Prevent Tumor Metastasis Research Articles

Phytochlorin-Based Sonosensitizers Combined with Free-Field Ultrasound for Immune-Sonodynamic Cancer Therapy.

Phytochlorins, a class of plant-derived tetrapyrroles, show great potential as sonosensitizers in sonodynamic therapy (SDT). The development of new phytochlorin-based sonosensitizers has significantly improved SDT, yet the absence of specialized sonodynamic systems limits their clinical translation. Herein, a dedicated ultrasound system along with a detailed step-by-step sonodynamic process from in vitro to in vivo is developed to activate phytochlorin-based sonosensitizers. Compared to standing-wave ultrasound, free-field ultrasound maintains stable acoustic pressure amplitudes and minimizes mechanical damage to cell membranes. In vitro experiments demonstrate that free-field ultrasound effectively activates naturally occurring phytochlorin, reducing the cavitation threshold for reactive oxygen species production and triggering immunogenic cell death. Furthermore, the intravenously injectable phytochlorin-based sonosensitizer (C34) enhances sonodynamic efficiency by reducing interfacial tension. Driven by in vivo free-field ultrasound, C34 effectively inhibits tumor growth in an orthotopic murine breast cancer model and elicits an immune response, preventing tumor metastasis. The reliable protocol provided by the free-field ultrasound system facilitates the activation of phytochlorin-based sonosensitizers while simultaneously stimulating the immune system, highlighting the potential of immune-sonodynamic therapy.

An Advanced Multivalent Ligand-Decorated Microsphere Enrichment System Efficiently Captures Circulating Tumor Cells In Vivo.

Capturing circulating tumor cells (CTCs) in vivo from the bloodstream lessens tumor metastasis and recurrence risks. However, the absence of CTC receptors due to epithelial-mesenchymal transition (EMT), the limited binding capacity of a single ligand, and the complexity of the blood flow environment significantly reduce the efficiency of CTC capture in vivo. Herein, a multivalent ligand-decorated microsphere enrichment system (MLMES) is crafted that incorporates a capture column replete with an immunosorbent that precisely recognizes and binds the stably expressed cluster of differentiation 44 (CD44) and glucose transporter protein 1 (GLUT1) receptors present on the exterior of CTCs. As peripheral blood flows through the column, CTCs are efficiently captured, achieving an in vivo capture rate of up to 64.2%, the highest reported to date. Moreover, the MLMES demonstrates excellent biocompatibility, broad-spectrum tumor cells capture, and storage stability. Importantly, it significantly eliminates a substantial quantity of CTCs from peripheral blood, reducing the risk of metastasis. This breakthrough method has broad clinical application potential in preventing tumor metastasis and recurrence, bringing new possibilities for improving cancer treatment.

Overexpression of PDSS2-Del2 in HCC promotes tumor metastasis by interacting with macrophages

Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide. According to the Global Cancer Statistics 2020, liver cancer remains the third cause of cancer death globally. Despite significant advances in systemic therapy, HCC still has one of the worst prognoses due to its frequent recurrence and metastasis. Previously we found that PDSS2-Del2 (prenyl diphosphate synthase subunit 2 with exon 2 deletion), a novel variant of PDSS2, could promote HCC metastasis and angiogenesis via activating NF-κB. In this study, we elucidate a novel mechanism by which PDSS2-Del2 enhances HCC metastasis. The overexpression of PDSS2-Del2 in HCC cells promotes the ubiquitination and degradation of SKOR1, consequently heightening SMAD3 phosphorylation. Subsequently, the expression and secretion of MST1 (macrophage stimulatory protein 1) are upregulated, resulting in enhanced recruitment of macrophages into tumor tissues where they differentiate into M2-type macrophages. Co-culture with PDSS2-Del2 overexpressed HCC cells activated the PI3K/AKT signaling pathway in macrophages, and more MMP2 and MMP9 were secreted, which facilitated HCC cell dissemination. Our study elucidates a novel molecular mechanism by which PDSS2-Del2 promotes HCC metastasis, which may contribute to the development of effective HCC clinical treatment and prevent tumor metastasis. Furthermore, MST1 could be a potential therapeutic target, and MST1 inhibitors might be integrated into clinical practice for HCC patients with high expression of PDSS2-Del2.

Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice

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.

Tumor-derived exosomes: unravelling the pathogenesis of pancreatic cancer with liver metastases and exploring the potential for clinical translation.

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.

Gpr54 deletion accelerates hair cycle and hair regeneration

GPR54, or KiSS-1R (Kisspeptin receptor), is key in puberty initiation and tumor metastasis prevention, but its role on hair follicles remains unclear. Our study shows that Gpr54 knockout (KO) accelerates hair cycle, synchronized hair regeneration and transplanted hair growth in mice. In Gpr54 KO mice, DPC (dermal papilla cell) activity is enhanced, with elevated expression of Wnts, VEGF, and IGF-1, which stimulate HFSCs. Gpr54 deletion also raises the number of CD34+ and Lgr5+ HFSCs. The Gpr54 inhibitor, kisspeptin234, promotes hair shaft growth in cultured mouse hair follicles and boosts synchronized hair regeneration in vivo. Mechanistically, Gpr54 deletion suppresses NFATC3 expression in DPCs and HFSCs, and decreases levels of SFRP1, a Wnt inhibitor. It also activates the Wnt/β-catenin pathway, promoting β-catenin nuclear localization and upregulating target genes such as Lef1 and ALP. Our findings suggest that Gpr54 deletion may accelerate the hair cycle and promote hair regeneration in mice by regulating the NAFTc3-SFRP1-Wnt signaling pathway. These findings suggest that Gpr54 could be a possible target for future hair loss treatments.

Injectable Polydopamine Nanoparticle-Incorporated Hydrogels for Antiangiogenesis and Stimulating Tumoricidal Immunity to Inhibit Metastasis and Recurrence Postresection.

Surgical resection is still the main means for clinical treatments of breast cancer, but the postoperative immunosuppressive microenvironment and neoangiogenesis of the residual tumors easily lead to tumor metastasis and recurrence, which will further endanger patients' lives. The combination of antiangiogenic therapy and immunotherapy may promote the mutually reinforced cycle of immune reprogramming and vascular normalization to avoid tumor metastasis and recurrence. Herein, we prepared polydopamine nanoparticles for improving tissue adhesion and enriching tumor-associated antigens. This nanoregulator together with regorafenib (REG) was further incorporated into a hydrogel developed from grafting adipic acid dihydrazide onto 2,2,6,6-tetramethylpiperidine-1-oxyl radical oxidized chitin and oxidized hyaluronic acid, which was injectable at the cavity after subcutaneous tumor surgery with good mechanical properties and degradability. The system showed long-term release of REG. After combining with anti-PD-L1, the hydrogel applied to the surgical wound exhibited a reduction in tumor metastasis and recurrence. This effect was achieved by suppressing angiogenesis and enhancing antitumor immunity, characterized by increased levels of effector T lymphocytes and activation of dendritic cells within tumors, spleens, and draining lymph nodes. The injectable hydrogel offers a promising strategy for postoperative management aimed at preventing tumor metastasis and recurrence.

Killing Two Birds with One Stone: Siglec-15 Targeting Integrated Bioactive Glasses Hydrogel for Treatment of Breast Cancer Bone Metastasis

Bone metastasis is a fatal consequence of breast cancer that occurs when patients fail to respond to conventional therapies and mainly result from a vicious cycle involving dysregulated bone homeostasis and uncontrolled tumor growth. Recent research has underscored the significance of Siglec-15, a membrane protein implicated in immunosuppression and osteoclast generation. Targeting Siglec-15 may disrupt the “vicious cycle” that causes bone metastases in patients with breast cancer. Herein, we explored the efficacy of targeting Siglec-15 in conjunction with photothermal chemotherapy to impede the progression of bone metastatic during breast cancer and repair tumor-induced osteolysis. First, we formulated an injectable photothermal bioactive glass (BG)-based hydrogel for the local delivery of Siglec-15 shRNA and doxorubicin. The results demonstrated that the hydrogel could kill tumor cells directly through photothermal chemotherapy, provoke intense immune responses and improve the local immunosuppressive microenvironment, which could effectively prevent tumor metastasis and recurrence in a murine model. The combined effect of BGs and Siglec15 shRNA can normalize dysregulated bone homeostasis at the bone metastasis site and significantly reduced bone destruction. Overall, the use of Siglec-15-targeting integrated BG hydrogels may provide a promising therapeutic strategy for treating bone metastasis caused by breast cancer.

A Prime-Boost Vaccination Approach Induces Lung Resident Memory CD8+ T Cells Derived from Central Memory T Cells That Prevent Tumor Lung Metastasis.

Memory T cells play a key role in immune protection against cancer. Vaccine-induced tissue-resident memory T (TRM) cells in the lung have been shown to protect against lung metastasis. Identifying the source of lung TRM cells can help to improve strategies, preventing tumor metastasis. Here, we found that a prime-boost vaccination approach using intramuscular DNA vaccine priming, followed by intranasal live-attenuated influenza-vectored vaccine (LAIV) boosting induced higher frequencies of lung CD8+ TRM cells compared with other vaccination regimens. Vaccine-induced lung CD8+ TRM cells, but not circulating memory T cells, conferred significant protection against metastatic melanoma and mesothelioma. Central memory T (TCM) cells induced by the DNA vaccination were major precursors of lung TRM cells established after the intranasal LAIV boost. Single-cell RNA sequencing analysis indicated that transcriptional reprogramming of TCM cells for differentiation into TRM cells in the lungs started as early as day 2 post the LAIV boost. Intranasal LAIV altered the mucosal microenvironment to recruit TCM cells via CXCR3-dependent chemotaxis and induced CD8+ TRM-associated transcriptional programs. These results identified TCM cells as the source of vaccine-induced CD8+ TRM cells that protect against lung metastasis. Significance: Prime-boost vaccination shapes the mucosal microenvironment and reprograms central memory T cells to generate lung resident memory T cells that protect against lung metastasis, providing insights for the optimization of vaccine strategies.

In situ formed reactive oxygen species-responsive dipyridamole prodrug hydrogel: Spatiotemporal drug delivery for chemoimmunotherapy

In the realm of combined cancer immunotherapy, the strategic combination of therapeutics targeting both cancer cells and macrophages holds immense potential. However, the major challenges remain on how to achieve facile spatiotemporal delivery of these therapies, allowing ease of manipulation and ensuring differential drug release for enhanced synergistic therapeutic effects. In the present study, we introduced a tumor microenvironment (TME)-adapted hydrogel with the phenylboronic acid-modified dipyridamole prodrug (DIPP) as a crosslinker. This prodrug hydrogel scaffold, 3BP@DIPPGel, could be formed in situ by a simple mixture of DIPP and poly(vinyl alcohol) (PVA), and loaded with a high ratio of 3-bromopyruvic acid (3BP). The 3BP@DIPPGel enables spatiotemporal localized delivery of dipyridamole (DIP) and 3BP with distinct release kinetics that effectively reshape the immunosuppressive TME. Upon reactive oxygen species (ROS) stimulation, 3BP@DIPPGel preferentially released 3BP, inducing tumor-specific pyroptosis via the ROS/BAX/caspase-3/GSDME signaling pathway and decreasing the secretion of chemokines such as CCL8 to counteract macrophage recruitment. Subsequently, the crosslinked DIP is released, triggering the tumor-associated macrophages (TAMs) polarization towards the immunostimulatory M1 phenotype via the CCR2/JAK2/STAT3 cascade signaling pathway. This dual action from 3BP@DIPPGel leads to the restoration of tumor cell immunogenicity with high efficacy and activation of immune cells. Furthermore, the 3BP@DIPPGel-based chemoimmunotherapy upregulates the expression of sialic-acid-binding Ig-like lectin 10 and hence sensitizing tumors to anti-CD24 therapy in the tumor-bearing mice. Therefore, this strategy can have significant potential in the prevention of tumor metastases and recurrence. To the best of our understanding, this study represents a pioneering showcase of tumor pyroptosis, induced by glycolytic inhibitors, which can be effectively coordinated with DIP-mediated TAM polarization for immune activation, offering a new paradigm for differentially sustained drug delivery to foster cancer immunotherapy.

Glycopolymeric Micellar Nanoparticles for Platelet-Mediated Tumor-Targeted Delivery of Docetaxel for Cancer Therapy.

The high level of accumulation of therapeutic agents in tumors is crucial for cancer treatment. Compared to the passive tumor-targeting effect, active tumor-targeting delivery systems, primarily mediated by peptides with high production costs and reduced circulation time, are highly desired. Platelet-driven technologies have opened new avenues for targeted drug delivery prevalently through a membrane coating strategy that involves intricate manufacturing procedures or the fucoidan-mediated hitchhiking method with limited platelet affinity. Here, a novel type of amphiphilic glycopolymer self-assembled micellar nanoparticle has been developed to adhere to naturally activated platelets in the blood. The simultaneous integration of fucose and sialic acid segments into glycopolymers enables closer mimicry of the structure of P-selectin glycoprotein ligand-1 (PSGL-1), thereby increasing the affinity for activated platelets. It results in the formation of glycopolymeric micelle-platelet hybrids, facilitating targeted drug delivery to tumors. The selective platelet-assisted cellular uptake of docetaxel (DTX)-loaded glycopolymeric micelles leads to lower IC50 values against 4T1 cells than that of free DTX. The directed tumor-targeting effect of activated platelets has significantly improved the tumor accumulation capacity of the glycopolymeric nanoparticles, with up to 21.0% found in tumors within the initial 0.2 h. Additionally, with acid-responsive drug release and inherent antimetastasis properties, the glycopolymeric nanoparticles ensured potent therapeutic efficacy, prolonged survival time, and reduced cardiotoxicity, presenting a new and unexplored strategy for platelet-directed drug delivery to tumors, showing promising prospects in treating localized tumors and preventing tumor metastasis.

H2S-Responsive NIR-II Fluorescent Nanozyme that Regulates Tumor Microenvironment for Activatable Synergistic CO Therapy/Catalytic Therapy/Immunotherapy.

Nanozyme catalytic therapy triggered by the tumor microenvironment (TME)-responsive enzyme-like catalytic activities is an emerging approach for tumor treatment. However, the poor catalytic efficiency of nanozymes in tumors and the toxic side effects on normal tissues limit their further development, primarily due to the limited uptake and penetration depth of nanozyme in tumor tissues. Here, a tumor-targeting TME and electric field stimuli-responsive nanozyme (AgPt@CaCO3-FA) is developed, which is capable of catalyzing the generation of ROS to induce cell death and releasing carbon monoxide (CO) specifically in tumor tissues for on-demand CO therapy and immunotherapy. Benefiting from the endogenous H2S activated NIR-II fluorescence (FL) imaging guidance, AgPt@CaCO3-FA can be delivered into the deeper site of tumor tissues resulted from the TME regulation via generated CO during the electrolysis process to improve the catalytic efficiency of nanozymes in tumors. Moreover, CO effectively relieve immunosuppression TME via reeducating tumor-supportive M2-like macrophages to tumoricidal M1-like macrophages and induce mitochondrial dysfunction by reducing mitochondrial membrane potential, triggering tumor cells apoptosis. The enzyme-like activities combined with CO therapy arouse distinct immunogenic cell death (ICD) effect. Therefore, AgPt@CaCO3-FA permits synergistic CO gas, catalytic therapy and immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence.

Dual‐Responsive Nanoreactor Initiates In Situ Generation of Copper Complex for Paraptosis‐Mediated Tumor Chemo‐Immunotherapy

AbstractParaptosis is a non‐apoptotic and caspase‐independent programmed cell death that can trigger immunogenic cell death (ICD) in tumor cells, representing a potent tactic to overcome immune tolerance to apoptosis. Here, this study demonstrates the construction of a dual‐responsive nanoreactor (MCGDH) to achieve paraptosis‐mediated ICD for chemo‐immunotherapy. Specifically, by doping Cu2+ into glutathione (GSH)‐responsive dendritic mesoporous silica nanoparticles, the platform (CGDMSN) is endowed with partial acid‐sensitivity. After loaded with 8‐hydroxyquinoline (8‐HQ), cell membrane fragments are coated onto the ammoniated CGDMSN surface to construct MCGDH. Upon internalization by tumor cells, the release of Cu2+ and 8‐HQ from MCGDH in response to the acidic pH and high concentration of GSH in the tumor microenvironment stimulates in situ generation of Cu(8‐HQ)2, inducing tumor cells paraptosis at a low copper dose. Moreover, MCGDH‐mediated paraptosis amplifies the immunogenicity of tumor cells, facilitating antigen presentation to dendritic cells and activating CD8+/CD4+ T cells immune responses. Furthermore, the combination of MCGDH and anti‐PD‐1 antibodies (αPD‐1) promotes the systemic anti‐tumor immune responses and long‐term immunological effect to vastly inhibit the primary/distant tumor growth and prevent tumor metastasis. This GSH/pH dual‐responsive nanoreactor serves as a selective platform for accelerating the development of chemo‐immunotherapy.

Atomic Force Microscopy Lifetime Analysis: An Intuitive Method for Evaluating Receptor Tyrosine Kinase Dimer-Targeting Inhibitors.

Overexpression of receptor tyrosine kinases (RTKs) or binding to ligands can lead to the formation of specific unliganded and liganded RTK dimers, and these two RTK dimers are potential targets for preventing tumor metastasis. Traditional RTK dimer inhibitor analysis was mostly based on end point assays, which required cumbersome cell handling and behavior monitoring. There are still challenges in developing intuitive process-based analytical methods to study RTK dimer inhibitors, especially those used to visually distinguish between unliganded and liganded RTK dimer inhibitors. Herein, taking the mesenchymal-epithelial transition factor (MET) receptor, an intuitive method for evaluating MET inhibitors has been developed based on atomic force microscopy (AFM) lifetime analysis. The time interval between the start of the force and the bond break point was regarded as the bond lifetime, which could reflect the stability of the MET dimer. The results showed that there was a significant difference in the lifetime (τ) of unliganded MET dimers (τ1 = 207.87 ± 4.69 ms) and liganded MET dimers (τ2 = 330.58 ± 15.60 ms) induced by the hepatocyte growth factor, and aptamer SL1 could decrease τ1 and τ2, suggesting that SL1 could inhibit both unliganded and liganded MET dimers. However, heparin only decreased τ2, suggesting that it could inhibit only the liganded MET dimer. AFM-based lifetime analysis methods could monitor RTK dimer status rather than provide overall average results, allowing for intuitive process-based analysis and evaluation of RTK dimers and related inhibitors at the single-molecule level. This study provides a novel complementary strategy for simple and intuitive RTK inhibitor research.

Targeting LINC070974 inhibits lung adenocarcinoma cell proliferation and progression by interacting with Y-box binding protein 1.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Increasing evidence suggests that long noncoding RNAs play crucial roles in lung cancer pathogenesis. We previously identified a novel lncRNA, LINC070974, which is associated with tumor cell proliferation. In the present study, we find that knockdown of LINC070974 inhibits cell proliferation, migration and invasion as well as tumor formation both in vitro and in nude mice. LINC070974 silencing also improves cisplatin efficacy in A549/DDP cells. The function of LINC070974 may depend on its interaction with YBX1. Knockdown of LINC070974 reduces the recruitment of YBX1 to the CCND1 promoter and delays tumor progression through its coregulatory genes, which are mainly involved in the p53 signaling pathway. We utilize nebulized inhalation to deliver siRNAs targeting LINC070974 and find that LINC070974 significantly prevents tumor metastasis and growth in lung tissues. These findings reveal the role of LINC070974 in lung cancer and suggest a promising therapeutic approach involving siRNA inhalation.

The Oncolytic virus VT1092M and an Anti-PD-L1 antibody synergize to induce systemic antitumor immunity in a murine bilateral tumor model

This study investigated the synergistic potential of an oncolytic herpes simplex virus armed with interleukin 12 (VT1092M) in combination with immune checkpoint inhibitors for enhancing antitumor responses. The potential of this combination treatment to induce systemic antitumor immunity was assessed using bilateral subcutaneous tumor and tumor re-challenge mouse models. The antitumor efficacy of various OV and ICI treatment combinations and the underlying mechanisms were explored through diverse analytical techniques, including flow cytometry and RNA sequencing. Using VT1092M, either alone or in combination with an anti-PD-L1 antibody, significantly reduced the sizes of both the injected and untreated abscopal tumors in a bilateral tumor mouse model. The combination therapy demonstrated superior antitumor efficacy to the other treatment conditions tested, which was accompanied by an increase in T cell numbers and CD8+T cell activation. Results from the survival and tumor re-challenge experiments showed that the combination therapy elicited long-term, tumor-specific immune responses, which were associated with tumor clearance and prolonged survival. Immune cell depletion assays identified CD8+T cells as the crucial mediators of systemic antitumor immunity during combination therapy. In conclusion, the combination of VT1092M and PD-L1 blockade emerged as a potent inducer of antitumor immune responses, surpassing the efficacy of each monotherapy. This synergistic approach holds promise for achieving robust and sustained antitumor immunity, with potential implications for preventing tumor metastasis in patients with cancer.

Heterogeneous-Structure-Based AuNBs@TiO2 Nano-Photosensitizers for Computed Tomography Imaging Guided NIR-II Photodynamic Therapy and Cancer Metastatic Prevention.

Photodynamic therapy (PDT) is a minimally invasive cancer treatment that, despite its significant attention, faces limitations in penetration depth, which restrict its effectiveness. Herein, it is found that gold nanobipyramid (AuNBs) coated with TiO2 can form a core-shell heterogeneous structure (AuNBs@TiO2) with strong absorption at second near infrared (NIR-II) region. A substantial quantity of reactive oxygen species (ROS), including singlet oxygen (1O2), superoxide anion radicals, and hydroxyl radicals, can be rapidly generated when subjecting the AuNBs@TiO2 aqueous suspension to 1064nm laser irradiation. The quantum yield for sensitization of 1O2 by AuNBs@TiO2 is 0.36 at 1064nm light excitation. In addition, the Au element as high-Z atoms in the nanosystem can improve the ability of computed tomographic (CT) imaging. As compared to commercial iohexol, the AuNBs@TiO2 nanoparticle exhibits significantly better CT imaging effect, which can be used to guide PDT. In addition, the nano-photosensitizer shows a remarkable therapeutic effect against established solid tumors and prevents tumor metastasis and potentiates immune checkpoint blockade therapy. More importantly, here the great potentials of AuNBs@TiO2 are highlighted as a theranostic platform for CT-guided cancer photodynamic immunotherapy.

PAD4 Inhibitor-Functionalized Layered Double Hydroxide Nanosheets for Synergistic Sonodynamic Therapy/Immunotherapy Of Tumor Metastasis.

Sonodynamic therapy (SDT) is demonstrated to trigger the systemic immune response of the organism and facilitate the treatment of metastatic tumors. However, SDT-mediated neutrophil extracellular traps (NETs) formation can promote tumor cell spread, thus weakening the therapeutic effectiveness of metastatic tumors. Herein, the amorphous CoW-layered double hydroxide (a-CoW-LDH) nanosheets are functionalized with a peptidyl arginine deiminase 4 (PAD4) inhibitor, i.e., YW3-56, to construct a multifunctional nanoagent (a-LDH@356) for synergistic SDT/immunotherapy. Specifically, a-CoW-LDH nanosheets can act as a sonosensitizer to generate abundant reactive oxygen species (ROS) under US irradiation. After loading with YW3-56, a-LDH@356 plus US irradiation not only effectively induces ROS generation and immunogenic cell death, but also inhibits the elevation of citrullinated histone H3 (H3cit) and the release of NETs, enabling a synergistic enhancement of anti-tumor metastasis effect. Using 4T1 tumor model, it is demonstrated that combining a-CoW-LDH with YW3-56 stimulates an anti-tumor response by upregulating the proportion of immune-activated cells and inducing polarization of M1 macrophages, and inhibits immune escape by downregulating the expression of PD-1 on immune cells under US irradiation, which not only arrests primary tumor progression with a tumor inhibition rate of 69.5% but also prevents tumor metastasis with the least number of lung metastatic nodules.

Photoactivated theranostic nanomaterials based on aggregation‐induced emission luminogens for cancer photoimmunotherapy

AbstractIn this study, a series of high liposoluble near‐infrared emissive aggregation‐induced emission luminogens with triphenylamine derivatives as donor units and 1‐indanone as electron acceptor units are developed. Specifically, MTTOI has promising lipid droplets targeting ability and viscosity‐response characteristics, and it can monitor the viscosity fluctuations in living cells in real time. It is found that MTTOI is able to fulfill the activation of the apoptosis‐related signaling pathways under white light, and it can also activate the ferroptosis to synergize apoptosis resulting in tumor elimination. Interestingly, the occurrence of ferroptosis is positively related to the enhancement of immunogenic cell‐death effect, thus boosting the tumor infiltration of CD8+ T cells and reducing the proportion of regulatory T cells by cooperating with dendritic cells, which can not only carry out primary antitumor treatment, but also prevent tumor metastasis through strong immunological memory effect. Moreover, in vivo experimental results confirm that MTTOI successfully effectuates fatty liver tissue imaging. MTTOI fluorescence signals can be captured at the tumor site after 3 days of administration due to its high fat‐solubility and ease of fusion with tumors. This classic example could promote the further development of phototherapeutic agents in preclinical research and clinical applications.

Tumor‐On‐A‐Chip Model Incorporating Human‐Based Hydrogels for Easy Assessment of Metastatic Tumor Inter‐Heterogeneity

AbstractThe coordinated migration of invasive tumor cells is a complex and dynamic mechanism driven by diverse cellular and molecular events. Unfortunately, the inherent heterogeneity within tumors raises multiple challenges in deciphering key biomarkers and novel therapeutic approaches to prevent tumor metastasis. Here, a microengineered tumor‐on‐a‐chip system incorporating human platelet lysate hydrogels is proposed to recreate the early metastatic process of tumor invasion and drug response. By co‐culturing human bone marrow mesenchymal stem cells with two tumor cell lines with distinct metastatic capability, the developed model can emulate the 3D tumor microarchitecture and inter‐heterogeneity regarding its intrinsic metastatic ability. The recreated microenvironment supports tumor and stromal cell movement, evidencing the synergistic tumor‐stromal cell and cell‐extracellular matrix interactions of an invading tumor. Through gene and protein expression analysis and exometabolomic profiling, this tumor‐on‐a‐chip platform provides evidence for the role of a dynamic environment as a key regulator of tumor metastatic ability. Additionally, the effect of doxorubicin treatment on tumor invasiveness and biomarker profile highlights the suitability of the established models for therapy assessment. Overall, this study presents a tumor‐on‐a‐chip model useful to pursue mechanistic studies on early metastatic events in a fully human‐derived microenvironment, while contributing with fundamental insights into biomolecular profiling.