Inhibited Lung Metastasis Research Articles

Synergistic Chemo-Immunotherapy Using pH-Responsive Nanoparticles in Breast Cancer Treatment: In Vitro and In Vivo Studies.

Recent research underscores the pivotal role of the heterogeneous multicellular interactome within the tumor microenvironment (TME) in tumor progression and survival. Tumor-associated macrophages (TAMs), among other nonmalignant cells in the TME, promote an immunosuppressive environment, fostering tumor cell survival, proliferation, and resistance. Hence, combining chemotherapy with immunomodulatory agents to transition TAMs to an immunostimulatory phenotype holds immense therapeutic potential. The present study focuses on developing tumor-responsive nanoparticles (NPs) for combined chemo-immunotherapy using resiquimod (RSQ), a TLR 7/8 agonist as an immunomodulator, and paclitaxel (PTX) as chemotherapeutics. A pH-responsive NP known as PHNP, tailored with a star-shaped PLGA conjugated with poly histidine, was engineered to selectively deliver a consistent ratio of PTX and RSQ directly to the tumor site. In vitro studies demonstrate enhanced drug release at pH 6.4, increased penetration in tumor spheroids, and increased cytotoxic efficacy against breast cancer cells. Furthermore, PHNPs activate macrophages for antitumor activity. In vivo studies demonstrated a notable rise in plasma AUC and improved delivery of drugs to the tumor using PHNPs, resulting in enhanced effectiveness against tumor growth in a mouse orthotopic breast cancer model. Notably, PHNP treatment elevated intratumoral ROS and apoptosis levels and inhibited lung metastasis. Overall, this study underscores the potential of the PTX and RSQ combination as a prospective combined chemo-immunotherapeutic modality.

Reengineering of Donor-Acceptor-Donor Structured Near-Infrared II Aggregation-Induced Emission Luminogens for Starving-Photothermal Antitumor and Inhibition of Lung Metastasis.

Electron acceptor possessing strong electron-withdrawing ability and exceptional stability is crucial for developing donor-acceptor-donor (D-A-D) structured aggregation-induced emission luminogens (AIEgens) with second near-infrared (NIR-II) emission. Although 6,7-diphenyl-[1,2,5] thiadiazolo [3,4-g] quinoxaline (PTQ) and benzobisthiadiazole (BBT) are widely employed as NIR-II building blocks, they still suffer from limited electron-withdrawing capacity or inadequate chemo-stability under alkaline conditions. Herein, a boron difluoride formazanate (BFF) acceptor is utilized to construct NIR-II AIEgen, which exhibits a better overall performance in terms of NIR-II emission and chemo-stability compared to the PTQ- and BBT-derived fluorophores. With finely tuned intramolecular motions and strong D-A interaction strength, TPE-BFF simultaneously exhibits high molar extinction coefficient (ε= 4.31 × 104 M-1cm-1), strong NIR-II emission (Φ = 0.49%) and photothermal effect (η = 58.5%), as well as high stability. Thanks to these merits, the thermosensitive nanoparticles constructed by integrating TPE-BFF and the antiglycolytic agent 2-deoxy-d-glucose (2DG) are successfully utilized for imaging-guided photothermal antitumor lung metastasis by regulating glycolysis and reducing ATP-dependent heat shock proteins. Combining experimental results and theoretical calculations, BFF proves to be an outstanding electron acceptor for the design of versatile NIR-II AIEgens. Overall, this study offers a promising alternative for developing multifunctional NIR-II AIEgens in biomedical applications.

Autophagy activator-loaded bicomponent peptide nanocarriers for phototherapy-triggered immunity enhancement against metastatic breast cancer

Mild autophagy accompanied with immunogenic cell death (ICD) effect destructs immune-associated antigens, weakening the immune response against tumor growth. To address this dilemma, we develop a peptide-based bicomponent nanocarrier with encapsulation of a cellular hyperautophagy activator (STF-62247) for near-infrared (NIR) photo/immunotherapy to eliminate primary and metastatic breast tumors. The electrostatic-driven nanodrug (PPNPs@STF) with active-targeting and efficient endosomal escape can induce specific ICD effect upon NIR laser irradiation, and trigger autophagy to a mild activation state. Notably, the simultaneously released STF-62247 precisely promotes autophagy to an overactivated state, resulting in autophagic death of tumor cells and further boosting ICD-related antigen presentation. More importantly, the combined photo/immunotherapy of PPNPs@STF not only inhibits tumor cell proliferation, but also promotes dendritic cells (DCs)-associated immune response. In 4 T1 tumor-bearing mice, PPNPs@STF effectively inhibits growth of primary and distant tumors, and suppresses lung metastasis with a minimized side effect. This study provides a hyperautophagy activator-assisted strategy that can enhance ICD-based antitumor immune response for the treatment of metastatic breast cancer.

PP2A negatively regulates NK cell T-bet expression and anti-tumor effector function.

The transcription factor T-bet is essential for the anti-tumor effector function of NK cells, but the mechanism regulating its expression in NK cells remains unclear. In this study, we aimed to identify an NK cell intrinsic regulator that controls T-bet expression. Using T-bet-luciferase reporter assay screening, we identified a protein phosphatase inhibitor as a potential activator of T-bet expression. A series of PP2A-specific inhibitors (PP2Ai) or PP2A siRNA induced the expression of T-bet. In PP2Ai-treated mice, the expressions of T-bet and its downstream effector molecules, granzyme B and IFN-γ, were also upregulated in NK cells. Mechanistically, PP2Ai increased the phosphorylation of mTOR and ribosomal protein S6 in NK cells, and mTOR inhibitor canceled the effects of PP2Ai in NK cells. Importantly, NK cells isolated from PP2Ai-treated mice showed higher cytotoxicity and IFN-γ production; therefore, they increased the anti-tumor effector function of NK cells. Accordingly, PP2Ai treatment inhibited lung metastasis of B16 melanoma by NK cell- and mTOR-dependent mechanisms. These results suggest that PP2A negatively regulates NK cell T-bet expression and effector function by an mTOR-dependent mechanism.

C-Reactive Protein Induces Immunosuppression by Activating FcγR2B in Pulmonary Macrophages to Promote Lung Metastasis.

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 pro-metastatic actions. Here, we reported that CRP promotes lung metastasis by dampening the anti-cancer 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 to wildtype mice. In addition, the lungs of CRP deficient mice were enriched for activated pulmonary macrophages, which could be reduced to the level of wildtype 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 pre-metastatic 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.

Biological evaluation of curdlan sulfate-based nanoparticles in trained immunity enhancement: In vitro and in vivo approaches

ObjectivesRecently, more and more evidences suggest that β-glucans can induce trained immunity and non-specific protections against pathogens. However, most of the reports evaluated the immunological activities of β-glucans through injection route but no nasal inhalation. In this study, the effects of curdlan sulfate-based nanoparticles, CS/O-HTCC on trained immunity through intranasal administration were evaluated. MethodsMacrophages were treated with CS/O-HTCC and the metabolisms of the macrophages were detected. Mice were intranasal administered with CS/O-HTCC for 3 times with a 14 days interval, then the antitumor or infection prevention effects were assessed. ResultsIn vitro, CS/O-HTCC enhanced the macrophage metabolism significantly through upregulating glycolysis (26.1 ± 4.3 mpH/min) and oxidative phosphorylation (36.0 ± 9.0 pmol/min) compared with that of negative group (7.5 ± 2.3 mpH/min and 19.5 ± 4.9 pmol/min). In vivo, CS/O-HTCC inhibited lung metastasis of B16F10 tumor cells and improved the survival time (26.5 days) of the nmice compared with negative group (19.5 days). Moreover, CS/O-HTCC prevented the lung infections by Escherichia coli or Streptococcus pneumoniae (less bacterial residual) and reduced lung damages. ConclusionsCS/O-HTCC can induce trained immunity through enhancing the metabolism of macrophages and enhance the non-specific protection against pathogens through intranasal immunization.

HIF-1α knockdown suppresses breast cancer metastasis via epithelial mesenchymal transition Abrogation

Lung metastasis, a leading cause of breast cancer mortality, lacks effective therapeutic options. Hypoxia-inducible factor 1-alpha (HIF-1α) plays important roles in breast cancer progression, but its direct impact on lung metastasis remains unclear. Herein, in this study, we investigated the role of HIF-1α in breast cancer lung metastasis and the potential of targeting it for therapeutic benefit. HIF-1α expression was knocked down in the 4T1 mouse mammary carcinoma cell line using a lentiviral vector. HIF-1α knockdown significantly reduced the migratory ability of 4T1 cells in vitro and lung metastasis in a mouse model. Mechanistically, HIF-1α knockdown decreased the expression of matrix metalloproteinases (MMP-2 and MMP-9) that degrade the extracellular matrix and suppressed the epithelial-to-mesenchymal transition (EMT) by increasing E-cadherin and decreasing vimentin expression. The findings of this study demonstrate that HIF-1α knockdown effectively inhibits lung metastasis of 4T1 cells both in vitro and in vivo by suppressing EMT. These results underscore a promising new approach for managing breast cancer metastasis.

Inhibition of STAT3 by 2-Methoxyestradiol suppresses M2 polarization and protumoral functions of macrophages in breast cancer

BackgroundBreast cancer metastasis remains the leading cause of cancer-related deaths in women worldwide. Infiltration of tumor-associated macrophages (TAMs) in the tumor stroma is known to be correlated with reduced overall survival. The inhibitors of TAMs are sought after for reprogramming the tumor microenvironment. Signal transducer and activator of transcription 3 (STAT3) is well known to contribute in pro-tumoral properties of TAMs. 2-Methoxyestradiol (2ME2), a potent anticancer and antiangiogenic agent, has been in clinical trials for treatment of breast cancer. Here, we investigated the potential of 2ME2 in modulating the pro-tumoral effects of TAMs in breast cancer.MethodsTHP-1-derived macrophages were polarized to macrophages with or without 2ME2. The effect of 2ME2 on macrophage surface markers and anti-inflammatory genes was determined by Western blotting, flow cytometry, immunofluorescence, qRT‒PCR. The concentration of cytokines secreted by cells was monitored by ELISA. The effect of M2 macrophages on malignant properties of breast cancer cells was determined using colony formation, wound healing, transwell, and gelatin zymography assays. An orthotopic model of breast cancer was used to determine the effect of 2ME2 on macrophage polarization and metastasis in vivo.ResultsFirst, our study found that polarization of monocytes to alternatively activated M2 macrophages is associated with the reorganization of the microtubule cytoskeleton. At lower concentrations, 2ME2 treatment depolymerized microtubules and reduced the expression of CD206 and CD163, suggesting that it inhibits the polarization of macrophages to M2 phenotype. However, the M1 polarization was not significantly affected at these concentrations. Importantly, 2ME2 inhibited the expression of several anti-inflammatory cytokines and growth factors, including CCL18, TGF-β, IL-10, FNT, arginase, CXCL12, MMP9, and VEGF-A, and hindered the metastasis-promoting effects of M2 macrophages. Concurrently, 2ME2 treatment reduced the expression of CD163 in tumors and inhibited lung metastasis in the orthotopic breast cancer model. Mechanistically, 2ME2 treatment reduced the phosphorylation and nuclear translocation of STAT3, an effect which was abrogated by colivelin.ConclusionsOur study presents novel findings on mechanism of 2ME2 from the perspective of its effects on the polarization of the TAMs via the STAT3 signaling in breast cancer. Altogether, the data supports further clinical investigation of 2ME2 and its derivatives as therapeutic agents to modulate the tumor microenvironment and immune response in breast carcinoma.

GSH-responsive polymeric micelles-based augmented photoimmunotherapy synergized with PD-1 blockade for eliciting robust antitumor immunity against colon tumor

Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What’s more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment.Graphical

Ultrasmall Enzyodynamic PANoptosis Nano-Inducers for Ultrasound-Amplified Hepatocellular Carcinoma Therapy and Lung Metastasis Inhibition.

Addressing the inefficiency of current therapeutic approaches for hepatocellular carcinoma is an urgent and pressing challenge. PANoptosis, a form of inflammatory programmed cell death, presents a dependable strategy for combating cancer by engaging multiple cell death pathways (apoptosis, pyroptosis, and necroptosis). In this study, an ultrasmall Bi2Sn2O7 nanozyme with ultrasound-magnified multienzyme-mimicking properties is designed and engineered as a PANoptosis inducer through destroying the mitochondrial function of tumor cells and enhancing the intracellular accumulation of toxic reactive oxygen species, finally triggering the activation of PANoptosis process. The role of PANoptosis inducer has been verified by the expression of related proteins, including cleaved Caspase 3, NLRP3, N-GSDMD, cleaved Caspase 1, p-MLKL, and RIPK3. The inclusion of external ultrasonic irradiation significantly augments the enzyodynamic therapeutic efficiency. In vitro and in vivo antineoplastic efficacy, along with inhibition of lung metastasis, validate the benefits of the Bi2Sn2O7-mediated PANoptosis pathway. This study not only elucidates the intricate mechanisms underlying Bi2Sn2O7 as a PANoptosis inducer, but also offers a novel perspective for the treatment of hepatocellular carcinoma.

Targeting POLRMT by IMT1 inhibits colorectal cancer cell growth

This study investigates the potential anti-colorectal cancer (CRC) activity of IMT1, a novel specific inhibitor of mitochondrial RNA polymerase (POLRMT). Single-cell RNA sequencing data reveal that POLRMT is overexpressed in CRC cells. Additionally, elevated POLRMT expression was observed in local CRC tissues and cells, while its expression remained relatively low in colon epithelial tissues and cells. IMT1 significantly inhibited colony formation, cell viability, proliferation, cell cycle progression, and migration in both primary and immortalized CRC cells. Furthermore, IMT1 induced apoptosis and cell death in CRC cells. The inhibition of POLRMT by IMT1 disrupted mitochondrial functions in CRC cells, leading to mitochondrial depolarization, oxidative damage, and decreased ATP levels. Using targeted shRNA to silence POLRMT closely mirrored the effects of IMT1, showing robust anti-CRC cell activity. Crucially, the efficacy of IMT1 was diminished in CRC cells with silenced POLRMT. Contrarily, boosting POLRMT expression externally by a lentiviral construct promoted the proliferation and migration of CRC cells. Importantly, treatment with IMT1 or silencing POLRMT in primary colon cancer cells decreased the phosphorylation of Akt1-S6K1, whereas overexpression of POLRMT had the opposite effect. In nude mice, orally administering IMT1 potently restrained primary colon cancer xenograft growth. IMT1 suppressed POLRMT activity, disrupted mitochondrial function, hindered Akt-mTOR activation, and prompted apoptosis within the xenograft tissues. In addition, IMT1 administration suppressed lung metastasis of primary colon cancer cells in nude mice. These combined results highlight the robust anti-CRC activity of IMT1 by specifically targeting POLRMT.

AURKB targets DHX9 to promote hepatocellular carcinoma progression via PI3K/AKT/mTOR pathway.

Aurora kinase B (AURKB) is known to play a carcinogenic role in a variety of cancers, but its underlying mechanism in liver cancer is unknown. This study aimed to investigate the role of AURKB in hepatocellular carcinoma (HCC) and its underlying molecular mechanism. Bioinformatics analysis revealed that AURKB was significantly overexpressed in HCC tissues and cell lines, and its high expression was associated with a poorer prognosis in HCC patients. Furthermore, downregulation of AURKB inhibited HCC cell proliferation, migration, and invasion, induced apoptosis, and caused cell cycle arrest. Moreover, AURKB downregulation also inhibited lung metastasis of HCC. AURKB interacted withDExH-Box helicase 9(DHX9) and targeted its expression in HCC cells. Rescue experiments further demonstrated that AURKB targeting DHX9 promoted HCC progression through the PI3K/AKT/mTOR pathway. Our results suggest that AURKB is significantly highly expressed in HCC and correlates with patient prognosis. Targeting DHX9 with AURKB promotes HCC progression via the PI3K/AKT/mTOR pathway.

The Importance of Suppressing Pathological Periostin Splicing Variants with Exon 17 in Both Stroma and Cancer.

Periostin (POSTN) is a type of matrix protein that functions by binding to other matrix proteins, cell surface receptors, or other molecules, such as cytokines and proteases. POSTN has four major splicing variants (PN1-4), which are primarily expressed in fibroblasts and cancer. We have reported that we should inhibit pathological POSTN (PN1-3), but not physiological POSTN (PN4). In particular, pathological POSTN with exon 17 is present in both stroma and cancer, but it is unclear whether the stroma or cancer pathological POSTN should be suppressed. We transplanted 4T1 cells (breast cancer) secreting POSTN with exon 17 into 17KO mice lacking POSTN exon 17 to suppress stromal POSTN with exon 17. The results show that 17KO mice had smaller primary tumors and fewer metastases. Furthermore, to suppress cancer POSTN with exon 17, 4T1 cells transfected with POSTN exon 17 skipping oligo or control oligo were transplanted from the tail vein into the lungs. The results show that POSTN exon 17 skipping oligo significantly suppressed lung metastasis. These findings suggest that it is important to suppress POSTN exon 17 in both stroma and cancer. Antibody targeting POSTN exon 17 may be a therapeutic candidate for breast cancer.

Propylene glycol alginate sodium sulfate suppressed lung metastasis by blocking P-selectin to recruit CD4 regulatory T cells

P-selectin has been shown to enhance growth and metastasis of mouse tumors by promoting regulatory T cell (Treg) infiltration into the tumors. Theoretically, a P-selectin antagonist could suppress the process. Popylene glycol alginate sodium sulfate (PSS) is a heparin-like marine drug, which was originally approved to treat cardiovascular disease in China. Previously, we reported that PSS was an effective P-selectin antagonist in vitro. However, it is unknown whether PSS can regulate Treg infiltration and its effect on lung metastasis in vivo. Our results showed that PSS at 30 mg/kg significantly suppressed lung metastasis and improved overall survival, with potency comparable to the positive control LMWH. Mechanistic study indicated that PSS blocked tumor cells adhesion and activated platelets by directly binding with activated platelet's P-selectin. Compared to the model group, PSS decreased the percent of Tregs by 63 % in lungs after treating for 21 days while increasing CD8+ T cells (1.59-fold) and Granzyme B+ CD8 T cells (2.08-fold)’ percentage for generating an adaptive response for systemic tumor suppression. The study indicated that the P-selectin antagonist, PSS, suppressed lung metastasis by inhibiting the infiltration of regulatory T cells (Treg) into the tumors.

Multifunctional single-component photosensitizers as metal-free ferroptosis inducers for enhanced photodynamic immunotherapy

Immunotherapy can enhance primary tumor efficacy, restrict distant growth, and combat lung metastasis. Unfortunately, it remains challenging to effectively activate the immune response. Here, tertiary butyl, methoxy, and triphenylamine (TPA) were utilized as electron donors to develop multifunctional photosensitizers (PSs). CNTPA-TPA, featuring TPA as the donor (D) and cyano as the acceptor (A), excelled in reactive oxygen species (ROS) generation due to its smaller singlet-triplet energy gap (ΔES-T) and larger spin-orbit coupling constant (SOC). Additionally, cyano groups reacted with glutamate (Glu) and glutathione (GSH), reducing intracellular GSH levels. This not only enhanced PDT efficacy but also triggered redox dyshomeostasis-mediated ferroptosis. The positive effects of photodynamic therapy (PDT) and ferroptosis promoted immunogenic cell death (ICD) and immune activation. By further combining anti-programmed cell death protein ligand-1 (anti-PD-L1) antibody, the powerful treatments of ferroptosis-assisted photodynamic immunotherapy significantly eradicated the primary tumors, inhibited the growth of distant tumors, and suppressed lung metastasis. In this study, a three-pronged approach was realized by single-component CNTPA-TPA, which simultaneously served as metal-free ferroptosis inducers, type-I photosensitizers, and immunologic adjuvants for near-infrared fluorescence imaging (NIR FLI)-guided multimodal phototheranostics of tumor. Statement of significance(1) CNTPA-TPA shared the smallest singlet-triplet energy gap and the largest spin-orbit coupling constant, which boosted intersystem crossing for efficient type-I photodynamic therapy (PDT);(2) Special reactions between cyano groups with glutamate and glutathione in mild conditions restricted the biosynthesis of intracellular GSH. GSH-depletion efficiently induced glutathione peroxidase 4 inactivation and lipid peroxide, resulting in ferroptosis of tumor cells;(3) The combination treatments of ferroptosis-assisted photodynamic immunotherapy induced by single-component CNTPA-TPA with the participation of anti-PD-L1 antibody resulted in increased T-cell infiltration and profound suppression of both primary and distant tumor growth, as well as lung metastasis.

A polymeric nanoplatform enhances the cGAS-STING pathway in macrophages to potentiate phagocytosis for cancer immunotherapy

Immunosuppressive tumor-associated macrophages (TAMs) account for a high proportion of the tumor tissue and significantly impede immunoefficacy. Furthermore, the signal regulatory protein α (SIRPα) expressed in TAMs adversely correlates with macrophage activation and phagocytosis, resulting in immunosurveillance escape. To address these difficulties, a mannose-modified, pH-responsive nanoplatform with resiquimod (R848) and 2′, 3′-cyclic GMP-AMP (cGAMP) co-encapsulation (named M-PNP@R@C) is designed to polarize TAMs and lower SIRPα expression. The co-delivery of R848 and cGAMP synergistically facilitates the polarization of TAMs from the anti-inflammatory M2 phenotype into the pro-inflammatory M1 phenotype, thereby enhancing antitumor immunotherapy. Remarkably, activation of the cGAMP-mediated stimulator of interferon genes (STING) in TAMs significantly downregulates the expression of SIRPα, which synergizes with the cluster of differentiation 47 (CD47) antibody for the dual blockade of the CD47-SIRPα axis. Further analysis of single-cell RNA sequencing indicates that STING activation downregulates SIRPα by regulating intracellular fatty acid oxidation metabolism. In vivo studies indicate that M-PNP@R@C significantly inhibits tumor growth with a potent antitumor immune response in melanoma graft tumor models. After synergy with anti-CD47, the double blockade strategies of the SIRPα/CD47 axis result in a notable inhibition of lung metastasis. A prolonged survival rate is observed after combination treatment with CD47 and programmed death ligand-1 antibodies for the triple immune checkpoint blockade. In summary, our study provides original insights into the potential role of the STING pathway in macrophage-based immunotherapy, thus offering a potential combinatorial strategy for cancer therapy.

Biomimetic gold nanocages incorporating copper-human serum albumin for tumor immunotherapy via cuproptosis-lactate regulation

Cancer immunotherapy remains a significant challenge due to insufficient proliferation of immune cells and the sturdy immunosuppressive tumor microenvironment. Herein, we proposed the hypothesis of cuproptosis-lactate regulation to provoke cuproptosis and enhance anti-tumor immunity. For this purpose, copper-human serum albumin nanocomplex loaded gold nanocages with bacterial membrane coating (BAu-CuNCs) were developed. The targeted delivery and disassembly of BAu-CuNCs in tumor cells initiated a cascade of reactions. Under near infrared (NIR) laser irradiation, the release of copper-human serum albumin (Cu-HSA) was enhanced that reacted with intratumoral glutathione (GSH) via a disulfide exchange reaction to liberate Cu2+ ions and exert cuproptosis. Subsequently, the cuproptosis effect triggered immunogenic cell death (ICD) in tumor by the release of damage associated molecular patterns (DAMPs) to realize anti-tumor immunity via robust production of cytotoxic T cells (CD8+) and helper T cells (CD4+). Meanwhile, under NIR irradiation, gold nanocages (AuNCs) promoted excessive reactive oxygen species (ROS) generation that played a primary role in inhibiting glycolysis, reducing the lactate and ATP level. The combine action of lower lactate level, ATP reduction and GSH depletion further sensitized the tumor cells to cuproptosis. Also, the lower lactate production led to the significant blockage of immunosuppressive T regulatory cells (Tregs) and boosted the anti-tumor immunity. Additionally, the effective inhibition of breast cancer metastasis to the lungs enhanced the anti-tumor therapeutic impact of BAu-CuNCs + NIR treatment. Hence, BAu-CuNCs + NIR concurrently induced cuproptosis, ICD and hindered lactate production, leading to the inhibition of tumor growth, remodeling of the immunosuppressive tumor microenvironment and suppression of lung metastasis. Therefore, leveraging cuproptosis-lactate regulation, this approach presents a novel strategy for enhanced tumor immunotherapy.

Platelet-Drug Conjugates Engineered via One-step Fusion Approach for Metastatic and Postoperative Cancer Treatment.

The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process. We demonstrate doxorubicin (DOX)-encapsulated liposomes conjugated with interleukin-15 (IL-15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.

Platelet‐Drug Conjugates Engineered via One‐step Fusion Approach for Metastatic and Postoperative Cancer Treatment

AbstractThe exploration of cell‐based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one‐step fusion process. We demonstrate doxorubicin (DOX)‐encapsulated liposomes conjugated with interleukin‐15 (IL‐15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.

Injectable nano-in situ-thermosensitive-hydrogels based on halofuginone and silver for postoperative treatment against triple-negative breast cancer

Postoperative distant metastasis and high recurrence rate causes a dilemma in treating triple-negative breast cancer (TNBC) owing to its unforeseeable invasion into various organs or tissues. The wealth of nutrition provided by vascular may facilitate the proliferation and angiogenesis of cancer cells, which further enhance the rates of postoperative metastasis and recurrence. Chemotherapy, as a systemic postoperative adjuvant therapy, is generally applied to diminish recurrence and metastasis of TNBC. Herein, an halofuginone-silver nano thermosensitive hydrogel (HTPM&AgNPs-gel) was prepared via a physical swelling method. The in vitro anticancer efficacy of HTPM&AgNPs-gel was analyzed by investigating cell proliferation, migration, invasion, and angiogenesis capacity. Furthermore, the in vivo anti-cancer activity of HTPM&AgNPs-gel was further appraised through the tumor suppression, anti-metastatic, anti-angiogenic, and anti-inflammatory ability. The optimized HTPM&AgNPs-gel, a thermosensitive hydrogel, showed excellent properties, including syringeability, swelling behavior, and a sustained release effect without hemolysis. In addition, HTPM&AgNPs-gel was confirmed to effectively inhibit the proliferation, migration, invasion, and angiogenesis of MDA-MB-231 cells. An evaluation of the in vivo anti-tumor efficacy demonstrated that HTPM&AgNPs-gel showed a stronger tumor inhibition rate (68.17%) than did HTPM-gel or AgNPs-gel used alone and exhibited outstanding biocompatibility. Notably, HTPM&AgNPs-gel also inhibited lung metastasis induced by residual tumor tissue after surgery and further blocked angiogenesis-related inflammatory responses. Taken together, the suppression of inflammation by interdicting the blood vessels adjoining the tumor and inhibiting angiogenesis is a potential strategy to attenuate the recurrence and metastasis of TNBC. HTPM&AgNPs-gel is a promising anticancer agent for TNBC as a local postoperative treatment.