Photodynamic therapy (PDT) has garnered increasing attention in cancer treatment due to its precise spatiotemporal selectivity and non-invasive nature. However, several challenges, including the inability of photosensitizers to discriminate between tumor and healthy tissues, as well as the limited tissue penetration depth of light sources, impede its broader application. To surmount these impediments, our research introduces a two-photon photosensitizer (TPSS) that specifically targets tumor overexpressing carbonic anhydrase IX (CA IX), thereby exhibiting exceptional specificity for tumor cells. Under two-photon laser stimulation, TPSS generates a large amount of reactive oxygen species (ROS), inducing cell pyroptosis and subsequently triggering a strong anti-tumor immune response. Additionally, proteomics analysis provides compelling evidence to elucidate the anti-tumor mechanism of TPSS in vivo. Through comprehensive immune assessments, TPSS under two-photon laser irradiation effectively activates both the innate and adaptive immune systems, efficiently suppressing the proliferation of distant metastatic tumors, underscoring its considerable therapeutic potential. Collectively, this study provides a viable strategy to overcome the limitations of PDT, highlighting the prospects of two-photon excitation photosensitizers.

Metastasis as the hallmark of cancer preferentially contributes to tumor recurrence and therapy resistance, aggrandizing the lethality of patients with cancer. Despite their robust suppressions of tumor progression, chemotherapeutics failed to attenuate cancer cell migration and even triggered pro-metastatic effects. In parallel, protease-activated receptor 2 (PAR2), a member of the G protein-coupled receptor subfamily, actively participates in cancer metastasis via multiple signal transduction pathways. CRISPR/Cas9 that is a dominating genome editing tool can evoke PAR2 knockout to inhibit cancer metastasis. However, the absence of valid delivery systems largely limits its efficacy. Herein, we nanosized polymeric platinum (NanoPt) as therapeutical drug carries to deliver CRISPR/Cas9 to elicit genome editing of PAR2, which drastically augmented anti-metastatic effects and alleviated systematic toxicity of platinum-based treatment in vitro and in vivo. More importantly, the NanoPt@Cas9-PAR2 initiated PAR2 deficiency to mechanistically attenuate EMT process and ferroptosis via RAGE/ERK signalling, consequently preventing cancer cell migration. Our findings indicate that NanoPt@Cas9-PAR2 that mitigated PAR2 signalling and cytotoxic effects of platinum could be a safe and powerful all-in-one combinatorial strategy for cancer treatment.

Lysyl oxidase-like-1 (LOXL1) is a copper-dependent amine oxidase that maintains the structural integrity of the extracellular matrix (ECM) by catalyzing the cross-linking of collagen and elastin. However, aberrations in LOXL1 expression can contribute to diseases like glaucoma, tissue fibrosis, and cancer. LOXL1 has been found to be overexpressed in various malignancies, playing a pivotal role in tumor growth and metastasis. Although some studies suggest tumor-suppressive attributes of LOXL1, its role in tumorigenesis remains controversial. Research on LOXL1 has been primarily focused on pseudoexfoliation syndrome/glaucoma, with limited reviews on its impact on cancer. This review aims to explore LOXL1 comprehensively, including its structure, biological effects, and regulatory processes. Emphasis is placed on understanding the relationship between LOXL1 and tumorigenesis, specifically how LOXL1 influences tumor microenvironment remodeling, tumorigenesis, and metastasis. The review also discusses potential therapeutic strategies targeting LOXL1 for anti-fibrosis and anti-tumor interventions.

Developing a catalytic nanoenzyme activated by the tumor microenvironment (TME) shows excellent potential for in situ cancer treatment. However, the rational design of a cascade procedure to achieve high therapeutic efficiency remains challenging. In this study, the colorectal TME-responsive multifunctional cascade nanoenzyme Cu2-xO@MnO2@glucose oxidase (GOx)@hyaluronic acid (HA) was developed to target in situ cancer starvation/chemodynamic therapy (CDT)/photothermal therapy (PTT). First, the MnO2 nanolayer specifically decomposes within the acidic TME to generate Mn2+ and oxygen (O2), thereby alleviating the hypoxic TME. Subsequently, Cu2-xO can be vulcanized into Cu2-xS by overexpressing sulfuretted hydrogen (H2S) gas in the colorectal tumor for a second near-infrared (NIR-II) light-triggered deep tissue PTT. Cu2-xS nanoparticles can react with hydrogen peroxide (H2O2) to generate hydroxyl radical (OH) for the CDT. In addition, GOx catalyzes the conversion of glucose into H2O2 for starvation therapy and enhances the CDT efficiency by self-supplying H2O2. Interestingly, the generated reactive oxygen species (ROS) induce immunogenic cell death (ICD), which further activates adaptive cancer immunity for anti-tumor immunotherapy. Finally, therapeutic efficiency was greatly improved after coating with tumor-targeted HA. Collectively, these TME-responsive cascade nanoenzymes can realize PTT, CDT starvation therapy, and immunotherapy, paving the way for the design of TME-responsive cascade nanoenzymes for synergistically enhanced tumor-specific therapy.

Despite the discovery of numerous oncogenes in colorectal cancer (CRC), the development of associated drugs is limited, posing a significant challenge for CRC treatment. Identification of novel druggable targets is therefore crucial for the therapeutic development of CRC. Here, we report the first investigation on therapeutics targeting the potent oncogene NUCKS1 to suppress cancer progression. NUCKS1-orientated bioinformatics screening of NUCKS1 inhibitors from our library of tRNA fragments originated from medicinal plants identified tRF-T36, a 5' tRNA fragment of tRNAAsn(GUU) of Chinese yew (Taxus chinensis), exhibiting stronger inhibitory effects than taxol against CRC progression. Mechanistically, tRF-T36 binds directly to the 3' UTR of NUCKS1 mRNA to downregulate its expressions via RNAi pathway. High-throughput RNA sequencing indicated that the downregulated NUCKS1 induced by tRF-T36 further inhibits PI3K/Akt pathway, as verified by the significantly efficacy decrease of tRF-T36 mimic in co-treatment with 740Y-P, an agonist of PI3K/Akt pathway. Collectively, our findings emphasize the importance of NUCKS1 as a promising druggable target for CRC. Furthermore, the present study provides the first siRNA sequence, tRF-T36 mimic, as small RNA drug candidate, thereby shedding light on CRC therapeutics.

Metastasis is a principal cause of patient morbidity and death from solid cancers with current therapies being inadequate.

Detailed genomic analyses document mutational differences between the initial tumor and metastatic clones, posing a challenge to current targeted therapies, which focus predominantly on the phenotype of primary tumors. Considering the diverse signaling cascades and numerous compensatory pathways in metastasis, designing broad-spectrum anti-metastatic therapies remains challenging. Although significant anti-cancer activity is evident in specific patients with advanced cancers and metastases treated with single or combination immunotherapies, there are limitations, i.e. toxicity, immune inhibitory 'cold' tumors and the tumor microenvironment (TME), and intra- and intertumoral heterogeneity. Accordingly, multidisciplinary strategies are required to attack metastases and the TME to obtain optimal therapeutic responses.

To create potent anti-metastatic agents, defining critical genes/proteins and drugs controlling discrete steps in the metastatic cascade are mandatory. Melanoma differentiation-associated gene-9 (MDA-9), Syndecan Binding Protein (SDCBP) or Syntenin (MDA-9/Syntenin) is robustly expressed and serves essential roles in cancer disease progression through protein-protein interactions with additional metastasis-associated molecules and pathways. The importance of MDA-9/Syntenin in the metastatic process is now established and first-in-class inhibitory molecules look promising with some moving toward clinical evaluation.

The spread of metastases is a crucial process in which some questions remain unanswered. In this work, we focus on tumor cells circulating in the bloodstream, the so-called Circulating Tumor Cells (CTCs). Our aim is to characterize their trajectories under the influence of hemodynamic and adhesion forces. We focus on already available in vitro measurements performed with a microfluidic device corresponding to the trajectories of CTCs - without or with different protein depletions - interacting with an endothelial layer. A key difficulty is the weak knowledge of the fluid velocity that has to be reconstructed. Our strategy combines a differential equation model - a Poiseuille model for the fluid velocity and an ODE system for the cell adhesion model - and a robust and well-designed calibration procedure. The parameterized model quantifies the strong influence of fluid velocity on adhesion and confirms the expected role of several proteins in the deceleration of CTCs. Finally, it enables the generation of synthetic cells, even for unobserved experimental conditions, opening the way to a digital twin for flowing cells with adhesion.

Colorectal carcinoma (CRC) is a deadly cancer with an aggressive nature, and how CRC tumor cells manage to translocate and proliferate in a new tissue environment remains not fully understood. Recently, higher-order chromatin structures and spatial genome organization are increasingly implicated in diseases including cancer, but in-depth studies of three-dimensional genome (3D genome) of metastatic cancer are currently lacking, preventing the understanding of the roles of genome organization during metastasis. Here we perform multi-omics profiling of matched normal colon, primary tumor, lymph node metastasis, liver metastasis and normal liver tissue from CRC patients using Hi-C, ATAC-seq and RNA-seq technologies. We find that widespread alteration of 3D chromatin structure is accompanied by dysregulation of genes including SPP1 during the tumorigenesis or metastasis of CRC. Remarkably, the hierarchy of topological associating domain (TAD) changes dynamically, which challenges the traditional view that the TAD structure between tumor and normal tissue is conservative. In addition, we define compartment stability score to measure large-scale alteration in metastatic tumors. To integrate multi-omics data and recognize candidate genes driving cancer metastasis, a pipeline is developed based on Hi-C, RNA-seq and ATAC-seq data. And three candidate genes ARL4C, FLNA, and RGCC are validated to be associated with CRC cell migration and invasion using in vitro knockout experiments. Overall, these data resources and results offer new insights into the involvement of 3D genome in cancer metastasis.

The tissue invasive capacity of cancer cells is determined by their phenotypic plasticity. For instance, mesenchymal to amoeboid transition has been found to facilitate the passage of cancer cells through confined environments. This phenotypic transition is also heavily regulated by the architecture of the actin cytoskeleton, which may increase myosin contractility and the intracellular pressure that is known to drive bleb formation. In this review, we highlight several Diaphanous related formins (DRFs) that have been found to promote or suppress bleb formation in cancer cells, which is a hallmark of amoeboid migration. Based on the work discussed here, the role of the DRFs in cancer(s) is worthy of further scrutiny in animal models, as they may prove to be therapeutic targets.

Although most cancer deaths are caused by metastasis, there are no effective therapeutic approaches. This study describes the efficacy of a short synthetic mRNA (s-mRNA) designed by the sequence of non-vesicular extracellular IL1β-mRNA found in the pre-metastatic lung of tumor-bearing mice. The administration of s-mRNA inhibits murine lung metastasis by inducing the innate and adaptive immune systems. s-mRNA binds to ZC3H12D, an RNA-binding protein on natural killer cells and cytotoxic T lymphocytes. The ZC3H12D-s-mRNA complex translocated to the nucleus without being involved in translation. This process induces cytolytic activity and cell death in cancer cells without inducing a cytokine storm, and immune cells retain their antitumor activity. Although the antitumor activity of cytotoxic lymphocytes declines as the disease progresses in cancer patients, s-mRNA induces sustained high killing capacities of natural killer cells and cytotoxic T lymphocytes from colon cancer patients. Therefore, s-mRNA could be a breakthrough solution to prevent metastasis.

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

Metastatic dissemination is driven by genetic, biochemical, and biophysical cues that favor the distant colonization of organs and the formation of life-threatening secondary tumors. We have previously demonstrated that endothelial cells (ECs) actively remodel during extravasation by enwrapping arrested tumor cells (TCs) and extruding them from the vascular lumen while maintaining perfusion. In this work, we dissect the cellular and molecular mechanisms driving endothelial remodeling. Using high-resolution intravital imaging in zebrafish embryos, we demonstrate that the actomyosin network of ECs controls tissue remodeling and subsequent TC extravasation. Furthermore, we uncovered that this cytoskeletal remodeling is driven by altered endothelial-calcium (Ca2+) signaling caused by arrested TCs. Accordingly, we demonstrated that the inhibition of voltage-dependent calcium L-type channels impairs extravasation. Lastly, we identified P2X4, TRP, and Piezo1 mechano-gated Ca2+ channels as key mediators of the process. These results further highlight the central role of endothelial remodeling during the extravasation of TCs and open avenues for successful therapeutic targeting.

Tremendous achievements in healthcare and science over the past 200 years have enhanced life expectancy in parallel with a shift from dogma to humanistic liberal education. Advancements in cancer have included vaccines treating causes of cancer (eg, hepatitis C- induced liver cancer and human papillomavirus-induced cervical cancer) along with improved cancer survival in children. In contrast, developments in cancer, frequently touted as "discoveries" or "breakthroughs" in media headlines, have been demonstrated to be ephemeral rather than game changers. In reality, cancer incidences are increasing, and relapse and mortality rates have not changed substantially. By this, we are experiencing today similar challenges to those before the so-called Humboldt reform. The trend towards managerialism with a focus on quantity in health care and science endangers their integrity.

Due to the complexity of integrity of healthcare and science, in-depth contemplation of this review contains foundations of actions in healthcare and science, information regarding cancer, as an example, quantity focus of healthcare, technology, publishing, marketing and media, predatory publishers, followed by psychologic and sociologic aspects which influence our perception.

A complex paradoxical transformation has occurred, in which quality and humanism have been replaced by quantity, revenue, and marketing, together with "citation silence", (ignoring original findings), and increased corruption and misconduct. This shift explains why the integrity of healthcare and science is being eroded.

Countries and societies are only as strong as their healthcare and science, both of which are only as strong as their emphasis on quality and integrity. Awareness of this situation may represent a first step toward a renewed focus on accountability.

The forkhead box A (FOXA) family has been extensively studied in cancer research; however, the role of FOXA3 in malignant tumors, particularly esophageal squamous cell carcinoma (ESCC), is not well understood. This study explores the expression and function of FOXA3 in ESCC, assessing its potential as a prognostic marker and therapeutic target.

This study analyzed FOXA3 expression in ESCC tissues and its correlation with patient prognosis. The effects of FOXA3 overexpression on ESCC cell proliferation, migration, and invasion were examined in ESCC cell lines in vitro. Additionally, an in vivo tumorigenesis assay was performed using subcutaneous injection to assess the impact of FOXA3 overexpression on tumor growth. Statistical analyses were conducted to determine the significance of the results.

FOXA3 expression was significantly reduced in ESCC tissues compared with it in paired adjacent normal tissues, and low FOXA3 expression was significantly associated with poor prognosis in ESCC patients. FOXA3 overexpression markedly inhibited ESCC cell proliferation, migration, and invasion. In addition, overexpression of FOXA3 repressed tumor growth in mice.

These findings indicate that FOXA3 acts as a tumor suppressor in ESCC, and its low expression is linked to poor outcomes. FOXA3 may serve as a potential diagnostic and therapeutic target for ESCC.

Non‑small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia‑inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient‑deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor‑associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC.

N7-methylguanosine (m7G) is an important RNA modification involved in epigenetic regulation that is commonly observed in both prokaryotic and eukaryotic organisms. Their influence on the synthesis and processing of messenger RNA, ribosomal RNA, and transfer RNA allows m7G modifications to affect diverse cellular, physiological, and pathological processes. m7G modifications are pivotal in human diseases, particularly cancer progression. On one hand, m7G modification-associated modulate tumour progression and affect malignant biological characteristics, including sustained proliferation signalling, resistance to cell death, activation of invasion and metastasis, reprogramming of energy metabolism, genome instability, and immune evasion. This suggests that they may be novel therapeutic targets for cancer treatment. On the other hand, the aberrant expression of m7G modification-associated molecules is linked to clinicopathological characteristics, including tumour staging, lymph node metastasis, and unfavourable prognoses in patients with cancer, indicating their potential as tumour biomarkers. This review consolidates the discovery, identification, detection methodologies, and functional roles of m7G modification, analysing the mechanisms by which m7G modification-associated molecules contribute to tumour development, and exploring their potential clinical applications in cancer diagnostics and therapy, thereby providing innovative strategies for tumour identification and targeted treatment.

Metastasis is a main cause of cancer-related death, and a deeper understanding of the metastatic process will inform more targeted and mechanistic approaches that can abrogate challenges in treatment efficacy and toxicity. Several steps throughout the metastatic cascade, from angiogenesis to secondary tumor formation, offer specific vulnerabilities to therapies that can lead to the decline or cessation of metastatic progression. A deeper understanding of the metastatic cascade also allows combination systemic therapies to be used synergistically. In this review, we describe current treatment modalities in the context of multiple steps of the metastatic cascade. We highlight their mechanisms and present their efficacy across multiple cancers. This work also presents targets within the metastatic cascade in need of more research that can advance the landscape of treatments and lead to the goal of metastatic cancer remission.

Tumors require ample protein synthesis to grow, and aminoacyl-tRNA synthetases, as critical translation factors, are expected to support cancer progression. Unexpectedly, overexpression of seryl-tRNA synthetase (SerRS) suppresses primary tumor growth of breast cancer. However, the effects of SerRS on metastasis have not been studied. We observe a decrease in SerRS expression in breast cancer patient metastases compared with matched primary tumors, suggesting an inhibitory role of SerRS in metastasis. Through mouse metastasis models using breast cancer cell lines overexpressing SerRS, we show that SerRS impedes not only primary tumor growth but also establishment of metastases, and the effect of SerRS on metastasis can be independent of its impact on the primary tumor. SerRS also inhibits tumor growth with induced, post-tumor-onset overexpression, demonstrating its potential as an anticancer therapeutic. Tumor RNA-seq analysis identified Wnt signaling among the top SerRS-regulated pathways. Using cell-based studies, we confirm SerRS suppresses Wnt signaling and metastatic processes in breast cancer cells. To the best of our knowledge, this is the first study to show a component of the translation machinery can act as both a tumor and metastasis suppressor.

Chemotherapy is the primary treatment option for pancreatic cancer, although nanocarrier-based drug delivery systems often struggle with multiple physiological barriers, limiting their therapeutic efficacy. Here, we developed a pH/reactive oxygen species (ROS) dual-sensitive self-adaptive nanocarrier (DATCPT) encapsulating camptothecin (CPT), an analog of the pancreatic chemotherapeutic drug irinotecan (CPT-11), to enhance chemotherapy outcomes in orthotopic pancreatic cancer by addressing multiple physiological barriers. The nanocarrier features a peripherally positively charged arginine (Arg) residue on DATCPT and is masked with an acid-labile 2,3-dimethylmaleic anhydride (DA) to improve circulation time. In the acidic tumor microenvironment (TME), DA dissociates, exposing arginine to facilitate nanocarrier binding and internalization of DATCPT. Subsequently, peroxynitrite (ONOO-) is generated by a cascade reaction between exposed Arg and ROS, which effectively activates matrix metalloproteinases (MMPs) to degrade the dense extracellular matrix (ECM) and enhance the deep accumulation and penetration of DATCPT. Meanwhile, ONOO- inhibits tumor metastasis by influencing mitochondrial function, preventing adenosine triphosphate (ATP) production, and inhibiting ATP-dependent tumor-derived microvesicles (TMVs). This study presents a promising strategy to develop efficient nanocarriers to address multiple physiological barriers in antipancreatic cancer therapy.

Cancer metastasis, the process by which tumour cells migrate and colonize distant organs from a primary site, is responsible for the majority of cancer-related deaths. Understanding the cellular and molecular mechanisms underlying this complex process is essential for developing effective metastasis prevention and therapy strategies. To this end, we systematically analysed 1786 bulk tissue samples from 13 cancer types, 988 463 single cells from 17 cancer types, and 40 252 spots from 45 spatial slides across 10 cancer types. The results of these analyses are compiled in the metsDB database, accessible at https://relab.xidian.edu.cn/metsDB/. This database provides insights into alterations in cell constitutions, cell relationships, biological pathways, molecular biomarkers, and drug responses during cancer metastasis at bulk, single-cell, and spatial levels. Users can perform cell or gene searches to obtain multi-view and multi-scale metastasis-related data. This comprehensive resource is invaluable for understanding the metastasis process and for designing molecular therapies.

The Ras-induced ERK pathway (Raf-MEK-ERK signaling cascade) regulates a variety of cellular responses including cell proliferation, survival, and migration. Activating mutations in RAS genes, particularly in the KRAS gene, constitutively activate the ERK pathway, resulting in tumorigenesis, cancer cell invasion, and metastasis. DA-Raf1 (DA-Raf) is a splicing isoform of A-Raf and contains the Ras-binding domain but lacks the kinase domain. Consequently, DA-Raf antagonizes the Ras-ERK pathway in a dominant-negative manner and can serve as a tumor suppressor that targets mutant Ras protein-induced tumorigenesis. We show here that MEK inhibitors and DA-Raf interfere with the in vitro collective cell migration and invasion of human KRAS-mutant carcinoma cell lines, the lung adenocarcinoma A549, colorectal carcinoma HCT116, and pancreatic carcinoma MIA PaCa-2 cells. DA-Raf expression was silenced in these cancer cell lines. All these cell lines had high collective migration abilities and invasion properties in Matrigel, compared with nontumor cells. Their migration and invasion abilities were impaired by suppressing the ERK pathway with the MEK inhibitors U0126 and trametinib, an approved anticancer drug. Expression of DA-Raf in MIA PaCa-2 cells reduced the ERK activity and hindered the migration and invasion abilities. Therefore, DA-Raf may function as an invasion suppressor protein in the KRAS-mutant cancer cells by blocking the Ras-ERK pathway when DA-Raf expression is induced in invasive cancer cells.

Circulating tumor cells (CTCs) are tumor cells that exist in human peripheral blood, which could spread to other tissues or organs via the blood circulation system and develop into metastatic foci, leading to tumor recurrence or metastasis in postoperative patients and thereby increasing the mortality of malignant tumor patients. Evaluation of CTC levels can be used for tumor metastasis prediction, prognosis evaluation, drug exploitation, individualized treatment, liquid biopsy, etc., which exhibit outstanding clinical application prospects. In recent years, accurately capturing and analyzing CTCs has become a research hotspot in the early diagnosis and precise treatment of tumors. This review summarized various enrichment and isolation technologies for evaluating CTCs based on the design principle and discussed the challenges and perspectives in this field.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates unique characteristics in anticancer therapies as it selectively induces apoptosis in cancer cells. However, most cancer cells are TRAIL-resistant. Odanacatib (ODN), a cathepsin K inhibitor, is considered a novel sensitizer for cancer treatment. Combination therapy between TRAIL and sensitizers is considered a potent platform that improves TRAIL-based anticancer therapies beyond TRAIL monotherapy. Herein, we developed ODN loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs) to target and treat TRAIL-resistant cancer. TRAIL-ODN-PLGA-NPs demonstrated a significant increase in cellular uptake via death receptors (DR5 and DR4) on surface of cancer cells. TRAIL-ODN-PLGA-NPs exposure destroyed more TRAIL-resistant cells compared to a single treatment with free drugs. The released ODN decreased the Raptor protein, thereby increasing damage to mitochondria by elevating reactive oxygen species (ROS) generation. Additionally, Bim protein stabilization improved TRAIL-resistant cell sensitization to TRAIL-induced apoptosis. The in vivo biodistribution study revealed that TRAIL-ODN-PLGA-NPs demonstrated high location and retention in tumor sites via the intravenous route. Furthermore, TRAIL-ODN-PLGA-NPs significantly inhibited xenograft tumor models of TRAIL-resistant Caki-1 and TRAIL-sensitive MDA-MB-231 cells.The inhibition was associated with apoptosis activation, Raptor protein stabilizing Bim protein downregulation, Bax accumulation, and mitochondrial ROS generation elevation. Additionally, TRAIL-ODN-PLGA-NPs affected the tumor microenvironment by increasing tumor necrosis factor-α and reducing interleukin-6. In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment.

Cancer presents a significant public health concern, particularly in the context of metastatic disease. Surgical removal of primary tumors, while essential, can inadvertently heighten the risk of metastasis. Thus, there is a critical need for innovative neoadjuvant therapies capable of curtailing metastatic progression before or immediately following tumor resection. Addressing this imperative, the papaya mosaic virus nanoparticle (PapMV) has demonstrated potent immunostimulatory capabilities against both viruses and tumors, effectively hindering their proliferation. Our study reveals that PapMV exerts a protective effect against lung metastasis when administered systemically prior to tumor implantation or during the early stages of metastasis in various mouse models of cancer. This anti-tumor effect is initiated by the recruitment of myeloid cells in the lungs. These cells adopt a pro-inflammatory profile, secreting cytokines such as IFN-α, thus fostering a tumor microenvironment inhospitable to tumor progression. Crucially, this protective mechanism hinges on the presence of macrophages before treatment. TLR7 and IFN-I signaling pathways also play pivotal roles in this process. Furthermore, our findings demonstrate that PapMV triggers the activation of the bone marrow emergency response, which accounts for the influx of myeloid cells into the lungs. This study unveils a novel aspect of PapMV's functionality. By bolstering the immune system, PapMV confers robust protection against metastasis at an early stage of disease progression. This discovery holds promise for therapeutic intervention, particularly as a preemptive measure prior to or just after surgical intervention.

Pancreatic cancer (PC) is one of the most malignant solid cancers, and PC metastasis, particularly liver metastasis, is a major cause of cancer mortality. A key event in tumor metastasis is the formation of pre-metastatic niche (PMN), which provides a microenvironment conducive to tumor cells colonization and progression. Various molecules loaded in tumor-derived exosomes (TDEs) contribute to PMN formation and distant tumor metastasis, by regulating immune and stromal cell function, inducing angiogenesis, and promoting metabolic reprogramming. Therefore, therapies targeting PMN may offer novel advantages to prevent tumor metastasis at an earlier stage. In this review, we summarize multifaceted mechanisms underlying hepatic PMN formation, with a focus on how PC TDEs participate in angiogenesis and vascular permeability, create immune suppressive microenvironment, remodel the extracellular matrix, and regulate metabolic reprogramming. In addition, we highlight the promise of TDEs for early diagnosis and effective therapy of PC liver metastases.

Lymph node metastasis is a critical indicator of cancer progression, profoundly affecting diagnosis, staging, and treatment decisions. This review article delves into the recent advancements in molecular imaging techniques for lymph nodes, which are pivotal for the early detection and staging of cancer. It provides detailed insights into how these techniques are used to visualize and quantify metastatic cancer cells, resident immune cells, and other molecular markers within lymph nodes. Furthermore, the review highlights the development of innovative, lymph node-targeted therapeutic strategies, which represent a significant shift towards more precise and effective cancer treatments. By examining cutting-edge research and emerging technologies, this review offers a comprehensive overview of the current and potential impact of lymph node-centric approaches on cancer diagnosis, staging, and therapy. Through its exploration of these topics, the review aims to illuminate the increasingly sophisticated landscape of cancer management strategies focused on lymph node assessment and intervention.

Vesicle Amine Transport-1 (VAT1) is a protein that is overexpressed in many cancers, including breast cancer, glioblastoma, and angiosarcoma. High VAT1 expression correlates with poor overall survival, and genetic knockout models of VAT1 indicate potent antimigratory activity, suggesting that VAT1 is a promising antimetastasis target. Recently, the natural product neocarzilin A (NCA) from Streptomyces carzinostaticus was reported to be the first validated small-molecule inhibitor of VAT1, having strong activity in metastasis models of angiosarcoma and breast cancer. While knockdown of VAT1 has no effect on cell viability, NCA has significant cytotoxicity, suggesting that NCA is not selective for VAT1. Additionally, NCA has poor aqueous solubility, making in vivo administration of NCA challenging and thus limiting its therapeutic potential. Here, we report the design, synthesis, bioactivity, and pharmacokinetics of novel NCA derivatives with improved drug-like properties. Specifically, we have developed derivatives with altered warheads, replacing chlorines on the trichloroketone with fluorines. Using a modified synthetic route, we accessed NCA derivatives with greater than 25-fold improvements in solubility and 30-fold improvements in the antimigratory to antiproliferative bioactivity ratio. The two best derivatives, along with the parent, were analyzed for oral bioavailability, with the two more soluble derivatives showing greatly improved bioavailability. Overall, these studies have resulted in the development of VAT1 inhibitors with improved properties, which will enable further study of the pharmacological inhibition of VAT1 as an antimetastatic strategy. Additionally, these studies provide insights into novel trihalomethyl ketone warheads and identify chlorodifluoroketone as a potent and selective new warhead.

Metarrestin (ML246) is a first-in-class pyrrole-pyrimidine-derived small molecule that selectively targets the perinucleolar compartment (PNC). PNC is a distinct subnuclear structure predominantly found in solid tumor cells. The occurrence of PNC demonstrates a positive correlation with malignancy, serving as an indicator of tumor aggressiveness, progression, and metastasis. Various promising preclinical results have led to the clinical translation of metarrestin into a first-in-human trial. This review aims to summarize (i) the current understanding of the structure and function of PNC and its role in cancer progression and metastasis, (ii) key findings from studies examining the effect of metarrestin on various cancers across the translational spectrum, including in vitro, in vivo, and human clinical trial studies, and (iii) the pharmaceutical relevance of metarrestin as a promising anticancer candidate. Furthermore, our molecular docking and MD simulation studies show that metarrestin binds to eEF1A1 and eEF1A2 with a strong and stable affinity and inhibits eEF1A2 more efficiently compared to eEF1A1. The promising results from preclinical studies suggest that metarrestin has the potential to revolutionize the treatment of cancer, heralding a paradigm shift in its therapeutic management.

Gastric cancer (GC) remains a significant global health challenge, particularly prevalent in East Asia. Despite advancements in various treatment modalities, the prognosis for patients, especially those in advanced stages, remains poor, highlighting the need for innovative therapeutic approaches. This review explores the promising potential of diterpenes, naturally occurring compounds with robust anticancer properties, derived from diverse sources such as plants, marine organisms, and fungi. Diterpenes have shown the ability to influence reactive oxygen species (ROS) generation, ferroptosis, and autophagy, positioning them as attractive candidates for novel cancer therapies. This review explores the mechanisms of action of diterpenes and their clinical implications for the treatment of GC. Additionally, it addresses the challenges in translating these compounds from preclinical studies to clinical applications, emphasizing the need for further research to enhance their therapeutic profiles and minimize potential side effects. The discussion underscores the importance of diterpenes in future anticancer strategies, particularly in the fight against gastric cancer.

Tumor metastasis is a complex phenomenon that poses significant challenges to current cancer therapeutics. While the biochemical signaling involved in promoting motile phenotypes is well understood, the role of biomechanical interactions has recently begun to be incorporated into models of tumor cell migration. Specifically, we propose the unjamming transition, adapted from physical paradigms describing the behavior of granular materials, to better discern the transition toward an invasive phenotype. In this review, we introduce the jamming transition broadly and narrow our discussion to the different modes of 3D tumor cell migration that arise. Then we discuss the mechanical interactions between tumor cells and their neighbors, along with the interactions between tumor cells and the surrounding extracellular matrix. We center our discussion on the interactions that induce a motile state or unjamming transition in these contexts. By considering the interplay between biochemical and biomechanical signaling in tumor cell migration, we can advance our understanding of biomechanical control in cancer metastasis.

Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (TH9) cells have shown promise in treating solid tumors. However, it is unclear whether TH9 cells can tackle more challenging situations, such as established lung metastases. Moreover, comprehensive exploration into the nuanced biological attributes of TH9 cells is imperative to further unravel their therapeutic potential.

We adoptively transferred TH1, TH9, and TH17 cells into subcutaneous, in situ, and established lung metastases models of osteosarcoma and triple-negative breast cancer, respectively, comparing their therapeutic efficacy within each distinct model. We employed flow cytometry and an in vivo imaging system to evaluate the accumulation patterns of TH1, TH9, and TH17 cells in the lungs after transfusion. We conducted bulk RNA sequencing on in vitro differentiated TH9 cells to elucidate the chemokine receptor CXCR4, which governs their heightened pulmonary tropism relative to TH1 and TH17 cell counterparts. Using Cd4 cre Cxcr4 flox/flox mice, we investigate the effects of CXCR4 on the lung tropism of TH9 cells. We performed mass spectrometry to identify the E3 ligase responsible for CXCR4 ubiquitination and elucidated the mechanism governing CXCR4 expression within TH9 cellular milieu. Ultimately, we analyzed the tumor immune composition after TH9 cell transfusion and evaluated the therapeutic efficacy of adjunctive anti-programmed cell death protein-1 (PD-1) therapy in conjunction with TH9 cells.

In this study, we provide evidence that TH9 cells exhibit higher lung tropism than TH1 and TH17 cells, thereby exhibiting exceptional efficacy in combating established lung metastases. CXCR4-CXCL12 axis is responsible for lung tropism of TH9 cells as ablating CXCR4 in CD4+ T cells reverses their lung accumulation. Mechanistically, tumor necrosis factor receptor-associated factor 6 (TRAF6)-driven hyperactivation of NF-κB signaling in TH9 cells inhibited ITCH-mediated ubiquitination of CXCR4, resulting in increased CXCR4 accumulation and enhanced lung tropism of TH9 cells. Besides, TH9 cells' transfusion significantly improved the immunosuppressed microenvironment. TH9 cells and anti-PD-1 exhibit synergistic effects in tumor control.

Our findings emphasized the innate lung tropism of TH9 cells driven by the activation of TRAF6, which supports the potential of TH9 cells as a promising therapy for established lung metastases.

Uveal melanoma (UM) is the most common intraocular primary malignancy in adults with highly metastatic characteristics. Currently, there are no effective therapies to prevent metastasis formation in UM, resulting in a poor prognosis. Herein, we report a novel lapatinib-loaded reductive-responsive nanoparticle platform prepared via the self-assembly of amphiphilic hyaluronic acid-cystamine-cholesteryl hemisuccinate conjugate to suppress the distant metastasis of UM. The platform can maintain a stable nanosphere structure in the physiological environment and effectively deliver the drug to UM tumor sites, enhancing intratumoral drug accumulation and penetration. Upon endocytosis, lapatinib-loaded nanoparticles rapidly disintegrate triggered by intracellular glutathione and release the payload, leading to considerable suppression of MuM-2B cell proliferation, invasion, and migration. Systemic administration of lapatinib-loaded nanoparticles into mice bearing lung metastases of UM resulted in significantly higher metastasis suppression compared to free lapatinib, with histological analyses indicating no detectable toxicity. This nanotherapeutic platform is expected to provide a promising approach for the safe and efficient prevention of metastasis in UM.

Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.

In different tumours, focal adhesion kinase (FAK), a nonreceptor tyrosine kinase, is upregulated and hence, it represents a promising target for cancer therapy. However, the development of FAK kinase inhibitors has faced a number of challenges. It is therefore imperative that new, effective FAK kinase inhibitors be identified promptly.

Small molecules that target FAK were identified through molecular docking and validated through surface plasmon resonance (SPR) and cell thermal shift analysis. We investigated the pharmacological effects of FAK kinase inhibitors using CCK-8, colony formation, EdU, and Transwell assays and cell cycle analysis. The molecular mechanism was determined via methods such as coimmunoprecipitation, RNA pull-down and RNA immunoprecipitation.

Here, we confirmed that diosmin (Dio) is an inhibitor of FAK and demonstrated its anti-proliferative and anti-metastatic effects in lung adenocarcinoma. Mechanistically, Dio inhibited tumour proliferation and metastasis by impeding the catalytic activity of FAK. Dio activated the ubiquitin proteasome pathway to induce Cyclin D1 degradation, while inhibiting tumour proliferation and reversing the epithelial mesenchymal transition (EMT) process by reducing the mRNA stability of Snail, thereby inhibiting cancer metastasis. In addition, the inhibitory effect of Dio on lung adenocarcinoma was validated in a mouse xenograft model.

These results support the tumour-promoting role of FAK in lung adenocarcinoma by stabilizing Cyclin D1 and Snail and suggest that Dio is a promising candidate for FAK inhibition.

Despite many studies on papillary thyroid carcinoma (PTC) in the past few decades, some critical and significant genes remain undiscovered. To explore genes that may play crucial roles in PTC, a detailed analysis of the expression levels, mutations, and clinical significance of Kallikrein-related peptidases (KLKs) family genes in PTC was undertaken to provide new targets for the precise treatment of the disease. A comprehensive analysis of KLK family genes was performed using various online tools, such as GEPIA, Kaplan-Meier Plotter, LinkedOmics, GSCA, TIMER, and Cluego. KLK7, KLK10, and KLK11 were critical factors of KLK family genes. Then, functional assays were carried out on KLK7/10/11 to determine their proliferation, migration, and invasion capabilities in PTC. The mRNA expression levels of KLK7, KLK10, KLK11, and KLK13 were significantly elevated in thyroid carcinoma, while KLK1, KLK2, KLK3 and KLK4 mRNA levels were decreased compared to normal tissues. Correlations between KLK2/7-12/15 expression levels and tumor stage were also observed in thyroid carcinoma. Survival analysis demonstrated that KLK4/5/7/9-12/14 was associated with overall survival in patients with thyroid cancer. Not only were KLK genes strongly associated with cancer-related pathways, but also KLK7/10/11 was associated with immune-cell infiltration. Finally, silencing KLK7/10/11 impaired human papillary thyroid carcinoma cells' growth, migration ability, and invasiveness. The increased expression of KLK7, KLK10, and KLK11 may serve as molecular markers to identify PTC patients. KLK7, KLK10, and KLK11 could be potential prognostic indicators and targets for precision therapy against PTC.

Distant metastasis is a prevalent cause of mortality in gastric cancer (GC) patients. Anoikis, a process that induces cell death when cells get detached from the extracellular matrix (ECM), acts as a barrier to tumor metastasis. To survive in the circulatory system and metastasize, tumor cells must acquire anoikis resistance. It is crucial to identify the molecular processes that cause resistance to anoikis in GC since this might lead to the discovery of novel treatment targets and improve the long-term survival of GC patients. In this study, we employed quantitative proteomics to identify growth differentiation factor 15 (GDF15) as a key factor in GC anoikis resistance. We found that GDF15 enhances protective autophagy, thereby promoting anoikis resistance in GC cells. Furthermore, through DNA pull down assay, activating transcription factor 2 (ATF2) was found to be a critical regulator of GDF15 expression, acting as a transcriptional activator of GDF15. Collectively, these discoveries indicate that ATF2 and GDF15 have great potential as target candidates for developing therapeutic strategies to address the metastasis of GC.

This study assesses the frequency of sarcopenia in patients with breast cancer (BC) and its association with mortality rates.

An all-encompassing search across (PubMed, Scopus, Web of Science, and CINAHL) was done, to identify studies, published until August 2023, that report data on sarcopenia and mortality in BC patients. A meta-analysis was then done using a random-effects model.

Out of 989 initially identified potential studies, 19 met inclusion criteria. Analysis of 15 studies showed a rate of sarcopenia of 38% (95% CI: 29-48%), with moderate heterogeneity (I 2 = 25.8%). Sarcopenia was linked to increased mortality risk in BC patients across 16 studies (HR: 1.77, CI: 1.35-2.32, p = <0.001) with both shorter and longer follow-up periods. Similarly, mortality risks were significantly higher in metastatic (HR: 1.52, CI: 1.14-2.03, p = 0.004) and non-metastatic (HR: 2.55, CI: 1.66-3.93, p < 0.001) BC patients with sarcopenia.

Our analysis demonstrates a substantial prevalence of sarcopenia in BC patients. Importantly, sarcopenia was significantly linked to an elevated risk of mortality in this population. Subgroup analyses, stratified by follow-up periods and disease stage, consistently reveal increased mortality risks associated with sarcopenia, underscoring its clinical relevance in both short- and long-term patient outcomes. Our findings further strengthen the need to recognize and address sarcopenia as a critical factor in BC management and prognosis.