Induction Of Immunogenic Cell Death Research Articles

Tumor phagocytosis-driven STING activation invigorates antitumor immunity and reprograms the tumor micro-environment

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 αvβ3, 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.

Doxorubicin-induced Immunogenic Cell Death Impairs Tumor Progression and Distant Metastasis in a 4T1 Breast Cancer Tumor Model.

Cancer is an individual disease and its formation and development are specific to each host. Conventional treatments are ineffective in complex cases, such as metastasis, and have severe adverse side effects. New strategies are needed to address the problem, and the use of immunogenic cell death (ICD) as a trigger or booster of the immune system through the exposure of damage-associated molecular patterns, along with tumor antigens, by cancerous cells is presented as an immunization approach in this work. For this purpose, 4T1 cells were exposed to doxorubicin (DOX) for 24 hours and then, these cells undergoing ICD were subcutaneously administered to mice. The ICD induction by DOX on 4T1 was assessed by flow cytometry and image analysis. This immunization process was performed three times and after the last administration, the immunized mice were challenged with a subcutaneous xenograft of live cancer cells. The results demonstrate that the mice immunized with cells undergoing ICD after exposure to DOX presented no primary tumor or indications of distant metastatic lesion development. In summary, our findings indicate that the immunization process utilizing ICD is indeed efficacious in managing this aggressive form of pre-clinical breast cancer.

Fucoidan based Ce6-chloroquine self-assembled hydrogel as in situ vaccines to enhance tumor immunotherapy by autophagy inhibition and macrophage polarization

Tumor vaccines have become a promising approach for cancer treatment by triggering antigen-specific responses against tumors. However, autophagy and immunosuppressive tumor microenvironment (TME) reduce antigen exposure and immunogenicity, which limit the effect of tumor vaccines. Here, we develop fucoidan (Fuc) based chlorin e6 (Ce6)-chloroquine (CQ) self-assembly hydrogels (CCFG) as in situ vaccines. Ce6 triggers immune response in situ by photodynamic therapy (PDT) induced immunogenic cell death (ICD) effect, which is further enhanced by macrophage polarization of Fuc and autophagy inhibition of CQ. In vivo studies show that CCFG effectively enhances antigen presentation under laser irradiation, which induces a powerful in situ vaccine effect and significantly inhibits tumor metastasis and recurrence. Our study provides a novel approach for enhancing tumor immunotherapy and inhibiting tumor recurrence and metastasis.

Injectable thermosensitive hydrogels loaded with irradiated tumor cell-derived microparticles and manganese activate anti-tumor immunity

Immunosuppressive tumor microenvironment and inadequate activation of the innate immune system are important reasons for the failure of systemic anti-tumor immunotherapy. Irradiated tumor cell-derived microparticles (RMPs) can induce immunogenic cell death (ICD) of tumor cells and inhibit the M2-like phenotype of tumor-associated macrophages (TAMs). The current study found that double-stranded DNA was enriched in RMPs, which combined with manganese ions (Mn2+), the natural activator of cGAS-STING signaling, and synergistically amplified cGAS-STING signaling cascade in antigen-presenting cells (APCs). On this basis, a polyamino acid thermosensitive hydrogel delivery system was designed to simultaneously load RMPs and Mn2+. The obtained RMPs@Mn2+ hydrogel exhibited thermosensitivity, biocompatibility and sustained release characteristics. The intratumoral injection of RMPs@Mn2+ slowly released RMPs and Mn2+, inducing ICD of tumor cells, continuously activating cGAS-STING signaling of APCs, reprograming TAMs to M1-like phenotype, and promoting the activation of dendritic cells in tumor draining lymph nodes. The full activation of innate immunity at the tumor site further promoted priming and tumor infiltration of T cells, leading to tumor regression. RMPs@Mn2+ combined with anti-PD-1 achieved strong anti-cancer efficacy in a refractory malignant ascites model, in which more than 50 % of mice with malignant ascites achieved complete regression and long-term immune memory.

Cascade piezocatalytic nanoprodrug for synergistic piezocatalytic therapy and sono-activated chemotherapy-augmented immunotherapy

Immune checkpoint blockade (ICB) has shown great promise in the management of various cancers. However, only a small percentage of patients profit from ICB therapy. Immunogenic cell death (ICD) has demonstrated its specific capability in reconstructing the tumor microenvironment (TME) and activating anti-tumor immunity. Herein, an ICD cascade enhancement based on BPTL nanoreactors is proposed to overcome the inadequate damage-associated molecular patterns of ICD inducers. BPTL nanoreactor is formed by incorporating the piezocatalytic BaTiO3 (T-BTO) nanoparticles and paclitaxel (PTX) prodrug that responds to reactive oxygen species (ROS) into liposome nanoparticles for synergistic piezocatalytic and sono-activated chemotherapy (SACT)-augmented immunotherapy. Ultrasound (US) irradiation of the designed BPTL initiates a superior piezodynamic effect and produces ROS by piezocatalytic therapy to trigger ICD. Subsequently, the generated ROS breaks up the thioketal bonds in BPTL, thereby leading to the on-demand release of PTX for SACT and augmented ICD activation. In vivo evaluation demonstrated that BTPL with US irradiation significantly eradicated primary and distant metastatic tumors and markedly prevented the lung metastasis. This nanoplatform combines US-triggered piezocatalytic therapy and SACT for ICD stimulation, providing a robust strategy for amplifying piezocatalytic effect-mediated immune response against tumors.

An unbiased lncRNAs dropout CRISPR-Cas9 screen reveals RP11-350G8.5 as a novel therapeutic target for Multiple Myeloma

Multiple Myeloma (MM) is an incurable malignancy characterised by altered expression of coding and non-coding genes promoting tumour growth and drug resistance. Although the crucial role of long non-coding RNAs (lncRNAs) in MM is clearly established, the function of the non-coding RNAome, which might allow the design of novel therapeutics, is largely unknown. We performed an unbiased CRISPR-Cas9 loss-of-function screen of 671 lncRNAs in MM cells and their Bortezomib (BZB)-resistant derivative. To rank functionally and clinically relevant candidates, we designed and used a bioinformatic prioritisation pipeline combining functional data from cellular screens with prognostic and transcriptional data from MM patients. With this approach, we unveiled and prioritised 8 onco-lncRNAs essential for MM cell fitness, associated with high expression and poor prognosis in MM patients. The previously uncharacterised RP11-350G8.5 emerged as the most promising target, irrespective of BZB resistance. We i) demonstrated the anti-tumoral effect obtained by RP11-350G8.5 inhibition in vitro and in vivo; ii) highlighted a modulation of the unfolded protein response and the induction of immunogenic cell death triggered by the RP11-350G8.5 knock-out, via RNA-sequencing and molecular studies; iii) characterised its cytoplasmic homing through RNA-FISH; iv) predicted its 2D structure and identified 2 G-quadruplex and 3 hairpin-forming regions by biophysical assays, including Thioflavin T, 1H-NMR and circular dichroism to pave the way to the development of novel targeted therapeutics. Overall we provided innovative insights about unexplored lncRNAs in MM and identified RP11-350G8.5 as an oncogenic target for treatment-naïve and BZB-resistant MM patients.

Zinc Coordination Lipid Nanoparticles Co-Delivering Calcium Peroxide and Chelating STING agonist for Enhanced Cancer Metalloimmunotherapy.

Metalloimmunotherapy has achieved great preclinical success against malignant tumors. Nonetheless, the limited immune cell infiltration and impaired immunogenicity within the tumor microenvironment (TME) significantly hinder its translation to clinical applications. In this study, a zinc coordination lipid nanoparticle is developed loaded with calcium peroxide hydrate (CaO2) nanoparticles and the STING agonist diABZI-2, which is termed A-CaO2-Zn-LNP. The release of Zn2+ from the A-CaO2-Zn-LNP and the calcium overload synergistically induced immunogenic cell death (ICD). In addition, CaO2 nanoparticles can consume H+ and release oxygen (O2) under acidic conditions. This treatment increased the pH and alleviated the hypoxia of the TME. Along with cGAS-STING activation by diABZI-2, A-CaO2-Zn-LNP ultimately results in enhanced anti-tumor systemic immunity and long-term immune memory via alleviating the immunosuppressive microenvironment. Taken together, A-CaO2-Zn-LNP offers a new nanoplatform that expands its application for cancer treatment by metalloimmunotheray.

Precise Regulation of Reactive Oxygen Species in Tumor Microenvironment for Alleviating Inhibitory Immunogenic Cell Death.

High level of C (ROS) within the tumor microenvironment (TME) not only damage tumor cells but also diminish the efficacy of immunogenic cell death (ICD) and the activity of tumor-infiltrating T lymphocytes, thereby limiting the effectiveness of immunotherapy. Therefore, precise modulation of ROS level is crucial to effectively eliminate tumor cells and activate ICD-induced immunotherapy. Here, an intelligent yolk shell nanoplatform (SPCCM) that features calcium carbonate shells capable of decomposing under acidic TME conditions, thereby releasing the natural antioxidant proanthocyanidins (PAs) and the photosensitizer Ce6 is designed. PAs scavenge ROS within tumors, extending the survival time of T lymphocytes, while Ce6, as an ICD inducer, generates high ROS concentrations upon laser irradiation, thus reaching the toxic threshold within tumor cells and inducing apoptosis. The resulting apoptotic cells serve as tumor-associated antigens, promoting dendritic cells (DCs) maturation, and activating ICD. By effectively neutralizing ROS in the TME, PAs sustainably reduce ROS level, thereby enhancing DCs activation and restoring antitumor immune cell activity suppressed by ROS (resulting in an eightfold increase in DCs activation). This study demonstrates effective synergistic effects between photodynamic therapy and immunotherapy by precisely modulating ROS level.

Biomimetic Tumor Cell Membrane‐Encapsulated Nanoparticles Combine NIR‐II Photothermal Therapy and Chemotherapy for Enhanced Immunotherapy in Triple‐Negative Breast Cancer

AbstractTo advance the understanding and potential treatment strategies for triple‐negative breast cancer (TNBC), particularly focusing on its high metastatic propensity and uncertain molecular targets, a biomimetic tumor cell membrane‐encapsulated nanodelivery system is developed for enhanced immunotherapy. This system is assembled with the second near‐infrared (NIR‐II) photothermal agent, chemotherapeutic drug, and programmed death‐ligand 1 (PD‐L1) inhibitors camouflaged by TNBC cell membranes. An NIR‐II Ag2S quantum dots (QDs) is introduced for not only realizing pronounced imaging‐guided photothermal therapy (PTT), but also co‐activating immunogenic cell death (ICD) with chemotherapy. Homologous targeting and camouflage properties endowed the nanodelivery system with excellent biocompatibility and efficient delivery ability to the tumor site, demonstrating excellent synergistic therapeutic efficacy. The release of damage‐associated molecular patterns (DAMP) marked the induction of ICD, crucial for reshaping the immune microenvironment. Further integration of α‐PD‐L1 achieved a 56.5% immune checkpoint inhibition rate, synergistically amplifying immune response to ultimately activate key cytokines, thereby achieving pronounced anti‐tumor immunotherapy effects. Notably, this approach realized a considerable reduction of metastatic nodules by 51.2% in the TNBC lung metastasis model. The proposed nanodelivery system extended tumor remission and effectively reduced lung metastasis, paving the way for a reliable and promising approach in TNBC immunotherapy.

Tartrolon D induces immunogenic cell death in melanoma

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. AimsThis study aimed to evaluate ICD induction by TRL. Main methodsCell viability was evaluated by SRB assay. Cell stress, cell death, ICD features and antigen-presenting molecules were evaluated by flow cytometry and immunoblot. Key findingsTRL 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. SignificanceIn 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.

Modulating glucose metabolism and relieving hypoxia for enhanced Chemo/Photoimmunotherapy with photosensitizing enzymatic nanodrugs

Photoimmunotherapy by photodynamic therapy (PDT) induces immunogenic cell death (ICD), providing anti-tumor treatment in a safe, precise, minimally invasive way. However, PDT-demanded massive oxygen consumption exacerbates the hypoxia and creates an acidic tumor microenvironment (TME), leading to an anaerobic glycolysis and immune escape condition. In this study, a natural anti-tumor resveratrol (RSV) nanodrug was introduced via Fe3+ coordination flash nanoprecipitation (cFNP) for enhanced aqueous solubility to specifically downregulate the expression of Pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), reduce the glucose resorption and lactate production, tipping the cellular balance from anaerobic glycolysis to oxidative phosphorylation (OXPHOS). RSV enhances the immunotherapy by suppressing tumor cell glycolysis and active the apoptotic cell death as well. Meanwhile, structural linker Fe3+ could also effectively catalyze the endogenous H2O2 in the tumor cells to generate oxygen in situ and relieve the hypoxic microenvironment, enhancing the PDT efficacy. This strategy can effectively modulate glucose metabolism and relieve hypoxia by Fe/RSV/ZnPc nanodrugs to greatly promote the synergistic chemo/photoimmunotherapy, providing a promising strategy to tackle the formulation of multi-therapeutic nanodrugs for clinical cancer therapy.

Bio-orthogonal click chemistry strategy for PD-L1-targeted imaging and pyroptosis-mediated chemo-immunotherapy of triple-negative breast cancer

BackgroundThe combination of programmed cell death ligand-1 (PD-L1) immune checkpoint blockade (ICB) and immunogenic cell death (ICD)-inducing chemotherapy has shown promise in cancer immunotherapy. However, triple-negative breast cancer (TNBC) patients undergoing this treatment often face obstacles such as systemic toxicity and low response rates, primarily attributed to the immunosuppressive tumor microenvironment (TME).Methods and resultsIn this study, PD-L1-targeted theranostic systems were developed utilizing anti-PD-L1 peptide (APP) conjugated with a bio-orthogonal click chemistry group. Initially, TNBC was treated with azide-modified sugar to introduce azide groups onto tumor cell surfaces through metabolic glycoengineering. A PD-L1-targeted probe was developed to evaluate the PD-L1 status of TNBC using magnetic resonance/near-infrared fluorescence imaging. Subsequently, an acidic pH-responsive prodrug was employed to enhance tumor accumulation via bio-orthogonal click chemistry, which enhances PD-L1-targeted ICB, the pH-responsive DOX release and induction of pyroptosis-mediated ICD of TNBC. Combined PD-L1-targeted chemo-immunotherapy effectively reversed the immune-tolerant TME and elicited robust tumor-specific immune responses, resulting in significant inhibition of tumor progression.ConclusionsOur study has successfully engineered a bio-orthogonal multifunctional theranostic system, which employs bio-orthogonal click chemistry in conjunction with a PD-L1 targeting strategy. This innovative approach has been demonstrated to exhibit significant promise for both the targeted imaging and therapeutic intervention of TNBC.Graphical abstract

Targeted Liposomal Co-delivery of an Immunogenic Cell Death Inducer and a Toll-Like Receptor 4 Agonist for Enhanced Cancer Chemo-immunotherapy.

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.

Nanomaterial-Mediated Delivery of MLKL Plasmids Sensitizes Tumors to Immunotherapy and Reduces Metastases.

Cancer immunotherapy has emerged as a promising approach for the induction of an antitumor response. While immunotherapy response rates are very high in some cancers, the efficacy against solid tumors remains limited caused by the presence of an immunosuppressive tumor microenvironment. Induction of immunogenic cell death (ICD) in the tumor can be used to boost immunotherapy response in solid cancers by eliciting the release of immune-stimulatory components. However, the delivery of components inducing ICD to tumor sites remains a challenge. Here, a novel delivery method is described for antitumor therapy based on MLKL (Mixed Lineage Kinase Domain-Like), a key mediator of necroptosis and inducer of ICD. A novel highly branched poly (β-amino ester)s (HPAEs) system is designed to efficiently deliver MLKL plasmid DNA to the tumor with consequent enhancement of immune antigen presentation for T cell responses in vitro, and improved antitumor response and prolonged survival in tumor-bearing mice. Combination of the therapy with anti-PD-1 treatment revealed significant changes in the composition of the tumor microenvironment, including increased infiltration of CD8+ T cells and tumor-associated lymphocytes. Overall, the HPAEs delivery system can enhance MLKL-based cancer immunotherapy and promote antitumor immune responses, providing a potential treatment to boost cancer immunotherapies.

NIR afterglow nanosystem for photodynamic therapy.

Within the milieu of immune dysfunction, reactive oxygen species (ROS) play a pivotal role in inducing immunogenic cell death (ICD), countering the dysregulated tumor microenvironment. However, the administration of ROS at indiscriminate dosages may provoke deleterious immune responses. Therefore, precise regulation of ROS production is crucial to achieve efficacious therapeutic outcomes. We engineered an innovative afterglow nanosystem which is capable of real-time monitoring of ROS levels. Our findings reveal that Ru/CYQ@CPPO exhibits a markedly enhanced and prolonged afterglow luminescence, coupled with superior singlet oxygen (O2) generation, compared to the commercially available indocyanine green (ICG). In vitro studies demonstrated that Ru/CYQ@CPPO exhibits remarkable efficacy in photodynamic therapy (PDT) under irradiation at a wavelength of 450 nm. Furthermore, a significant correlation (R 2 = 0.987) was observed between the intensity of afterglow luminescence and the rate of cancer cell inhibition.

Interference of ATP-Adenosine Axis by Engineered Biohybrid for Amplifying Immunogenic Cell Death-Mediated Antitumor Immunotherapy.

Immunogenic cell death (ICD) often results in the production and accumulation of adenosine (ADO), a byproduct that negatively impacts the therapeutic effect as well as facilitates tumor development and metastasis. Here, an innovative strategy is elaborately developed to effectively activate ICD while avoiding the generation of immunosuppressive adenosine. Specifically, ZIF-90, an ATP-responsive consumer, is synthesized as the core carrier to encapsulate AB680 (CD73 inhibitor) and then coated with an iron-polyphenol layer to prepare the ICD inducer (AZTF), which is further grafted onto prebiotic bacteria via the esterification reaction to obtain the engineered biohybrid (Bc@AZTF). Particularly, the designed Bc@AZTF can actively enrich in tumor sites and respond to the acidic tumor microenvironment to offload AZTF nanoparticles, which can consume intracellular ATP (iATP) content and simultaneously inhibit the ATP-adenosine axis to reduce the accumulation of adenosine, thereby alleviating adenosine-mediated immunosuppression and strikingly amplifying ICD effect. Importantly, the synergy of anti-PD-1 (αPD-1) with Bc@AZTF not only establishes a collaborative antitumor immune network to potentiate effective tumoricidal immunity but also activates long-lasting immune memory effects to manage tumor recurrence and rechallenge, presenting a new paradigm for ICD treatment combined with adenosine metabolism.

Impact of Genomic Mutation on Melanoma Immune Microenvironment and IFN-1 Pathway-Driven Therapeutic Responses.

The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors.

A pH-triggered N-oxide polyzwitterionic nano-drug loaded system for the anti-tumor immunity activation research

Triple negative breast cancer (TNBC) has the characteristics of low immune cell infiltration, high expression of tumor programmed death ligand 1 (PD-L1), and abundant cancer stem cells. Systemic toxicity of traditional chemotherapy drugs due to poor drug selectivity, and chemotherapy failure due to tumor drug resistance and other problems, so it is particularly important to find new cancer treatment strategies for TNBC with limited treatment options. Both the anti-tumor natural drugs curcumin and ginsenoside Rg3 can exert anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells, reducing PD-L1 expression, and reducing cancer stem cells. However, they have the disadvantages of poor water solubility, low bioavailability, and weak anti-tumor effect of single agents. We used vinyl ether bonds to link curcumin (Cur) with N-O type zwitterionic polymers and at the same time encapsulated ginsenoside Rg3 to obtain hyperbranched zwitterionic drug-loaded micelles OPDEA-PGED-5HA@Cur@Rg3 (PPH@CR) with pH response. In vitro cell experiments and in vivo animal experiments have proved that PPH@CR could not only promote the maturation of dendritic cells (DCs) and increase the CD4+ T cells and CD8+ T cells by inducing ICD in tumor cells but also reduce the expression of PD-L1 in tumor tissues, and reduce cancer stem cells and showed better anti-tumor effects and good biological safety compared with free double drugs, which is a promising cancer treatment strategy.

A Diketopyrrolopyrrole-Based All-in-One Nanoplatform for Self-Reinforcing Mild Photothermal Therapy Cascade Immunotherapy for Tumors.

Mild photothermal therapy (PTT) has attracted attention for effectively avoiding the severe side effects associated with high-temperature tumor ablation. However, its progress is hindered by the limited availability of high-performance photothermal agents (PTAs) and the thermoresistance of cancer cells induced by heat shock reactions. Herein, this work proposes a new strategy to expand the library of high-performance organic small-molecule PTAs and utilize it to construct a multifunctional nano-theranostic platform. By incorporating additional acceptors and appropriate π-bridges, a diketopyrrolopyrrole-based dye BDB is developed, which exhibits strong absorption and bright fluorescence emission in the near-infrared (NIR)region. Subsequently, BDB is co-coated with the heat shock protein (HSP) inhibitor tanespimycin (17-AAG) using the functional amphiphilic polymers DSPE-Hyd-PEG2000-cRGD to form an all-in-one nanoplatform BAG NPs. As a result, BAG NPs can precisely target tumor tissue, guide the treatment process in real-time through NIR-II fluorescence/photoacoustic/photothermal imaging, and release 17-AAG on demand to enhance mild PTT. Additionally, the mild PTThas been demonstrated to induce immunogenic cell death (ICD) and activate a systemic anti-tumor immune response, thereby suppressing both primary and distant tumors. Overall, this study presents a multifunctional nanoplatform designed for precise mild PTT combined with immunotherapy for effective tumor treatment.

Engineered bacteria-mediated augmentation of sialoglycan degradation strategy and immunogenic chemotherapy to boost effective cancer therapy

Sialic acid, as the new immunosuppressive molecule, is positively correlated with tumor progression, metastasis, and drug resistance. Although targeting desialylation strategy has promising implications for regulating immunosuppressive environment and sensitizing chemotherapy, delivery strategies that integrate the amplifying effects of desialylation and immunogenic chemotherapy are still unexplored. Here, we engineered an Escherichia coli Nissle 1917 hybrid (SSE@ZIF-90/Oxa) to integrate the co-delivery of sialidase and immunogenic cell death inducers which were expected to boost strong antitumor response. In the tumor-hypoxic environment, engineered SSE bacteria exert hypoxia-responsive sialidase expression and periodic lysis to release sialidase, disrupting the sialoglycan-mediated immune suppression. ZIF-90/Oxa was hybridized on the surface of SSE to further induce ICD effect to recruit more infiltration of immune cells. In melanoma models in male mice, this SSE@ZIF-90/Oxa facilitated the co-delivery of sialidase and Oxa both deeply penetrated into and across tumor, suppressed the tumor, and prolonged the survival time of mice, by markedly increasing mature DCs, TNF-α+ CD8+ T cells, and M1 macrophages, while reducing PD-1+CD8+ T cells and Tregs, indicating effective activation of anti-tumor immune cells. Thus, our study provides an intelligent biohybrid therapeutic platform for boosting the combined effect of desialylation-based immunotherapy and immunogenic chemotherapy.