Tumor Lung Metastasis Research Articles

Self-delivered sonodynamic nanomedicine for enhanced tumor immunotherapy by simultaneously reversing the immunosuppression and immune resistance

Sonodynamic therapy (SDT) shows potential for noninvasive eradication of local solid tumors. However, its efficacy in suppressing metastatic tumors is limited by factors such as insufficient tumor accumulation, the immunosuppressive tumor microenvironment, and acquired immune tolerance. To address these challenges, we developed self-delivering sonodynamic nanomedicine incorporating Toll-like receptor (TLR) agonists R848 and programmed death-ligand 1 (PD-L1) inhibitors JQ1 for combined SDT and immunotherapy. These nanomedicines enhanced tumor accumulation of sonosensitizers, enabling potent SDT and induction of immunogenic cell death (ICD). Additionally, the co-encapsulated R848 and JQ1 alleviated tumor immunosuppression and immune tolerance, synergizing effectively with SDT to elicit a robust antitumor immune response. By integrating enhanced SDT with activated antitumor immunity, significant inhibition of primary, distant, and lung metastatic tumors was achieved. This study introduces a novel approach for combining SDT with immunotherapy using self-assembled active pharmaceutical ingredients.

Saprophytic fungus (Ganoderma sessile) restrained Treg recruitment in the tumor microenvironment by down-regulating CCL28/CCR10 pathway

Ganoderma sessile, a saprophytic fungus, is a traditional Chinese medicinal material used in Chinese folk medicine and cuisine for its potential to enhance cancer patients immunity in clinical practice. However, the underlying mechanisms of its therapeutic effects remain elusive. Therefore, we explored the edible value to determine the underlying mechanisms of GS through multiple breast cancer models. GS was found to suppress tumor growth and lung metastasis, and prolong survival after surgery. It significantly increased tumor-infiltrating CD44HiCD62LHiCD8+ TCM cells while decreasing CD4+CD25+CD127− Treg cells in both lymph nodes and tumors. The mechanism behind GS’s effects primarily involved modulation of the Hif1-a/CCL28 pathway associated with Treg recruitment. Furthermore, GS could reduce CCR10 levels on the surface of Tregs. Collectively, GS inhibits tumor growth and pulmonary metastasis by restraining Treg recruitment through downregulation of the CCL28/CCR10 pathway—a finding which highlights its potential as a natural anti-tumor immune agent warranting further exploration.

Olaparib enhancing radiosensitization and anti-metastatic effect of oral cancer by targeting IL-17A signal.

We tested whether the PARP inhibitor, Olaparib, can effectively enhance radiosensitivity while inhibiting OSCC growth and metastasis in vitro and in vivo. Patient samples were used for survival validation. The present study investigated the effect of Olaparib and ionizing radiation (IR) on clonogenic, migratory, and invasive ability in human IR-sensitive (OML1) and IR-resistant (OML1-R) OSCC cell lines. We next explored the underlying mechanism with ELISA and a Western blotting assay. Two in vivo mouse models were established to investigate the efficacy of Olaparib combined with radiotherapy (RT) on local tumor growth and lung metastasis. IL-17A expression was confirmed in tissue specimens of OSCC patients by immunohistochemistry. We found that Olaparib, in combination with IR, substantially inhibited cell growth, migration, and invasion in vitro. Mechanistically, the Olaparib treatment significantly reduced the secretion of IL-17A in irradiated OSCC cells by attenuating NF-κB and p38 activity. Consistently, Olaparib enhanced the radiosensitivity and, with RT, synergistically reduced both tumor growth and lung metastasis in mice. In addition, OSCC patients with high IL-17A expression were substantially associated with an increased risk of lymph node involvement and worse survival. This study has highlighted that Olaparib displays radiosensitizing and antimetastatic effects by inhibiting the IL-17A-dependent signal. Remarkably, Olaparib could provide a remarkable anticancer efficacy to improve treatment response in OSCC patients with recurrent/metastatic disease after RT.

Engineered manganese-BODIPY coordinated nanoadjuvants for enhanced NIR-II photo-metalloimmunotherapy

Immunotherapy, a pivotal and promising approach for tumor treatment, has demonstrated prominent clinical efficacy. However, its effectiveness is often impeded by insufficient antitumor immune responses attributed to the immunosuppressive tumor microenvironment (TME). The combination of immune activation through the stimulator of interferon genes (STING) pathway and phototherapy holds great potential for surmounting this challenge in advanced tumor immunotherapy. Herein, a novel manganese-boosted NIR-II photo-metalloimmunotherapy is proposed to synergistically enhance antitumour efficacy by fabricating Mn2+-BODIPY-based coordinated photo-immune nanoadjuvants (BMR), modified with tumor-targeted peptide cRGD. The obtained BMR could effectively deliver Mn2+ to tumor sites, and immunogenic cell death (ICD) was evoked by localized photothermal ablation of tumors using NIR-II laser irradiation. Simultaneously, pH-responsive release of Mn2+ would trigger the activation of STING pathway to promote the production of type I interferons (I-IFNs), significantly facilitating the maturation of dendritic cells (DCs) and polarization of macrophages to M1 phenotypes. Furthermore, by synergistically initiating systematic and robust antitumour immune responses, the BMR-mediated NIR-II photo-metalloimmunotherapy achieved remarkable therapeutic efficacy against both primary and lung metastasis of B16F10 tumors. Overall, in light of the versatile functionalities and synthetic flexibility of coordinated nanoadjuvants, formulated with photofunctional ligands and diverse metal ions, this work provides new insights into the design of metal coordination nanomedicine for effective antitumor photo-metalloimmunotherapy.

High-affinity T cell receptor ImmTAC® bispecific efficiently redirects T cells to kill tumor cells expressing the cancer testis antigen PRAME

Abstract PRAME (Preferentially expressed Antigen in Melanoma) is a cancer testis antigen expressed in several tumor indications, representing an attractive anti-cancer target. However, its intracellular location limits targeting by traditional methods. PRAME peptides are presented on the surface of tumor cells by human leukocyte antigen (HLA) molecules, indicating that a T cell receptor (TCR)-based strategy that redirects T cells to kill PRAME+ tumors could be a novel immunotherapeutic option. We confirm that PRAME protein is expressed in cutaneous melanoma, including rare subtypes with limited treatment options, as well as primary and metastatic lung, breast, endometrial and ovarian tumors. Furthermore, PRAME is expressed homogeneously across tumors with distinct oncogenic mutations, mutation burden, PD-L1 expression, immune infiltration and features of immune checkpoint resistance. Immunopeptidomic analysis of primary tumors detected HLA class I-restricted PRAME peptides. A TCR recognizing PRAME peptide SLLQHLIGL was engineered to high affinity and fused to a CD3 engaging domain to create a TCRxCD3 bispecific molecule (Immune mobilizing monoclonal TCR Against Cancer, ImmTAC®) with the ability to redirect polyclonal T cells to efficiently kill PRAME+ cells. The degree of T cell activation was positively correlated with peptide-HLA abundance, with as few as 10 epitopes per cell sufficient for target cell killing. Impaired ImmTAC®-redirected cytotoxicity of exhausted T cells was rescued using an anti-PD-1 antibody, supporting the use of a combination strategy to treat tumors with active PDL1-PD1 axes. Our data demonstrate selective and efficient T cell activation and killing by a PRAME-directed TCRxCD3 bispecific, supporting further investigation in multiple cancer indications.

Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer

We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.

Transarterial embolization for the management of emergent hemoptysis in patients with primary and metastatic lung tumors

Transarterial embolization for the management of emergent hemoptysis in patients with primary and metastatic lung tumors

DSTYK Inhibition Sensitizes Non-Small Cell Lung Cancer To Taxane-Based Chemotherapy

Chemotherapy continues to be the standard treatment for patients non-eligible to targeted or immune-based therapies; however, treatment resistance remains a major clinical challenge. We previously found that expression levels of DSTYK, a poorly explored dual serine/threonine and tyrosine kinase frequently amplified in cancer, identifies lung cancer patients exhibiting poor response to immune checkpoint inhibitors and showed that its inhibition sensitizes to immunotherapy. Seeking to explore the potential of DSTYK targeting in additional indications, we investigated the functional relevance and actionability of DSTYK in lung cancer chemoresistance. We show that DSTYK depletion specifically sensitizes lung cancer cells to taxane-based chemotherapy, particularly in combination with carboplatin. Mechanistically, DSTYK ablation remodels the cytoskeleton and impairs distant invasion and metastatic outgrowth in vivo. DSTYK downregulation sensitizes both primary and metastatic lung tumors to chemoimmunotherapy treatment leading to tumor regression in mouse models. Consistently, clinical data of early - in the neoadjuvant and adjuvant settings- and advanced lung cancer patients show a strong correlation between DSTYK amplification and taxane resistance, underscoring the clinical significance of our findings to inform treatment decision-making. Collectively, our data indicates that DSTYK amplification may be a predictor of resistance to taxane-based treatments and represents an actionable target for these patients.

A Multifunctional Exosome with Dual Homeostasis Disruption Augments cGAS-STING-Mediated Tumor Immunotherapy by Boosting Ferroptosis.

Ferroptosis has shown great potential in activating antitumor immunity. However, the cunning tumor cells can evade ferroptosis by increasing the efflux of iron and promoting the production of the reductant glutathione to mitigate oxidative stress. Herein, a multifunctional exosome loaded with manganese-doped iron oxide nanoparticles (MnIO), GW4869, and l-buthionine sulfoximine (BSO) is developed to disrupt the iron metabolism homeostasis and redox homeostasis to enhance tumor immunotherapy. The efficient transport of MnIO by exosomes and the inhibition of iron exocytosis by GW4869 led to a high retention of up to 29.57% ID/g for iron in the tumors. Such a high retention of iron, in combination with the BSO-induced disruption of the redox homeostasis, effectively promotes the ferroptosis of tumor cells. Consequently, the multifunctional exosomes that noticeably enhance ferroptosis by dual homeostasis disruption provoke the cGAS-STING-based antitumor immune response and effectively suppress tumor growth and lung metastasis in orthotopic breast cancer.

The carcinogenesis of esophageal squamous cell cancer is positively regulated by USP13 through WISP1 deubiquitination.

The objective was to determine whether USP13 stabilizes WISP1 protein and contributes to tumorigenicity and metastasis in ESCC through the Wnt/CTNNB1 signaling pathway. ESCC cell lines (KYSE150 and TE10) were treated with the proteasome inhibitor MG-132, followed by siRNA screening of deubiquitinases (DUBs) to identify regulators of WISP1. Mass spectrometry, immunoprecipitation, and in vitro functional assays were conducted to explore the interaction between USP13 and WISP1 and to assess the effects of USP13 downregulation on cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and apoptosis. Additionally, in vivo experiments using mouse models were performed to evaluate the impact of USP13 knockdown on tumor growth and metastasis. USP13 was identified as a key regulator of WISP1, stabilizing its protein levels through deubiquitination. Downregulation of USP13 resulted in reduced WISP1 protein stability, decreased cell proliferation, migration, and EMT, and increased apoptosis in vitro. In vivo, USP13 knockdown significantly inhibited tumor growth and lung metastasis. WISP1 overexpression in USP13-knockdown cells partially rescued these phenotypes, confirming the functional role of the USP13/WISP1 axis. Furthermore, knockdown of USP13 or WISP1 impaired the activation of the Wnt/CTNNB1 signaling pathway and reduced immune checkpoint marker expression, indicating a mechanism by which USP13 promotes immune evasion in ESCC. USP13 stabilizes WISP1 through deubiquitination, enhancing ESCC progression by activating the Wnt/CTNNB1 pathway and promoting immune evasion, making USP13 a potential therapeutic target in ESCC.

SAR1A Induces Cell Growth and Epithelial–Mesenchymal Transition Through the PI3K/AKT/mTOR Pathway in Head and Neck Squamous Cell Carcinoma: An In Vitro and In Vivo Study

Objectives: Head and neck squamous cell carcinoma (HNSCC) ranks sixth globally, with a 50% five-year survival rate. SAR1A exhibits high expression levels in various tumor types, yet its specific role in HNSCC remains to be clarified. Methods: In vitro assays, such as CCK8, EdU, colony formation, wound-healing, transwell, and Western blotting analyses, as well as in vivo assays, such as tumor xenografts and lung metastasis models, were conducted to evaluate the impacts of SAR1A on HNSCC proliferation, migration, and invasion. Transcriptome sequencing and KEGG enrichment pathway analysis revealed evident alterations in the PI3K/AKT/mTOR(PAM) pathways. LY294002 (a PI3K/AKT inhibitor) was used to investigate the role of the PAM pathway in proliferation, migration, and invasion in HNSCC. Results: Univariate and multivariate Cox regression were conducted to screen SAR1A as a gene prognostic biomarker in HNSCC, and it was validated in the Cancer Genome Atlas (TCGA) database. Functional assays demonstrated that the depletion of SAR1A leads to suppressed proliferation, migration, and invasion of HNSCC cells. This is accompanied by a decrease in the expression of epithelial–mesenchymal transition (EMT)-related markers in HNSCC cell lines. In addition, the diminished capacities of proliferation, migration, and invasion observed in SAR1A knockdown cells were reversed upon the overexpression of SAR1A. Furthermore, RNA-seq and KEGG enrichment analysis demonstrated a significant alteration in the PAM pathway following SAR1A knockdown. LY294002 effectively mitigated the increased proliferation, migration, and invasion induced by SAR1A overexpression. Conclusions: SAR1A facilitates HNSCC proliferation and EMT via the PI3K/AKT/mTOR pathway.

Human adipose-derived stem cells promote migration of papillary thyroid cancer cell via leptin pathway

Introduction Obesity is associated with the incidence and poor prognosis of thyroid cancer, but the mechanism is not fully understood. The aim of this study was to investigate the effects of human adipose-derived stem cells (ADSCs) on the invasion and migration of thyroid cancer cells. Methods ADSCs-conditioned medium (ADSC-CM) was collected to culture thyroid cancer cell lines TPC-1 cells and BCPAP cells. The effects of ADSCs on thyroid cancer cell proliferation were determined by CCK8 and EdU assays, and the effects on migration were determined by Transwell and wound closure assays. Leptin neutralizing antibodies (NAB) were added to ADSC-CM to block leptin. In animal experiments, TPC-1 cells and BCPAP cells were injected into the tail vein of nude mice, and the leptin receptor antagonist peptide allo-aca was injected subcutaneously to block the leptin pathway. The number and size of metastatic lung tumours were observed after 8 weeks. Results ADSC-CM significantly promoted the invasion and migration of thyroid cancer cells and upregulated their matrix metalloproteinase 2 (MMP-2) levels, while NAB with the addition of leptin reduced the invasion and migration of thyroid cancer cells and downregulated MMP-2 levels. Allo-aca treatment reduced the number of metastatic lung nodules formed by thyroid cancer cells in nude mice and reduced the diameter of metastatic lesions. Conclusion ADSCs upregulate MMP-2 levels of thyroid cancer cells through exocrine leptin, thereby promoting cancer cell migration, which may be one of the key mechanisms by which obesity increases the invasiveness of thyroid cancer.

Drug-Free Mesoporous Silica Nanoparticles Enable Suppression of Cancer Metastasis and Confer Survival Advantages to Mice with Tumor Xenografts.

Despite advancements in nanomedicine for drug delivery, many drug-loaded nanoparticles reduce tumor sizes but often fail to prevent metastasis. Mesoporous silica nanoparticles (MSNs) have attracted attention as promising nanocarriers. Here, we demonstrated that MSN-PEG/TA 25, with proper surface modifications, exhibited unique antimetastatic properties. In vivo studies showed that overall tumor metastasis decreased in 4T1 xenografts mice treated with MSN-PEG/TA 25 with a notable reduction in lung tumor metastasis. In vitro assays, including wound-healing, Boyden chamber, tube-formation, and real-time cell analyses, showed that MSN-PEG/TA 25 could modulate cell migration of 4T1 breast cancer cells and interrupt tube formation by human umbilical vein endothelial cells (HUVECs), key factors in suppressing cancer metastasis. The synergistic effect of MSN-PEG/TA 25 combined with liposomal-encapsulated doxorubicin (Lipo-Dox) significantly boosted mouse survival rates, outperforming Lipo-Dox monotherapy. We attributed the improved survival to the antimetastatic capabilities of MSN-PEG/TA 25. Moreover, Dox-loaded MSN-PEG/TA 25 suppressed primary tumors while retaining the antimetastatic effect, thereby enhancing therapeutic outcomes and overall survival. Western blot and qPCR analyses revealed that MSN-PEG/TA 25 interfered with the phosphorylation of ERK, FAK, and paxillin, thus impacting focal adhesion turnover and inhibiting cell motility. Our findings suggest that drug-free MSN-PEG/TA 25 is highly efficient for cancer treatment via suppressing metastatic activity and angiogenesis.

A Tumor-Homing Nanoframework for Synergistic Microwave Tumor Ablation and Provoking Strong Anticancer Immunity Against Metastasis.

Microwave thermotherapy (MT) is a clinical local tumor ablation modality, but its applications are limited by its therapeutic efficacy and safety. Therefore, developing sensitizers to optimize the outcomes of MT is in demand in clinical practice. Herein, we engineered a special nanoframework (i.e., FdMI) based on a fucoidan-decorated zirconium metal-organic framework incorporating manganese ions and liquid physisorption for microwave tumor ablation. The monodisperse nanoframework exhibited both microwave thermal effects and microwave dynamic effects, which could effectively kill cancer cells by efficient intracellular drug delivery. Through fucoidan-mediated targeting of P-selectin in the tumor microenvironment (TME), the FdMI effectively accumulated in tumor regions, leading to significant eradication of orthotropic triple-negative breast cancer (TNBC) and aggressive Hepa1-6 liver tumors by the synergistic effects of microwave thermotherapy/dynamic therapy (MT/MDT). The eradication of primary tumors could activate systemic immune responses, which effectively inhibited distant TNBC tumors and lung metastasis of Hepa1-6 liver tumors, respectively. This work not only engineered nanoparticle sensitizers for tumor-targeted synergistic MT/MDT but also demonstrated that nanocarrier-based microwave tumor ablation could stimulate antitumor immunity to effectively inhibit distant and metastatic tumors, demonstrating the high potential for effectively managing advanced malignant tumors.

Ultrasound-triggered and glycosylation inhibition-enhanced tumor piezocatalytic immunotherapy.

Nanocatalytic immunotherapy holds excellent potential for future cancer therapy due to its rapid activation of the immune system to attack tumor cells. However, a high level of N-glycosylation can protect tumor cells, compromising the anticancer immunity of nanocatalytic immunotherapy. Here, we show a 2-deoxyglucose (2-DG) and bismuth ferrite co-loaded gel (DBG) scaffold for enhanced cancer piezocatalytic immunotherapy. After the implantation in the tumor, DBG generates both reactive oxygen species (ROS) and piezoelectric signals when excited with ultrasound irradiation, significantly promoting the activation of anticancer immunity. Meanwhile, 2-DG released from ROS-sensitive DBG disrupts the N-glycans synthesis, further overcoming the immunosuppressive microenvironment of tumors. The synergy effects of ultrasound-triggered and glycosylation inhibition enhanced tumor piezocatalytic immunotherapy are demonstrated on four mouse cancer models. A "hot" tumor-immunity niche is produced to inhibit tumor progress and lung metastasis and elicit strong immune memory effects. This work provides a promising piezocatalytic immunotherapy for malignant solid tumors featuring both low immunogenicity and high levels of N-glycosylation.

Antimetastatic effect of nanodiamond-conjugated quercetin against colon cancer: an in vivo study.

Quercetin (Q) is a compound that can inhibit the growth of cancer cells in the colon; however, to do so, a high dose is needed, requiring a drug delivery system to target cancer endothelial cells directly. This study investigates the potency of nanodiamond-conjugated quercetin (NDQ) as an anticancer drug against colon cancer in Rattus norvegicus induced by N-methyl N-Nitrosourea (MNU). This study is experimental-based and was designed using a six-group treatment method, namely normal control (KN: not treated by MNU, nanodiamond (ND), or Q); negative control (K-: treated by MNU); positive control (K+: treated by MNU and capecitabine); ND (treated by MNU and NDs); Q (treated by MNU and Q); and NDQ (treated by MNU and NDQ). To induce colon cancer in rats, MNU (10 mg/Kg BW) was administrated intrarectally three times per week for four weeks. The treatment of Q (40 mg/Kg BW) or NDQ (40 mg/Kg BW) was given intraperitoneally twice a week for 6 weeks. Cancer progression of all cohorts was evaluated by performing body and colon weight measurements, which involved the following: ELISA assay-specific to metastatic marker matrix metalloprotein-9 (MMP-9), carcinoembryonic antigen (CEA), hypoxia-inducible factor 1 α (HIF1α), vascular endothelial growth factor, protein 53 (p53) and immunohistochemistry staining of Caspase-3 and Ki-67 proteins. Observation of cancer metastasis to the lung was also performed. NDQ significantly inhibited cancer aggressiveness by causing an increment in body weight gain and the growth rate-while reducing the colon weight compared to the K- group. Moreover, decreased levels of MMP-9, CEA, HIF-1α, and Ki67 and increased levels of p53 and Caspase-3 were more significant in the NDQ group than in the Q group. The lung tumor metastases in the NDQ group were fewer than in the K- group. NDQ increased Q's anticancer activity, suggesting that NDs have an effective drug delivery property.

Non-emergent hemoptysis in patients with primary or metastatic lung tumors: The role of transarterial embolization

PurposeTo evaluate the role of systemic arterial embolization for the management of non-emergent hemoptysis in patients with primary or metastatic lung tumors. Materials and methodsThis is a retrospective single center study of consecutive patients who underwent systemic arterial embolization for non-emergent hemoptysis between 2011 and 2023. Study endpoints included technical success, clinical success (partial or complete resolution of hemoptysis) and overall survival. Hemoptysis-free and overall survival were estimated using the Kaplan-Meier method. Predictive factors for hemoptysis-free survival and overall survival were evaluated using univariate analysis (Cox regression). Post-procedural 30-day adverse events were recorded in line with Common Terminology Criteria for Adverse Events (CTCAE) v5.0. ResultsA total of 30 patients were identified. Technical success was achieved in 24/30 (80 %) patients. Clinical success following embolization was achieved in 23/30 (76.7 %) patients. Median length of hospitalization was 5 days (Range: 1 to 16 days). Median overall survival was 194 days (95 % CI: 89 to 258). Median hemoptysis-free survival was 286 days (95 % CI: 42 to not reached). No significant clinical or procedural predictors of hemoptysis-free survival or overall survival were identified. Serious adverse events (CTCAE Grade > 3) occurred in 1 patient (3.4 % − fatal respiratory failure). ConclusionEmbolization of non-emergent hemoptysis in patients with lung malignancies is safe and effective. Recurrence is however high in this patient population, likely due to the nature of the underlying disease.

Engineering cell membrane-camouflaged COF-based nanosatellite for enhanced tumor-targeted photothermal chemoimmunotherapy

Dendritic cells (DCs) activation is crucial for regulating the antitumor immune response. However, the tumor's immunosuppressive environment significantly impedes antigen presentation and DCs maturation, thereby limiting the effectiveness of cancer immunotherapy. To address this challenge, we developed tumor cell membrane-coated covalent organic framework (COF) nanoparticles, loaded with mannose-modified gold nanoparticles and doxorubicin (Dox). This created a cell membrane-camouflaged COF-based nanosatellite designed to enhance tumor-targeted chemoimmunotherapy. The nanosatellite exhibits distinct photothermal properties and releases Dox in a pH-sensitive manner, targeting tumor cells to induce immunogenic cell death (ICD) and expose a wealth of antigens. Crucially, the COF structure is selectively degraded to release mannose-modified gold nanoparticles in the acidic environment. These nanoparticles capture antigens from the ICD and efficiently transport them to lymph nodes rich in DCs, facilitated by mannose receptor mediation. As a result, antigens are effectively presented to DCs, activating the immune response, significantly hindering tumor growth and lung metastasis in mice, and extending survival. This study pioneered innovative nano-preparations aimed at enhancing tumor immunotherapy.

An Exogenous Ketone Ester Slows Tumor Progression in Murine Breast and Renal Cancer Models.

Ketone esters (KEs) exhibit promise as anti-cancer agents but their impact on spontaneous metastases remains poorly understood. Although consumption of a ketogenic diet (KD) that is low in carbohydrates and high in fats can lead to KE production in vivo, the restrictive composition of KDs may diminish adherence in cancer patients. We investigated the effects of an exogenous ketone ester-supplemented (eKET), carbohydrate-replete diet on tumor growth, metastasis, and underlying mechanisms in orthotopic models of metastatic breast (4T1-Luc) and renal (Renca-Luc) carcinomas. Mice were randomized to diet after tumor challenge. Administration of KEs did not alter tumor cell growth in vitro. However, in mice, our eKET diet increased circulating β-hydroxybutyrate and inhibited primary tumor growth and lung metastasis in both models. Body composition analysis illustrated the overall safety of eKET diet use, although it was associated with a loss of fat mass in mice with renal tumors. Immunogenetic profiling revealed divergent intratumoral eKET-related changes by tumor type. In mammary tumors, Wnt and TGFβ pathways were downregulated, whereas in renal tumors, genes related to hypoxia and DNA damage repair were downregulated. Thus, our eKET diet exerts potent antitumor and antimetastatic effects in both breast and renal cancer models, albeit with different modes of action and physiologic effects. Its potential as an adjuvant dietary approach for patients with diverse cancer types should be explored further.

Jiedu recipe, a compound Chinese herbal medicine, suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment

ObjectiveTumor-derived exosomes (TDEs) play crucial roles in intercellular communication. Hypoxia in the tumor microenvironment enhances secretion of TDEs and accelerates tumor metastasis. Jiedu recipe (JR), a traditional Chinese medicinal formula, has demonstrated efficacy in preventing the metastasis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unknown. MethodsAnimal experiments were performed to investigate the metastasis-preventing effects of JR. Bioinformatics analysis and in vitro assays were conducted to explore the potential targets and active components of JR. TDEs were assessed using nanoparticle tracking analysis (NTA) and Western blotting (WB). Exosomes derived from normoxic or hypoxic HCC cells (H-TDEs) were collected to establish premetastatic mouse models. JR was intragastrically administered to evaluate its metastasis-preventive effects. WB and lysosomal staining were performed to investigate the effects of JR on lysosomal function and autophagy. Bioinformatics analysis, WB, NTA, and immunofluorescence staining were used to identify the active components and potential targets of JR. ResultsJR effectively inhibited subcutaneous-tumor-promoted lung premetastatic niche development and tumor metastasis. It inhibited the release of exosomes from tumor cells under hypoxic condition. JR treatment promoted both lysosomal acidification and suppressed secretory autophagy, which were dysregulated in hypoxic tumor cells. Quercetin was identified as the active component in JR, and the epidermal growth factor receptor (EGFR) was identified as a potential target. Quercetin inhibited EGFR phosphorylation and promoted the nuclear translocation of transcription factor EB (TFEB). Hypoxia-impaired lysosomal function was restored, and secretory autophagy was alleviated by quercetin treatment. ConclusionJR suppressed HCC metastasis by inhibiting hypoxia-stimulated exosome release, restoring lysosomal function, and suppressing secretory autophagy. Quercetin acted as a key component of JR and regulated TDE release through EGFR-TFEB signaling. Our study provides a potential strategy for retarding tumor metastasis by targeting H-TDE secretion.Please cite this article as: Jia WT, Xiang S, Zhang JB, Yuan JY, Wang YQ, Liang SF, Lin WF, Zhai XF, Shang Y, Ling CQ, Cheng BB. Jiedu recipe, a compound Chinese herbal medicine, suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment through the EGFR-TFEB signaling pathway. J Integr Med. 2024; Epub ahead of print.