualized treatment strategies.

Metastasis is a leading cause of cancer-related deaths, with the liver being the most frequent site of metastasis in colorectal cancer. Previous studies have predominantly focused on the influence of the primary tumor itself on metastasis, with relatively limited research examining the changes within target organs.

Using an orthotopic mouse model of colorectal cancer, single-cell sequencing was employed to profile the transcriptomic landscape of pre-metastatic and metastatic livers. The analysis focused on identifying cellular and molecular changes within the hepatic microenvironment, with particular emphasis on inflammatory pathways and immune cell populations.

A neutrophil subpopulation with high Prok2 expression was identified, showing elevated levels in the pre-metastatic and metastatic liver. Increased infiltration of Prok2⁺ neutrophils correlated with poor prognosis in liver metastatic colorectal cancer patients. In the liver metastatic niche (MN), these neutrophils showed high App and Cd274 (PD-L1) expression, suppressing macrophage phagocytosis and promoting T-cell exhaustion.

A Prok2⁺ neutrophil subpopulation infiltrated both pre-metastatic and macro-metastatic liver environments, potentially driving immunosuppression through macrophage inhibition and T-cell exhaustion. Targeting Prok2⁺ neutrophils could represent a novel therapeutic strategy for preventing liver metastasis in colorectal cancer patients.

The tumour microenvironment is the "hotbed" of tumour cells, providing abundant extracellular support for growth and metastasis. However, the tumour microenvironment is not static and is constantly remodelled by a variety of cellular components, including tumour cells, through mechanical, biological and chemical means to promote metastasis. Focal adhesion plays an important role in cell-extracellular matrix adhesion. An in-depth exploration of the role of focal adhesion in tumour metastasis, especially their contribution at the biomechanical level, is an important direction of current research. In this review, we first summarize the assembly of focal adhesions and explore their kinetics in tumour cells. Then, we describe in detail the role of focal adhesion in various stages of tumour metastasis, especially its key functions in cell migration, invasion, and matrix remodelling. Finally, we describe the anti-tumour strategies targeting focal adhesion and the current progress in the development of some inhibitors against focal adhesion proteins. In this paper, we summarize for the first time that focal adhesion play a positive feedback role in pro-tumour metastatic matrix remodelling by summarizing the five processes of focal adhesion assembly in a multidimensional way. It is beneficial for researchers to have a deeper understanding of the role of focal adhesion in the biological behaviour of tumour metastasis and the potential of focal adhesion as a therapeutic target, providing new ideas for the prevention and treatment of metastases.

High-grade serous ovarian cancer (HGSOC) is a highly aggressive and deadly gynecological cancer, with metastasis being a key factor in its poor prognosis. Historically, HGSOC was thought to spread primarily through the peritoneal cavity, but recent research has revealed additional routes of metastasis, including the blood and lymphatic systems. This review discusses the complex processes of HGSOC metastasis, focusing on peritoneal immune suppression, stromal reprogramming, and the role of circulating tumor cells in blood-based spread. We also explore the clinical significance of lymphatic metastasis, particularly its impact on patient outcomes. Gaining insight into molecular and genetic drivers, such as BRCA mutations and interactions within the immune microenvironment, is essential for developing targeted treatments. Future studies should aim to enhance experimental models, identify early detection markers, and investigate novel therapeutic approaches to effectively address HGSOC metastasis and improve patient survival.

Although lymphatic vessels (LVs) are present in many tumors, their importance in cancer has long been underestimated. In contrast to the well-studied tumor-associated blood vessels, LVs were previously considered to function as passive conduits for tumor metastasis. However, emerging evidence over the last two decades has shed light on their critical role in locally shaping the tumor microenvironment (TME). Here we review the involvement of LVs in tumor progression, metastasis, and modulation of anti-tumor immune response.

Tumor metastasis involves a series of complex and coordinated processes, which is the main cause of patient death and still a significant challenge in cancer treatment. Pre-metastatic niches (PMN), a specialized microenvironment that develops in distant organs prior to the arrival of metastatic cancer cells, plays a crucial role in driving tumor metastasis. The development of PMN depends on a complex series of cellular and molecular components including tumor-derived factors, bone marrow-derived cells, resident immune cells, and extracellular matrix. Fibrinogen, a key factor in the typical blood clotting process, is related to tumor metastasis and prognosis, according to a growing body of evidence in recent years. Fibrinogen has emerged as an important factor in mediating the formation of tumor microenvironment. Nevertheless, a clear and detailed mechanism by which fibrinogen promotes tumor metastasis remains unknown. In this review, we first explore the roles of fibrinogen in the development of PMN from four perspectives: immunosuppression, inflammation, angiogenesis, and extracellular matrix remodeling. We highlight the significance of fibrinogen in shaping PMN and discuss its potential therapeutic values, opening new avenues for targeting fibrinogen to prevent or treat metastasis.

Oral squamous cell carcinoma (OSCC) is frequently observed as the predominant malignancy affecting the oral cavity, with distant metastasis greatly affecting the treatment and long-term outlook for individuals with OSCC. Immune checkpoint inhibitors are a highly promising cancer treatment strategy currently available, but they are only successful for a small fraction of individuals with OSCC. Due to the insufficient understanding of the immune escape mechanisms in OSCC, coupled with disappointing treatment outcomes for patients with highly heterogeneous metastatic diseases, there is an urgent need for further exploration of immune target therapy strategies. This review discusses the mechanisms by which OSCC cells evade immune surveillance and attack, focusing on four aspects: metastasis-initiating cells, increased immune suppression, immune escape of dormant cells, and immune stromal crosstalk during metastasis. Additionally, we explore new areas in immune therapy for OSCC. In summary, our investigation offers fresh perspectives on the relationship between the tumor microenvironment and immune molecules, highlighting the importance of overcoming immune evasion for the development of novel therapies to manage OSCC metastasis and enhance patient outcomes.

Liver metastasis is a leading cause of mortality from malignant tumors and significantly impairs the efficacy of therapeutic interventions. In recent years, both preclinical and clinical research have made significant progress in understanding the molecular mechanisms and therapeutic strategies of liver metastasis. Metastatic tumor cells from different primary sites undergo highly similar biological processes, ultimately achieving ectopic colonization and growth in the liver. In this review, we begin by introducing the inherent metastatic-friendly features of the liver. We then explore the panorama of liver metastasis and conclude the three continuous, yet distinct phases based on the liver's response to metastasis. This includes metastatic sensing stage, metastatic stress stage, and metastasis support stage. We discuss the intricate interactions between metastatic tumor cells and various resident and recruited cells. In addition, we emphasize the critical role of spatial remodeling of immune cells in liver metastasis. Finally, we review the recent advancements and the challenges faced in the clinical management of liver metastasis. Future precise antimetastatic treatments should fully consider individual heterogeneity and implement different targeted interventions based on stages of liver metastasis.

Metastasis is responsible for most cancer-related deaths. Different cancers have their own preferential sites of metastases, a phenomenon termed metastatic organotropism. The mechanisms underlying organotropism are multifactorial and include the generation of a pre-metastatic niche (PMN), metastatic homing, colonization, dormancy, and metastatic outgrowth. Historically, studies of metastatic organotropism have been limited by a lack of models allowing direct comparison of cells exhibiting different patterns of tropism. However, new innovative models and large-scale sequencing efforts have propelled organotropism research. Herein, we summarize the recent discoveries in metastatic organotropism regulation, focusing on lung, liver, brain, and bone tropism. We discuss how emerging technologies are continuing to improve our ability to model and, hopefully, predict and treat organotropism.

S100A4 is a Ca2+-binding protein involved in multiple chronic inflammatory and neoplastic conditions. This review focuses on recent advances in the understanding of S100A4 function in immune cells, comparing and contrasting S100A4 regulation of immune responses in cancer and chronic inflammatory diseases. We provide evidence that S100A4 regulation of immune cell function has a profound role in promoting the pathogenesis of cancer and pro-inflammatory conditions. Finally, we discuss relevant future directions to target S100A4 therapeutically in different disease states.

Pancreatic cancer liver metastasis is an important factor leading to dismal prognoses. The details of adaptive immune remodeling in liver metastasis, especially the role of neutrophils, remain elusive. Here, combined single-cell sequencing with spatial transcriptomics results revealed that liver metastases exhibit more aggressive transcriptional characteristics and higher levels of immunosuppression compared with the primary tumor. We identified neutrophils_S100A12 (S100 calcium binding protein A12) cells as the pivotal pro-metastatic cluster, specifically distributed at the invasive front of the metastatic lesions. Mechanistically, our findings indicated that nuclear factor erythroid 2 (NFE2) is a key transcription factor regulating neutrophil phenotypic polarization. Metastatic tumors produce transforming growth factor β to activate the SMAD3 pathway within neutrophils, inducing NFE2-driven polarization. NFE2 promotes the transcription of peptidylarginine deiminase 4 by binding to its promoter, leading to the generation of neutrophil extracellular traps at the invasive front. Collectively, our data demonstrate that NFE2-driven neutrophil polarization is a potential target for anti-metastatic therapy.

Over the past few years, the tumor microbiome is increasingly recognized for its multifaceted involvement in cancer initiation, progression, and metastasis. With the application of 16S ribosomal ribonucleic acid (16S rRNA) sequencing, the intratumoral microbiome, also referred to as tumor-intrinsic or tumor-resident microbiome, has also been found to play a significant role in the tumor microenvironment (TME). Understanding their complex functions is critical for identifying new therapeutic avenues and improving treatment outcomes. This review first summarizes the origins and composition of these microbial communities, emphasizing their adapted diversity across a diverse range of tumor types and stages. Moreover, we outline the general mechanisms by which specific microbes induce tumor initiation, including the activation of carcinogenic pathways, deoxyribonucleic acid (DNA) damage, epigenetic modifications, and chronic inflammation. We further propose the tumor microbiome may evade immunity and promote angiogenesis to support tumor progression, while uncovering specific microbial influences on each step of the metastatic cascade, such as invasion, circulation, and seeding in secondary sites. Additionally, tumor microbiome is closely associated with drug resistance and influences therapeutic efficacy by modulating immune responses, drug metabolism, and apoptotic pathways. Furthermore, we explore innovative microbe-based therapeutic strategies, such as engineered bacteria, oncolytic virotherapy, and other modalities aimed at enhancing immunotherapeutic efficacy, paving the way for microbiome-centered cancer treatment frameworks.

Pancreatic cancer remains one of the most challenging malignancies to treat due to its late-stage diagnosis, aggressive progression, and high resistance to existing therapies. This review examines the latest advancements in early detection, and therapeutic strategies, with a focus on emerging biomarkers, tumor microenvironment (TME) modulation, and the integration of artificial intelligence (AI) in data analysis. We highlight promising biomarkers, including microRNAs (miRNAs) and circulating tumor DNA (ctDNA), that offer enhanced sensitivity and specificity for early-stage diagnosis when combined with multi-omics panels. A detailed analysis of the TME reveals how components such as cancer-associated fibroblasts (CAFs), immune cells, and the extracellular matrix (ECM) contribute to therapy resistance by creating immunosuppressive barriers. We also discuss therapeutic interventions that target these TME components, aiming to improve drug delivery and overcome immune evasion. Furthermore, AI-driven analyses are explored for their potential to interpret complex multi-omics data, enabling personalized treatment strategies and real-time monitoring of treatment response. We conclude by identifying key areas for future research, including the clinical validation of biomarkers, regulatory frameworks for AI applications, and equitable access to innovative therapies. This comprehensive approach underscores the need for integrated, personalized strategies to improve outcomes in pancreatic cancer.

Heterogeneous roles of complement C3 have been implicated in tumor metastasis and are highly context dependent. However, the underlying mechanisms linking C3 to tumor metastasis remain elusive in renal cell carcinoma (RCC). Here, we demonstrate that C3 of RCC cell-derived extracellular vesicles (EVs) contributes to metastasis via polarizing tumor-associated macrophages (TAMs) into the immunosuppressive phenotype and recruiting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, EV C3 induces the secretion of CCL2 and CXCL1 by lung macrophages and subsequently enhances TAM polarization and PMN-MDSC recruitment. Notably, targeting the CCL2/CCR2 or CXCL1/CXCR2 axis with the inhibitors RS504393 or Navarixin, respectively, effectively suppresses lung metastasis induced by RCC-derived C3 in a mouse model. Clinically, RCC patients with high expression of C3 demonstrate poor prognosis. Collectively, our findings reveal that tumor-derived EV C3 induces an immunosuppressive tumor microenvironment via TAMs, and thus promoting RCC metastasis.

Liver and lung metastases demonstrate distinct biological, particularly immunological, characteristics. We investigated whether preoperative complete blood count (CBC) parameters, which may reflect the immune system condition, predict early dissemination to the liver and lungs in colorectal cancer (CRC).

In this retrospective single-centre study, we included 268 resected CRC cases with complete 2-year follow-up and analysed preoperative CBC for association with early liver or lung metastasis development. Next, selected CBC and clinicopathological parameters were analysed with uni- and multivariable Cox regression. Independent factors affecting liver or lung metastasis-free survival were incorporated into composite scores, which were further evaluated with receiver operating characteristic (ROC) curves and dichotomised using a modified, specificity-focused, Youden approach to identify particularly high-risk patients.

Compared to metastasis-free patients, early liver metastases were related to decreases in red blood cells, haematocrit, lymphocytes and elevated monocyte-to-lymphocyte ratio, while lung metastases to lower eosinophil counts. A composite score of independent factors (erythrocytopenia, lower lymphocyte count and pN) yielded HR of 8.01 (95% CI 3.45-18.57, p < 0.001) for liver-specific metastasis-free survival (MFS). For lung-specific MFS, the combination of eosinopenia, pN and primary tumour location showed HR of 13.69 (95% CI 4.34-43.20, p < 0.001).

Early CRC metastases to the liver and lungs are associated with partially divergent clinicopathological and peripheral blood features. We propose simple, clinically implementable scores, based on routinely assessed parameters, to identify patients with an increased risk of early dissemination to the liver or lungs. After validation in independent cohorts, these scores may provide easily available prognostic information.

The pre-metastatic niche constructed by cancer-associated fibroblasts (CAFs) plays a key role in the hypoxic tumor microenvironment (TME), promoting hepatocellular carcinoma (HCC) metastasis. Integrin, which is involved in cell-to-cell or cell-to-matrix interactions and TME regulation, affects tumor metastasis. However, the complex interactions between integrin-mediated HCC cells and CAFs remain unclear. Co-culture experiments were used to assess the behaviors of HCC cells and CAFs, demonstrating HCC metastatic traits and CAFs activation in vitro. Transcriptome sequencing analysis and molecular detection identified key genes, with overexpression and knockdown experiments further confirming their roles in HCC progression. Xenograft models validated these findings in vivo. We showed that HCC cells induced the conversion of normal hepatic stellate cells (HSCs) into CAFs and recruit additional CAFs, driven by lactate produced by HCC. Integrin beta 4 (ITGB4) was identified as a key gene in the process. Inhibiting ITGB4 reduced lactate secretion, reversed CAFs activation and recruitment, and decreased HCC metastasis, while overexpressing ITGB4 significantly enhanced these malignant phenotypes. ITGB4 influences glycolysis and HCC metastasis through the AKT/HK2 signaling pathway, and CAFs activation and recruitment through the TGF-β/Smads signaling pathway. Compared to tumors derived from control cells, ITGB4-knockdown tumors showed fewer and smaller intrahepatic metastatic nodules, reduced lactate production and CAFs formation, along with inhibition of AKT/HK2 and TGF-β/Smads signaling pathways. Our findings highlighted the impact of hypoxia on HCC progression, revealing the roles of ITGB4-mediated glycolysis and lactate-induced CAFs in the pre-metastatic niche on HCC metastasis.

Despite remarkable progress in basic oncology, practical results remain unsatisfactory. This discrepancy is partly due to the exclusive focus on processes within the cancer cell, which results in a lack of recognition of cancer as a systemic disease. It is evident that a wise balance is needed between two alternative methodological approaches: reductionism, which would break down complex phenomena into smaller units to be studied separately, and holism, which emphasizes the study of complex systems as integrated wholes. A consistent holistic approach has so far led to the notion of cancer as a special organ, stimulating debate about its function and evolutionary significance. This article discusses the role of cancer as a mechanism of purifying selection of the gene pool, the correlation between hereditary and sporadic cancer, the cancer interactome, and the role of metastasis in a lethal outcome. It is also proposed that neutralizing the cancer interactome may be a novel treatment strategy.

Recurrence and metastasis remain the leading cause of death in breast cancer patients due to the lack of effective treatment. A microenvironment suitable for cancer cell growth, referred to as pre-metastatic niche (PMN), is formed in distant organs before metastasis occurs. Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells with immunosuppressive effects. They can expand in large numbers in breast cancer patients and participate in the formation of PMN. MDSCs can remodel the extracellular matrix of pulmonary vascular endothelial cells and recruit cancer stem cells to promote the lung metastasis of breast cancer. Furthermore, MDSCs facilitate immune evasion of breast cancer cells to impact the efficacy of immunotherapy. It is proposed that MDSCs represent a potential therapeutic target for the inhibition of recurrence and metastasis in breast cancer. Therapeutic strategies targeting MDSCs have shown promising efficacy in preclinical studies and clinical trials. This review presents a summary of the principal factors involved in the recruitment and activation of MDSCs during the formation of PMN, and outlines MDSCs functions such as immunosuppression and the current targeted therapies against MDSCs, aiming to provide new ideas for the treatment of distant metastases in breast cancer.

Salivary adenoid cystic carcinoma (SACC) tends to metastasize to the lungs in the early stages of the disease. Factors secreted by the primary tumor can induce the formation of a supportive microenvironment in distant organs prior to metastasis, a process known as pre-metastatic niche (PMN) formation. Extracellular vesicles (EVs) participate in PMN formation. In this study, α2,6-sialylation of EVs derived from SACC cells with high metastatic potential increased vascular permeability, thereby facilitating tumor metastasis to the lungs. Mechanistic studies indicated that EV α2,6-sialylation triggers protein kinase R-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-dependent activation of endoplasmic reticulum (ER) stress in the endothelium, leading to the disruption of vascular endothelial cadherin membrane expression. Sialidase or an ER stress inhibitor rescued vascular permeability induced by SACC EVs, which decreased the number of SACC cells extravasating into the lungs both in vitro and in vivo. This study identified a critical role of α2,6-sialylation of SACC EVs in lung metastasis. The findings indicate that EV α2,6-sialylation-induced ER stress in endothelial cells might be a therapeutic target for preventing SACC lung metastasis.

Macrophages that acquire an immunosuppressive phenotype play a crucial role in establishing the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to distant organs. Our study showed that increased activity of the aryl hydrocarbon receptor (AHR) in lung macrophages plays a crucial role in establishing the immunosuppressive PMN in breast cancer. Specifically, AHR activation led to high expression of PD-L1 on macrophages by directly binding to the promoter of Pdl1. This upregulation of PD-L1 promoted the differentiation of regulatory T cells (Tregs) within the PMN, further enhancing immunosuppressive conditions. Mice with Ahr conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR levels in PMN macrophages were induced by GM-CSF, which was secreted by breast cancer cells. Mechanistically, the activated STAT5 signaling pathway induced by GM-CSF prevented AHR from being ubiquitinated, thereby sustaining its activity in macrophages. In breast cancer patients, the expression of AHR and PD-L1 was correlated with increased Treg cell infiltration, and higher levels of AHR were associated with a poor prognosis. These findings reveal that the crosstalk of breast cancer cells, lung macrophages, and Treg cells via the GM-CSF-STAT5-AHR-PD-L1 cascade modulates the lung pre-metastatic niche during breast cancer progression.

C-reactive protein (CRP) is a liver-derived acute phase reactant that is a clinical marker of inflammation associated with poor cancer prognosis. Elevated CRP levels are observed in many types of cancer and are associated with significantly increased risk of metastasis, suggesting that CRP could have prometastatic actions. In this study, we reported that CRP promotes lung metastasis by dampening the anticancer capacity of pulmonary macrophages in breast cancer and melanoma. Deletion of CRP in mice inhibited lung metastasis of breast cancer and melanoma cells without significantly impacting tumor growth compared with wild-type mice. In addition, the lungs of CRP-deficient mice were enriched for activated pulmonary macrophages, which could be reduced to the level of wild-type mice by systemic administration of human CRP. Mechanistically, CRP blocked the activation of pulmonary macrophages induced by commensal bacteria in a FcγR2B-dependent manner, thereby impairing macrophage-mediated immune surveillance to promote the formation of a premetastatic niche in the lungs of tumor-bearing mice. Accordingly, treatment with specific CRP inhibitors activated pulmonary macrophages and attenuated lung metastasis in vivo. These findings highlight the importance of CRP in lung metastasis, which may represent an effective therapeutic target for patients with advanced solid cancers in clinics. Significance: CRP maintains host-commensal tolerance by inhibiting pulmonary macrophage activation and can be targeted to remodel the premetastatic niche in the lung to lower the risk of cancer metastasis. See related commentary by Saal et al., p. 4121.

Cancer cells secrete extracellular vesicles (EV) encapsulating bioactive cargoes to facilitate inter-organ communication in vivo and are emerging as critical mediators of tumor progression and metastasis, a condition which is often accompanied by a dysregulated cholesterol metabolism. Whether EVs are involved in the control of cholesterol homeostasis during tumor metastasis is still undefined and warrant further investigation. Here, we find that breast cancer-derived exosomal miR-9-5p induces the expression of HMGCR and CH25H, two enzymes involved in cholesterol synthesis and the conversion of 25-hydroxycholesterol from cholesterol by targeting INSIG1, INSIG2 and ATF3 genes in the liver. Notably, in vivo miR-9-5p antagomir treatment and genetic CH25H ablation prevents tumor metastasis in a mouse model of breast cancer. Thus, our findings reveal the regulatory mechanism of tumor-derived miR-9-5p in liver metastasis by linking oxysterol metabolism and Kupffer cell polarization, shedding light on future applications for cancer diagnosis and treatment.