RESUMEN
Background: Effective innate immunity activation could dramatically improve the anti-tumor efficacy and increase the beneficiary population of immunotherapy. However, the anti-tumor effect of unimodal immunotherapy is still not satisfactory. Methods: Herein, a novel relay-type innate immunity activation strategy based on photo-immunotherapy mediated by a water-soluble aggregation-induced emission luminogen, PEG420-TQ, with the assistant of toll-like receptor 7 (TLR-7) agonist, imiquimod (R837), was developed and constructed. Results: The strategy could promote tumor cells to undergo immunogenic cell death (ICD) induced by the well-designed PEG420-TQ@R837 (PTQ@R) nanoplatform under light irradiation, which in turn enhanced the infiltration of immune cells and the activation of innate immune cells to achieve the first innate immunity activation. The second innate immunity activation was subsequently achieved by drug delivery of R837 via apoptotic bodies (ApoBDs), further enhancing the anti-tumor activity of infiltrated immune cells. Conclusion: The strategy ultimately demonstrated robust innate immunity activation and achieved excellent performance against tumor growth and metastasis. The construction of the relay-type innate immunity activation strategy could provide a new idea for the application of immunotherapy in clinical trials.
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Imiquimod , Inmunidad Innata , Inmunoterapia , Inmunidad Innata/efectos de los fármacos , Animales , Inmunoterapia/métodos , Ratones , Imiquimod/uso terapéutico , Imiquimod/farmacología , Línea Celular Tumoral , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Agua/química , Receptor Toll-Like 7/agonistas , Femenino , Fototerapia/métodos , Nanopartículas/química , Ratones Endogámicos BALB C , Muerte Celular Inmunogénica/efectos de los fármacos , Rayos InfrarrojosRESUMEN
The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.
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Mitocondrias , Neoplasias , Microambiente Tumoral , Animales , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Humanos , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Apoptosis/efectos de los fármacos , Femenino , Muerte Celular Inmunogénica/efectos de los fármacos , Ratones Endogámicos C57BL , Nanopartículas/química , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia/métodosRESUMEN
Tumor immunotherapy, especially immune checkpoint inhibitors (ICIs), has been applied in clinical practice, but low response to immune therapies remains a thorny issue. Oncolytic viruses (OVs) are considered promising for cancer treatment because they can selectively target and destroy tumor cells followed by spreading to nearby tumor tissues for a new round of infection. Immunogenic cell death (ICD), which is the major mechanism of OVs' anticancer effects, is induced by endoplasmic reticulum stress and reactive oxygen species overload after virus infection. Subsequent release of specific damage-associated molecular patterns (DAMPs) from different types of tumor cells can transform the tumor microenvironment from "cold" to "hot". In this paper, we broadly define ICD as those types of cell death that is immunogenic, and describe their signaling pathways respectively. Focusing on ICD, we also elucidate the advantages and disadvantages of recent combination therapies and their future prospects.
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Muerte Celular Inmunogénica , Inmunoterapia , Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Viroterapia Oncolítica/métodos , Humanos , Muerte Celular Inmunogénica/efectos de los fármacos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Animales , Virus Oncolíticos/fisiología , Virus Oncolíticos/inmunología , Microambiente Tumoral/inmunología , Estrés del Retículo Endoplásmico/inmunología , Transducción de SeñalRESUMEN
Tartrolon D (TRL) is produced by Teredinibacter turnerae, a symbiotic cellulose-degrading bacteria in shipworm gills. Immunogenic cell death (ICD) induction contributes to a better and longer-lasting response to anticancer treatment. Tumor cells undergoing ICD trigger activation of the immune system, as a vaccine. AIMS: This study aimed to evaluate ICD induction by TRL. MAIN METHODS: Cell viability was evaluated by SRB assay. Cell stress, cell death, ICD features and antigen-presenting molecules were evaluated by flow cytometry and immunoblot. KEY FINDINGS: TRL showed antiproliferative activity on 7 tumor cell lines (L929, HCT 116, B16-F10, WM293A, SK-MEL-28, PC-3M, and MCF-7) and a non-tumor cell (HEK293A), with an inhibition concentration mean (IC50) ranging from 0.03 µM to 13 µM. Metastatic melanomas, SK-MEL-28, B16-F10, and WM293A, were more sensitive cell lines, with IC50 ranging from 0.07 to 1.2 µM. TRL induced apoptosis along with autophagy and endoplasmic reticulum stress and release of typical damage-associated molecular patterns (DAMPs) of ICD such calreticulin, ERp57, and HSP70 exposure, and HMGB1 release. Additionally, melanoma B16-F10 exposed to TRL increased expression of antigen-presenting molecules MHC II and CD1d and induced activation of splenocytes of C57BL/6 mice. SIGNIFICANCE: In spite of recent advances provided by target therapy and immunotherapy, advanced metastatic melanoma is incurable for more than half of patients. ICD inducers yield better and long-lasting responses to anticancer treatment. Our findings shed light on an anticancer candidate of marine origin that induces ICD in melanoma.
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Muerte Celular Inmunogénica , Melanoma , Humanos , Muerte Celular Inmunogénica/efectos de los fármacos , Línea Celular Tumoral , Melanoma/inmunología , Melanoma/patología , Melanoma/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Ratones , Autofagia/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HEK293 , Calreticulina/metabolismoRESUMEN
Prostate cancer presents as a challenging disease, as it is often characterized as an immunologically "cold" tumor, leading to suboptimal outcomes with current immunotherapeutic approaches in clinical settings. Photodynamic therapy (PDT) harnesses reactive oxygen species generated by photosensitizers (PSs) to disrupt the intracellular redox equilibrium. This process induces DNA damage in both the mitochondria and nucleus, activating the process of immunogenic cell death (ICD) and the cGAS-STING pathway. Ultimately, this cascade of events leads to the initiation of antitumor immune responses. Nevertheless, existing PSs face challenges, including suboptimal tumor targeting, aggregation-induced quenching, and insufficient oxygen levels in the tumor regions. To this end, a versatile bionic nanoplatform has been designed for the simultaneous delivery of the aggregation-induced emission PS TPAQ-Py-PF6 and paclitaxel (PTX). The cell membrane camouflage of the nanoplatform leads to its remarkable abilities in tumor targeting and cellular internalization. Upon laser irradiation, the utilization of TPAQ-Py-PF6 in conjunction with PTX showcases a notable and enhanced synergistic antitumor impact. Additionally, the nanoplatform has the capability of initiating the cGAS-STING pathway, leading to the generation of cytokines. The presence of damage-associated molecular patterns induced by ICD collaborates with these aforementioned cytokines lead to the recruitment and facilitation of dendritic cell maturation. Consequently, this elicits a systemic immune response against tumors. In summary, this promising strategy highlights the use of a multifunctional biomimetic nanoplatform, combining chemotherapy, PDT, and immunotherapy to enhance the effectiveness of antitumor treatment.
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Muerte Celular Inmunogénica , Inmunoterapia , Proteínas de la Membrana , Nucleotidiltransferasas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Neoplasias de la Próstata , Humanos , Nucleotidiltransferasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/patología , Muerte Celular Inmunogénica/efectos de los fármacos , Muerte Celular Inmunogénica/efectos de la radiación , Proteínas de la Membrana/metabolismo , Masculino , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Ratones , Paclitaxel/química , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Porfirinas/química , Porfirinas/farmacologíaRESUMEN
Ferroptosis is a unique type of cell death, characterized by its reliance on iron dependency and lipid peroxidation (LPO). Consequently, small-molecule ferroptosis modulators have garnered substantial interest as a promising avenue for cancer therapy. Herein, we explored the ferroptosis sensitivity of epigenetic modulators and found that the antiproliferative effects of class I histone deacetylase (HDAC) inhibitors are significantly reliant on ferroptosis. Subsequently, we developed a novel series of HDAC inhibitors, identifying HL-5s with robust inhibitory activity against class I HDACs, particularly HDAC1. Notably, HL-5s induces ferroptosis by augmenting LPO production. Mechanistically, HL-5s increased the YB-1 acetylation and inhibited the Nrf2/HO-1 signaling pathway. Furthermore, HL-5s not only significantly suppresses tumor growth in the PC-9 xenograft model but also remodels the tumor microenvironment in the LLC allograft model. Our study has unveiled that class I HDAC inhibitors can exert antitumor effects by triggering ferroptosis, and HL-5s may serve as a promising candidate for future cancer treatment.
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Antineoplásicos , Bencimidazoles , Ferroptosis , Inhibidores de Histona Desacetilasas , Muerte Celular Inmunogénica , Ferroptosis/efectos de los fármacos , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/síntesis química , Animales , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Bencimidazoles/farmacología , Bencimidazoles/química , Muerte Celular Inmunogénica/efectos de los fármacos , Histona Desacetilasas/metabolismo , Línea Celular Tumoral , Relación Estructura-Actividad , Descubrimiento de Drogas , Proliferación Celular/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Enhanced glucose metabolism has been reported in many cancers. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme involved in the pentose phosphate pathway, which maintains NADPH levels and protects cells from oxidative damage. We recently found that low G6PD expression correlates with active tumor immunity. However, the mechanism involving G6PD and tumor immunity remained unclear. METHODS: We conducted in vitro studies using G6PD-knocked down malignant melanoma cells, pathway analysis using the GEO dataset, in vivo studies in combination with immune checkpoint inhibitors (ICIs) using a mouse melanoma model, and prognostic analysis in 42 melanoma patients and 30 lung cancer patients who were treated with ICIs. RESULTS: Inhibition of G6PD, both chemically and genetically, has been shown to decrease the production of NADPH and reduce their oxidative stress tolerance. This leads to cell death, which is accompanied by the release of high mobility group box 1 and the translocation of calreticulin to the plasma membrane. These findings suggested that inhibiting G6PD can induce immunogenic cell death. In experiments with C57BL/6 mice transplanted with G6PD-knockdown B16 melanoma cells and treated with anti-PD-L1 antibody, a significant reduction in tumor size was observed. Interestingly, inhibiting G6PD in only a part of the lesions increased the sensitivity of other lesions to ICI. Additionally, out of 42 melanoma patients and 30 lung cancer patients treated with ICIs, those with low G6PD expression had a better prognosis than those with high G6PD expression (p=0.0473; melanoma, p=0.0287; lung cancer). CONCLUSION: G6PD inhibition is a potent therapeutic strategy that triggers immunogenic cell death in tumors, significantly augmenting the efficacy of immunotherapies.
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Glucosafosfato Deshidrogenasa , Muerte Celular Inmunogénica , Inmunoterapia , Glucosafosfato Deshidrogenasa/metabolismo , Glucosafosfato Deshidrogenasa/antagonistas & inhibidores , Animales , Humanos , Ratones , Inmunoterapia/métodos , Muerte Celular Inmunogénica/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Femenino , Ratones Endogámicos C57BL , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Línea Celular Tumoral , Masculino , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Melanoma/patologíaRESUMEN
Here we report a brand-new bioactive polymer featuring sulfonium moieties that exhibits the capability of inducing immunogenic cell death (ICD) for anticancer therapy. The optimized polysulfonium presents a wide spectrum of potent anticancer activity and remarkable selectivity. In-depth mechanistic studies reveal that the polymer exerts its cytotoxic effects on cancer cells through a membrane-disrupting mechanism. This further initiates the release of a plethora of damage-associated molecular patterns, effectively triggering ICD and resulting in systemic anticancer immune responses. Notably, the compound demonstrated significant efficacy in suppressing tumor growth in the B16-F10 melanoma tumor model. Furthermore, it exhibits robust immune memory effects, effectively suppressing tumor recurrence and metastasis in both the rechallenge model and the lung metastatic tumor model. To the best of our knowledge, the study represents the pioneering exportation of cationic polysulfoniums, showcasing not only their remarkable safety and efficacy against primary tumors but also their unique ability in activating long-term immune memory.
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Antineoplásicos , Muerte Celular Inmunogénica , Polímeros , Animales , Muerte Celular Inmunogénica/efectos de los fármacos , Ratones , Humanos , Línea Celular Tumoral , Polímeros/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Compuestos de Sulfonio/química , Compuestos de Sulfonio/farmacología , Compuestos de Sulfonio/uso terapéutico , Melanoma Experimental/inmunología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patologíaRESUMEN
The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival. In this study, we examine the biological consequences of disrupting the ERK-MYD88 interaction through the ERK D-recruitment site (DRS), while preserving ERK's kinase activity. Our results indicate that EI-52, a small-molecule benzimidazole targeting ERK-MYD88 interaction induces an HRI-mediated integrated stress response (ISR), resulting in immunogenic apoptosis specific to cancer cells. Additionally, EI-52 exhibits anti-tumor efficacy in patient-derived tumors and induces an anti-tumor T cell response in mice in vivo. These findings suggest that inhibiting the ERK-MYD88 interaction may be a promising therapeutic approach in cancer treatment.
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Bencimidazoles , Quinasas MAP Reguladas por Señal Extracelular , Factor 88 de Diferenciación Mieloide , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Humanos , Animales , Ratones , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Línea Celular Tumoral , Bencimidazoles/farmacología , Apoptosis/efectos de los fármacos , Muerte Celular Inmunogénica/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Femenino , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
The field of oncology has transformed in recent years, with treatments shifting from traditional surgical resection and radiation therapy to more diverse and customized approaches, one of which is immunotherapy. ICD (immunogenic cell death) belongs to a class of regulatory cell death modalities that reactivate the immune response by facilitating the interaction between apoptotic cells and immune cells and releasing specific signaling molecules, and DAMPs (damage-associated molecular patterns). The inducers of ICD can elevate the expression of specific proteins to optimize the TME (tumor microenvironment). The use of nanotechnology has shown its unique potential. Nanomaterials, due to their tunability, targeting, and biocompatibility, have become powerful tools for drug delivery, immunomodulators, etc., and have shown significant efficacy in clinical trials. In particular, these nanomaterials can effectively activate the ICD, trigger a potent anti-tumor immune response, and maintain long-term tumor suppression. Different types of nanomaterials, such as biological cell membrane-modified nanoparticles, self-assembled nanostructures, metallic nanoparticles, mesoporous materials, and hydrogels, play their respective roles in ICD induction due to their unique structures and mechanisms of action. Therefore, this review will explore the latest advances in the application of these common nanomaterials in tumor ICD induction and discuss how they can provide new strategies and tools for cancer therapy. By gaining a deeper understanding of the mechanism of action of these nanomaterials, researchers can develop more precise and effective therapeutic approaches to improve the prognosis and quality of life of cancer patients. Moreover, these strategies hold the promise to overcome resistance to conventional therapies, minimize side effects, and lead to more personalized treatment regimens, ultimately benefiting cancer treatment.
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Muerte Celular Inmunogénica , Inmunoterapia , Nanoestructuras , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Muerte Celular Inmunogénica/efectos de los fármacos , Nanoestructuras/uso terapéutico , Nanoestructuras/química , Animales , Inmunoterapia/métodos , Microambiente Tumoral/inmunologíaRESUMEN
Anticancer chemo-immunotherapy has gained considerable attention across various scientific domains as a prospective approach for the comprehensive eradication of malignant tumors. Recent research has particularly been focused on traditional anthracycline chemo drugs, such as doxorubicin and mitoxantrone. These compounds trigger apoptosis in tumor cells and evoke immunogenic cell death (ICD). ICD is a pivotal initiator of the cancer-immunity cycle by facilitating the release of damage-associated molecular patterns (DAMPs). The resultant DAMPs released from cancer cells effectively activate the immune system, resulting in an increase in tumor-infiltrating T cells. In this study, we have innovated a co-delivery strategy involving folate-modified liposomes to deliver doxorubicin and monophosphoryl lipid A (MPLA) simultaneously to tumor tissue. The engineered liposomes exploit the overexpression of folate receptors within the tumor tissues. Delivered doxorubicin initiates ICD at the tumor cells, further enhancing the immunogenic stimulus. Additionally, MPLA helps T cell priming by activating antigen-presenting cells. This intricate interplay culminates in a synergistic effect, ultimately resulting in an augmented and potentiated anticancer chemo-immunotherapeutic liposomal treatment.
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Doxorrubicina , Muerte Celular Inmunogénica , Inmunoterapia , Lípido A , Liposomas , Receptor Toll-Like 4 , Liposomas/química , Doxorrubicina/farmacología , Doxorrubicina/química , Animales , Muerte Celular Inmunogénica/efectos de los fármacos , Humanos , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/metabolismo , Ratones , Lípido A/análogos & derivados , Lípido A/química , Lípido A/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/terapia , Línea Celular Tumoral , Femenino , Antineoplásicos/química , Antineoplásicos/farmacología , Ácido Fólico/químicaRESUMEN
The utilization of traditional therapies (TTS), such as chemotherapy, reactive oxygen species-based therapy, and thermotherapy, to induce immunogenic cell death (ICD) in tumor cells has emerged as a promising strategy for the activation of the antitumor immune response. However, the limited effectiveness of most TTS in inducing the ICD effect of tumors hinders their applications in combination with immunotherapy. To address this challenge, various intelligent strategies have been proposed to strengthen the immune activation effect of these TTS, and then achieve synergistic antitumor efficacy with immunotherapy. These strategies primarily focus on augmenting the tumor ICD effect or facilitating the antigen (released by the ICD tumor cells) presentation process during TTS, and they are systematically summarized in this review. Finally, the existing bottlenecks and prospects of TTS in the application of tumor immune regulation are also discussed.
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Inmunoterapia , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Animales , Muerte Celular Inmunogénica/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Immunogenic cell death (ICD) holds the potential for in situ tumor vaccination while concurrently eradicating tumors and stimulating adaptive immunity. Most ICD inducers, however, elicit insufficient immune responses due to negative feedback against ICD biomarkers, limited infiltration of antitumoral immune cells, and the immunosuppressive tumor micro-environment (TME). Recent findings highlight the pivotal roles of stimulators of interferon gene (STING) activation, particularly in stimulating antigen-presenting cells (APCs) and TME reprogramming, addressing ICD limitations. Herein, we introduced 'tumor phagocytosis-driven STING activation', which involves the activation of STING in APCs during the recognition of ICD-induced cancer cells. We developed a polypeptide-based nanocarrier encapsulating both doxorubicin (DOX) and diABZI STING agonist 3 (dSA3) to facilitate this hypothesis in vitro and in vivo. After systemic administration, nanoparticles predominantly accumulated in tumor tissue and significantly enhanced anticancer efficacy by activating tumor phagocytosis-driven STING activation in MC38 and TC1 tumor models. Immunological activation of APCs occurred within 12 h, subsequently leading to the activation of T cells within 7 days, observed in both the TME and spleen. Furthermore, surface modification of nanoparticles with cyclic RGD (cRGD) moieties, which actively target integrin αvß3, enhances tumor accumulation and eradication, thereby verifying the establishment of systemic immune memory. Collectively, this study proposes the concept of tumor phagocytosis-driven STING activation and its effectiveness in generating short-term and long-term immune responses.
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Doxorrubicina , Proteínas de la Membrana , Ratones Endogámicos C57BL , Fagocitosis , Microambiente Tumoral , Animales , Proteínas de la Membrana/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Fagocitosis/efectos de los fármacos , Doxorrubicina/administración & dosificación , Femenino , Nanopartículas/administración & dosificación , Nanopartículas/química , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Ratones , Muerte Celular Inmunogénica/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/efectos de los fármacos , Antibióticos Antineoplásicos/administración & dosificación , Humanos , Péptidos/administración & dosificación , Péptidos/químicaRESUMEN
Despite impressive advances in immune checkpoint blockade therapy, its efficacy as a standalone treatment remains limited. The influence of chemotherapeutic agents on tumor immunotherapy has progressively come to light in recent years, positioning them as promising contenders in the realm of combination therapy options for tumor immunotherapy. Herein, we present the rational design, synthesis, and biological evaluation of the first example of a Co(III) prodrug (Co2) capable of eliciting a localized cytotoxic effect while simultaneously inducing a systemic immune response via type II immunogenic cell death (ICD). To enhance its pharmacological properties, a glutathione-sensitive polymer was synthesized, and Co2 was encapsulated into polymeric nanoparticles (NP-Co2) to improve efficacy. Furthermore, NP-Co2 activates the GRP78/p-PERK/p-eIF2α/CHOP pathway, thereby inducing ICD in cancer cells. This facilitates the transformation of "cold tumors" into "hot tumors" and augments the effectiveness of the PD-1 monoclonal antibody (αPD-1). In essence, this nanomedicine, utilizing Co(III) prodrugs to induce ICD, provides a promising strategy to enhance chemotherapy and αPD-1 antibody-mediated cancer immunotherapy.
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Cobalto , Chaperón BiP del Retículo Endoplásmico , Muerte Celular Inmunogénica , Inmunoterapia , Nanomedicina , Profármacos , Profármacos/administración & dosificación , Profármacos/química , Profármacos/farmacología , Profármacos/uso terapéutico , Cobalto/química , Cobalto/administración & dosificación , Animales , Inmunoterapia/métodos , Muerte Celular Inmunogénica/efectos de los fármacos , Humanos , Nanomedicina/métodos , Línea Celular Tumoral , Nanopartículas/administración & dosificación , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Ratones Endogámicos C57BL , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Ratones , Femenino , Polímeros/química , Polímeros/administración & dosificación , Ratones Endogámicos BALB CRESUMEN
Introduction: Current therapeutic strategies, including immune checkpoint blockade (ICB), exhibit limited efficacy in treating hepatocellular carcinoma (HCC). Nanoparticles, particularly those that can accumulate specifically within tumors and be activated by sonodynamic therapy (SDT), can induce immunogenic cell death (ICD); however, ICD alone has not achieved satisfactory therapeutic effectiveness. This study investigates whether combining ICB with ICD induced by nanoparticle-mediated SDT could enhance anti-tumor immunity and inhibit HCC growth. Methods: We developed an iron-based micelle nanodelivery system encapsulating the Near-Infrared Dye IR-780, which was surface-modified with a cyclic tripeptide composed of arginine-glycine-aspartic acid (cRGD). This led to the synthesis of targeted IR780@FOM-cRGD nanoparticles. These nanoparticles were specifically engineered to kill tumor cells under sonication, activate immunogenic cell death (ICD), and be used in conjunction with immune checkpoint blockade (ICB) for the treatment of hepatocellular carcinoma (HCC). Results: The synthesized IR780@FOM-cRGD nanoparticles had an average diameter of 28.23±1.750 nm and a Zeta potential of -23.95±1.926. Confocal microscopy demonstrated that IR780@FOM-cRGD could target HCC cells while minimizing toxicity to healthy cells. Upon sonodynamic activation, these nanoparticles consumed significant amounts of oxygen and generated substantial reactive oxygen species (ROS), effectively killing tumor cells and inhibiting the proliferation, invasion, and migration of H22 cells. Hemolysis assays confirmed the in vivo safety of the nanoparticles, and in vivo fluorescence imaging revealed significant accumulation in tumor tissues. Mouse model experiments showed that combining ICB(which induced by Anti-PD-L1) with ICD (which induced by IR780@FOM-cRGD), could effectively activated anti-tumor immunity and suppressed tumor growth. Discussion: This study highlights the potential of IR780@FOM-cRGD nanoparticles to facilitate tumor eradication and immune activation when used in conjunction with Anti-PD-L1 therapy. This combination represents a non-invasive, efficient, and targeted approach for the treatment of hepatocellular carcinoma (HCC). By integrating sonodynamic therapy with immunotherapy, this strategy promises to substantially improve the effectiveness of traditional treatments in combating HCC, offering new avenues for clinical application and therapeutic innovation.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animales , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/inmunología , Ratones , Nanopartículas/química , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/inmunología , Línea Celular Tumoral , Antígeno B7-H1/inmunología , Humanos , Indoles/química , Indoles/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/química , Terapia por Ultrasonido/métodos , Oligopéptidos/química , Oligopéptidos/farmacología , Muerte Celular Inmunogénica/efectos de los fármacos , Micelas , Terapia Combinada/métodos , Ratones Endogámicos BALB C , Inmunoterapia/métodosRESUMEN
BACKGROUND: In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. METHODS: We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. RESULTS: HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.
Asunto(s)
Muerte Celular Inmunogénica , Proteínas de la Membrana , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/inmunología , Animales , Humanos , Muerte Celular Inmunogénica/efectos de los fármacos , Femenino , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Línea Celular Tumoral , Ratones Endogámicos BALB C , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismoRESUMEN
microRNAs (miRNAs) are small, non-coding RNAs that regulate expression of multiple genes. MiR-193a-3p functions as a tumor suppressor in many cancer types, but its effect on inducing specific anti-tumor immune responses is unclear. Therefore, we examined the effect of our lipid nanoparticle (LNP) formulated, chemically modified, synthetic miR-193a-3p mimic (INT-1B3) on anti-tumor immunity. INT-1B3 inhibited distant tumor metastasis and significantly prolonged survival. INT-1B3-treated animals were fully protected against challenge with autologous tumor cells even in absence of treatment indicating long-term immunization. Protection against autologous tumor cell challenge was hampered upon T cell depletion and adoptive T cell transfer abrogated tumor growth. Transfection of tumor cells with our miR-193a-3p mimic (1B3) resulted in tumor cell death and apoptosis accompanied by increased expression of DAMPs. Co-culture of 1B3-transfected tumor cells and immature DC led to DC maturation and these mature DC were able to stimulate production of type 1 cytokines by CD4+ and CD8+ T cells. CD4-CD8- T cells also produced type 1 cytokines, even in response to 1B3-transfected tumor cells directly. Live cell imaging demonstrated PBMC-mediated cytotoxicity against 1B3-transfected tumor cells. These data demonstrate for the first time that miR-193a-3p induces long-term immunity against tumor development via modulation of the tumor microenvironment and induction of immunogenic cell death.
Asunto(s)
MicroARNs , Nanopartículas , Microambiente Tumoral , MicroARNs/genética , Animales , Microambiente Tumoral/inmunología , Ratones , Humanos , Nanopartículas/química , Muerte Celular Inmunogénica/efectos de los fármacos , Línea Celular Tumoral , Linfocitos T/inmunología , Linfocitos T/metabolismo , Apoptosis , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ratones Endogámicos C57BL , Inmunidad Celular , Linfocitos T CD8-positivos/inmunología , Femenino , Transfección , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/patología , Citocinas/metabolismo , LiposomasRESUMEN
BACKGROUND: Ovarian cancer (OC) has the highest fatality rate among all gynecological malignancies, necessitating the exploration of novel, efficient, and low-toxicity therapeutic strategies. Ferroptosis is a type of programmed cell death induced by iron-dependent lipid peroxidation and can potentially activate antitumor immunity. Developing highly effective ferroptosis inducers may improve OC prognosis. RESULTS: In this study, we developed an ultrasonically controllable two-dimensional (2D) piezoelectric nanoagonist (Bi2MoO6-MXene) to induce ferroptosis. A Schottky heterojunction between Bi2MoO6 (BMO) and MXene reduced the bandgap width by 0.44 eV, increased the carrier-separation efficiency, and decreased the recombination rate of electron-hole pairs under ultrasound stimulation. Therefore, the reactive oxygen species yield was enhanced. Under spatiotemporal ultrasound excitation, BMO-MXene effectively inhibited OC proliferation by more than 90%, induced lipid peroxidation, decreased mitochondrial-membrane potential, and inactivated the glutathione peroxidase and cystathionine transporter protein system, thereby causing ferroptosis in tumor cells. Ferroptosis in OC cells further activated immunogenic cell death, facilitating dendritic cell maturation and stimulating antitumor immunity. CONCLUSION: We have succeeded in developing a highly potent ferroptosis inducer (BMO-MXene), capable of inhibiting OC progression through the sonodynamic-ferroptosis-immunogenic cell death pathway.
Asunto(s)
Ferroptosis , Muerte Celular Inmunogénica , Neoplasias Ováricas , Ferroptosis/efectos de los fármacos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Humanos , Animales , Línea Celular Tumoral , Muerte Celular Inmunogénica/efectos de los fármacos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Bismuto/farmacología , Bismuto/químicaRESUMEN
Immunogenic cell death (ICD) can activate adaptive immune response in the host with normal immune system. Some synthetic chemotherapeutic drugs and natural compounds have shown promising results in cancer treatment by triggering the release of damage-associated molecules (DAMPs) to trigger ICD. However, most chemotherapeutic drugs exhibit non-selective cytotoxicity and may also induce and promote metastasis, thereby significantly reducing their clinical efficacy. Among the natural compounds that can induce ICD, plant-derived compounds account for the largest proportion, which are of increasing value in the treatment of cancer. Understanding which plant-derived natural compounds can induce ICD and how they induce ICD is crucial for developing strategies to improve chemotherapy outcomes. In this review, we focus on the recent findings regarding plant-derived natural compounds that induce ICD according to the classification of flavonoids, alkaloids, glycosides, terpenoids and discuss the potential mechanisms including endoplasmic reticulum (ER) stress, DNA damage, apoptosis, necroptosis autophagy, ferroptosis. In addition, plant-derived natural compounds that can enhance the ICD induction ability of conventional therapies for cancer treatment is also elaborated. The rational use of plant-derived natural compounds to induce ICD is helpful for the development of new cancer treatment methods.
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Muerte Celular Inmunogénica , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Muerte Celular Inmunogénica/efectos de los fármacos , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Daño del ADN/efectos de los fármacosRESUMEN
BACKGROUND: Chimeric antigen receptor natural killer (CAR-NK) therapy holds great promise for treating hematologic tumors, but its efficacy in solid tumors is limited owing to the lack of suitable targets and poor infiltration of engineered NK cells. Here, we explore whether immunogenic cell death (ICD) marker ERp57 translocated from endoplasmic reticulum to cell surface after drug treatment could be used as a target for CAR-NK therapy. METHODS: To target ERp57, a VHH phage display library was used for screening ERp57-targeted nanobodies (Nbs). A candidate Nb with high binding affinity to both human and mouse ERp57 was used for constructing CAR-NK cells. Various in vitro and in vivo studies were performed to assess the antitumor efficacy of the constructed CAR-NK cells. RESULTS: We demonstrate that the translocation of ERp57 can not only be induced by low-dose oxaliplatin (OXP) treatment but also is spontaneously expressed on the surface of various types of tumor cell lines. Our results show that G6-CAR-NK92 cells can effectively kill various tumor cell lines in vitro on which ERp57 is induced or intrinsically expressed, and also exhibit potent antitumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the antitumor activity of G6-CAR-NK92 cells is synergistically enhanced by the low-dose ICD-inducible drug OXP. CONCLUSION: Collectively, our findings suggest that ERp57 can be leveraged as a new tumor antigen for CAR-NK targeting, and the resultant CAR-NK cells have the potential to be applied as a broad-spectrum immune cell therapy for various cancers by combining with ICD inducer drugs.