Enhanced antitumor chemo-immunotherapy by local co-delivery of chemotherapeutics,immune checkpoint blocking antibody and IDO inhibitor using an injectable polypeptide hydrogel

The efficiency of antitumor immunotherapy is usually limited by the immunosuppressive tumor microenvironment (TME). In this study, we developed a chemo-immunotherapy strategy that is able to improve the immunosuppressive TME for enhancing the antitumor efficacy. The chemo-immunotherapy was achieved by the topical co-delivery of a chemotherapeutic drug, Doxorubicin (DOX), an immune checkpoint blocking antibody targeting programmed cell death protein 1 (aPD-1), and an indoleamine-2,3-dioxygenase (IDO) inhibitor, 1-methyl-d -tryptophan (d -1MT) by using a thermosensitive polypeptide hydrogel. It was revealed that the sustained DOX release from the hydrogel caused the immunogenic cell death (ICD) of B16F10 cells in vitro, and the tumor cell lysates subsequently promoted the activation of dendritic cells (DCs). After intratumoral injection into B16F10 melanoma-bearing mice, the DOX/aPD-1/D-1MT co-loaded hydrogel exhibited enhanced tumor inhibition efficacy and prolonged animal survival time, compared to the DOX/aPD-1/D-1MT mixed solution, DOX-loaded hydrogel or DOX/aPD-1 co-loaded hydrogel. The improvement of immunosuppressive TME and enhancement of antitumor immune response after the local chemo-immunotherapy were demonstrated by the augmented activation of DCs and increased infiltration of CD8⁺ and CD4⁺ T cells, as well as enhanced secretion of pro-inflammatory cytokines. Therefore, the hydrogel-based local chemo-immunotherapy system holds great potential for effective antitumor treatment.     

Applying nanotechnology to boost cancer immunotherapy by promoting immunogenic cell death

Tumor immunotherapy, especially immune checkpoint blockade(ICB), has revolutionized the cancer field.However, the limited response of tumors to immunotherapy is a major obstacle. Tumor immunogenic cell death(ICD) is a death mode of tumor cells that can promote tumor immunity. ICD can induce strong antitumor immune responses through the ectopic exposure of calreticulin on the plasma membrane surface and the release of the non-histone nuclear protein high-mobility group box 1(HMGB1), ATP, and inte...     

Catalytic immunotherapy-photothermal therapy combination for melanoma by ferroptosis-activating vaccine based on artificial nanoenzyme

Tumor cell vaccine is a promising approach for cancer therapy to activate tumor immune, which can be achieved by tumor cells immunogenic cell death (ICD), converting in situ tumors into endogenous vaccination strategy, and ferroptosis has been proved to induce ICD occurrence. Ferroptosis is triggered by artificial nanoenzyme copper telluride mimicking peroxidase and glutathione oxidase, based on which the ferroptosis-activating vaccine (termed as CM CTNPs@OVA) was designed and established for catalytic immunotherapy. Owing to photothermal effect of copper telluride, photothermal therapy (PTT) was combined for an intensive cancer therapeutic effect. CM CTNPs@OVA was composed of solid mesoporous copper telluride nanoparticles, ovalbumin (OVA) loaded in mesoporous, and melanoma cell membrane coating surface. In in vitro and in vivo investigations, CM CTNPs@OVA, with particle size of 113.7 ± 1.7 nm, was certified to release copper ions for ferroptosis initiation, and OVA directly maturated dendritic cell (DC) as exogenous antigens extracellularly. ICD was then induced by ferroptosis pathway and PTT to release damage-associated molecular patterns for DC maturation and subsequent T cells recruitment. CM CTNPs@OVA-treated melanoma with exited inhibition rate, proving that the strategy of catalytic immunotherapy-PTT combination by ferroptosis-activating vaccine possessed massive potential for melanoma therapy based on nanoenzyme copper telluride.     

Nanoparticle‐Mediated Immunogenic Cell Death Enables and Potentiates Cancer Immunotherapy

Cancer immunotherapies that train or stimulate the inherent immunological systems to recognize, attack, and eradicate tumor cells with minimal damage to healthy cells have demonstrated promising clinical responses in recent years. However, most of these immunotherapeutic strategies only benefit a small subset of patients and cause systemic autoimmune side effects in some patients. Immunogenic cell death (ICD)‐inducing modalities not only directly kill cancer cells but also induce antitumor immune responses against a broad spectrum of solid tumors. Such strategies for generating vaccine‐like functions could be used to stimulate a “cold” tumor microenvironment to become an immunogenic, “hot” tumor microenvironment, working in synergy with immunotherapies to increase patient response rates and lead to successful treatment outcomes. This Minireview will focus on nanoparticle‐based treatment modalities that can induce and enhance ICD to potentiate cancer immunotherapy.     

Metal-DNA Nanocomplexes Enhance Chemo-dynamic Therapy by Inhibiting Autophagy-Mediated Resistance

Chemo-dynamic therapy (CDT) based on the Fenton or Fenton-like reaction has emerged as a promising approach for cancer treatment. However, autophagy-mediated self-protection mechanisms of cancer cells pose a significant challenge to the efficacy of CDT. Herein, we developed metal-DNA nanocomplexes (DACs-Mn) to enhance CDT via DNAzyme inhibition of autophagy. Specifically, Mn-based catalyst in DACs-Mn was used to generate highly hydroxyl radicals (⋅OH) that kill cancer cells, while the ATG5 DNAzyme incorporated into DACs-Mn inhibited the expression of autophagy-associated proteins, thereby improving the efficacy of CDT. By disrupting the self-protective pathway of cells under severe oxidative stress, this novel approach of DACs-Mn was found to synergistically enhance CDT in both in vitro and in vivo models, effectively amplifying tumor-specific oxidative damage. Notably, the Metal-DNA nanocomplexes can also induce immunogenic cell death (ICD), thereby inhibiting tumor metastasis. Specifically, in a bilateral tumor model in mice, the combined approach of CDT and autophagy inhibition followed by immune checkpoint blockade therapy shown significant potential as a novel and effective treatment modality for primary and metastatic tumors.     

The Course of Immune Stimulation by Photodynamic Therapy: Bridging Fundamentals of Photochemically Induced Immunogenic Cell Death to the Enrichment of T‐Cell Repertoire

Photodynamic therapy (PDT) is a potentially immunogenic and FDA‐approved antitumor treatment modality that utilizes the spatiotemporal combination of a photosensitizer, light and oftentimes oxygen, to generate therapeutic cytotoxic molecules. Certain photosensitizers under specific conditions, including ones in clinical practice, have been shown to elicit an immune response following photoillumination. When localized within tumor tissue, photogenerated cytotoxic molecules can lead to immunogenic cell death (ICD) of tumor cells, which release damage‐associated molecular patterns and tumor‐specific antigens. Subsequently, the T‐lymphocyte (T cell)–mediated adaptive immune system can become activated. Activated T cells then disseminate into systemic circulation and can eliminate primary and metastatic tumors. In this review, we will detail the multistage cascade of events following PDT of solid tumors that ultimately lead to the activation of an antitumor immune response. More specifically, we connect the fundamentals of photochemically induced ICD with a proposition on potential mechanisms for PDT enhancement of the adaptive antitumor response. We postulate a hypothesis that during the course of the immune stimulation process, PDT also enriches the T‐cell repertoire with tumor‐reactive activated T cells, diversifying their tumor‐specific targets and eliciting a more expansive and rigorous antitumor response. The implications of such a process are likely to impact the outcomes of rational combinations with immune checkpoint blockade, warranting investigations into T‐cell diversity as a previously understudied and potentially transformative paradigm in antitumor photodynamic immunotherapy.     

Metalloimmunotherapy with Rhodium and Ruthenium Complexes: Targeting Tumor-Associated Macrophages

Tumor associated macrophages (TAMs) suppress the cancer immune response and are a key target for immunotherapy. The effects of ruthenium and rhodium complexes on TAMs have not been well characterized. To address this gap in the field, a panel of 22 dirhodium and ruthenium complexes were screened against three subtypes of macrophages, triple-negative breast cancer and normal breast tissue cells. Experiments were carried out in 2D and biomimetic 3D co-culture experiments with and without irradiation with blue light. Leads were identified with cell-type-specific toxicity toward macrophage subtypes, cancer cells, or both. Experiments with 3D spheroids revealed complexes that sensitized the tumor models to the chemotherapeutic doxorubicin. Cell surface exposure of calreticulin, a known facilitator of immunogenic cell death (ICD), was increased upon treatment, along with a concomitant reduction in the M2-subtype classifier arginase. Our findings lay a strong foundation for the future development of ruthenium- and rhodium-based chemotherapies targeting TAMs.     

Oxygen-Deficient Molybdenum Oxide Nanosensitizers for Ultrasound-Enhanced Cancer Metalloimmunotherapy

Oxygen-deficient molybdenum oxide (MoO_X) nanomaterials are prepared as novel nanosensitizers and TME-stimulants for ultrasound (US)-enhanced cancer metalloimmunotherapy. After PEGylation, MoO_X-PEG exhibits efficient capability for US-triggered reactive oxygen species (ROS) generation and glutathione (GSH) depletion. Under US irradiation, MoO_X-PEG generates a massive amount of ROS to induce cancer cell damage and immunogenic cell death (ICD), which can effectively suppress tumor growth. More importantly, MoO_X-PEG itself further stimulates the maturation of dendritic cells (DCs) and triggeres the activation of the cGAS-STING pathway to enhance the immunological effect. Due to the robust ICD induced by SDT and efficient DC maturation stimulated by MoO_X-PEG, the combination treatment of MoO_X-triggered SDT and aCTLA-4 further amplifies antitumor therapy, inhibits cancer metastases, and elicits robust immune responses to effectively defeat abscopal tumors.     

Endoplasmic reticulum targeted AIE bioprobe as a highly efficient inducer of immunogenic cell death

Focused oxidative stress of the specific organelles(e.g., endoplasmic reticulum(ER) and mitochondrion) of cancer cells can boost the immunogenic cell death(ICD) effect for cancer immunotherapy. Herein, an ER-targeted bioprobe with aggregationinduced emission(AIE) characteristics(TPE-PR-FFKDEL) was rationally designed and synthesized by integrating a new AIE photosensitizer with ER targeting peptide, which has been demonstrated to be able to efficiently induce ER oxidative stress to evoke ICD. Compared with the photosensitizer hypericin that is well-known as an ER-targeted ICD inducer, TPE-PR-FFKDEL can lead to more robust emission of immunostimulatory damage-associated molecular patterns such as surface-exposed calreticulin, ATP secretion, and high-mobility group protein B1(HMGB1) and heat shock protein 70(HSP 70) expression.Furthermore, a range of immune responses are activated to protect mice from the attack of cancer cells in vivo.     

2D graphene oxide-l-arginine-soybean lecithin nanogenerator for synergistic photothermal and NO gas therapy

Nitric oxide (NO) gas therapy has been regarded as a promising strategy for cancer treatment. However, its therapeutic efficiency is still unsatisfying due to the limitations of monotherapy. Previous preclinical and clinical studies have shown that combination therapy could significantly enhance therapeutic efficiency. Herein, a graphene oxide (GO)-l-arginine (l-Arg, a natural NO donor) hybrid nanogenerator is developed followed by surface functionalization of soybean lecithin (SL) for synergistic enhancement of cancer treatment through photothermal and gas therapy. The resultant GO-Arg-SL nanogenerator not only exhibited good biocompatibility and excellent endocytosis ability, but also exhibited excellent photothermal conversion capability and high sensitivity to release NO within tumor microenvironment via inducible NO synthase (iNOS) catalyzation. Moreover, the produced hyperthermia and intracellular NO could synergistically kill cancer cells both in vitro and in vivo. More importantly, this nanogenerator can efficiently eliminate tumor while inhibiting the tumor recurrence because of the immunogenic cell death (ICD) elicited by NIR laser-triggered hyperthermia and the immune response activation by massive NO generation. We envision that the GO-Arg-SL nanogenerator could provide a potential strategy for synergistic photothermal and gas therapy.     

Polymeric STING Pro-agonists for Tumor-Specific Sonodynamic Immunotherapy

The efficacy of combination immunotherapy has been limited by tumor specificity and immune-related adverse events (irAEs). Herein, we report the development of polymeric STING pro-agonists (PSPA), whose sono-immunotherapeutic efficacy is activated by sono-irradiation and elevated glutathione (GSH) within the tumor microenvironment (TME). PSPA is composed of sonosensitizers (semiconducting polymer) and STING agonists (MSA-2) via the GSH-activatable linkers. Under sono-irradiation, PSPA serves as a sonosensitizer to generate ¹O₂ and induce immunogenic cell death (ICD) of malignant tumor cells. Furthermore, MSA-2 is released specifically in tumor microenvironment with highly expressed GSH, minimizing off-target side effects. The activation of the STING pathway elevates the interferon-β level and synergizes with SDT to enhance the anti-tumor response. Therefore, this work proposes a universal approach for spatiotemporal regulation of cancer sono-immunotherapy.     

Tumour‐Targeted Drug Delivery with Mannose‐Functionalized Nanoparticles Self‐Assembled from Amphiphilic β‐Cyclodextrins

Multivalent mannose‐functionalized nanoparticles self‐assembled from amphiphilic β‐cyclodextrins (β‐CDs) facilitate the targeted delivery of anticancer drugs to specific cancer cells. Doxorubicin (DOX)‐loaded nanoparticles equipped with multivalent mannose target units were efficiently taken up via receptor‐mediated endocytosis by MDA‐MB‐231 breast cancer cells that overexpress the mannose receptor. Upon entering the cell, the intracellular pH causes the release of DOX, which triggers apoptosis. Targeting by multivalent mannose significantly improved the capability of DOX‐loaded nanoparticles to inhibit the growth of MDA‐MB‐231 cancer cells with minimal side effects in vivo. This targeted and controlled drug delivery system holds promise as a nanotherapeutic for cancer treatment.     

Sodium Bicarbonate Nanoparticles for Amplified Cancer Immunotherapy by Inducing Pyroptosis and Regulating Lactic Acid Metabolism

Although immunotherapy has a broad clinical application prospect, it is still hindered by low immune responses and immunosuppressive tumor microenvironment. Herein, a simple and drug-free inorganic nanomaterial, alkalescent sodium bicarbonate nanoparticles (NaHCO₃ NPs), is prepared via a fast microemulsion method for amplified cancer immunotherapy. The obtained alkalescent NaHCO₃ regulates lactic acid metabolism through acid-base neutralization so as to reverse the mildly acidic immunosuppressive tumor environment. Additionally, it can further release high amounts of Na⁺ ions inside tumor cells and induce a surge in intracellular osmolarity, and thus activate the pyroptosis pathway and immunogenic cell death (ICD), release damage-associated molecular patterns (DAMPs) and inflammatory factors, and improve immune responses. Collectively, NaHCO₃ NPs observably inhibit primary/distal tumor growth and tumor metastasis through acid neutralization remitted immunosuppression and pyroptosis induced immune activation, showing an enhanced antitumor immunity efficiency. This work provides a new paradigm for lactic acid metabolism and pyroptosis mediated tumor treatment, which has a potential for application in clinical tumor immunotherapy.     

Recent Progress in Boosted PDT Induced Immunogenic Cell Death for Tumor Immunotherapy

With the rapid development of materials science,photosensitive materials have been widely used in the field of immunogenic cell death(ICD),which was on account of the reactive oxygen species(ROS)generation by photosensitizer under light irradiation inducing cellular oxidative stress during the dying of cells.Considerable researches related to photodynamic therapy(PDT)induced ICD were conducted and exhibited brilliant performance in cancer immunotherapy.Herein,a variety of different strategies for PDT induced ICD have been summarized and discussed to provide researchers more inspiration for cancer immunotherapy.     

Perylene-Based Reactive Oxygen Species Supergenerator for Immunogenic Photochemotherapy against Hypoxic Tumors

Reactive oxygen species (ROS) can act as cytotoxic radicals to directly kill tumor cells and concurrently trigger immunogenic cell death (ICD) to efficiently achieve tumor therapy. Thus motivated, we herein present one perylene monoamide-based ROS supergenerator (PMIC-NC) that not only induces hypoxia-enhanced Type-I ROS burst aided by proton transients but also triggers Type-I/II ROS production by electron or energy transfer under near-infrared (NIR) light irradiation and also elicits a strong ICD effect. More interesting, the mitochondria- and lung-specific distribution of PMIC-NC also boosts the tumor therapeutic efficiency. As a result, PMIC-NC was employed for NIR-triggered photodynamic therapy, hypoxia-enhanced chemotherapy and also displayed robust immunogenicity for systemic tumor eradication. This work thus contributes one proof-of-concept demonstration of perylene as an integrated therapeutic platform for efficient immunogenic photochemotherapy against hypoxic tumors.     

Self-oxygenated co-assembled biomimetic nanoplatform for enhanced photodynamic therapy in hypoxic tumor

Photodynamic therapy (PDT) has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death (ICD) effects. However, the strategy is limited in the innate hypoxic tumor microenvironment. There are two key elements for the realization of enhanced PDT: specific cellular uptake and release of the photosensitizer in the tumor, and a sufficient amount of oxygen to ensure photodynamic efficiency. Herein, self-oxygenated biomimetic nanoparticles (CS@M NPs) co-assembled by photosensitizer prodrug (Ce6-S-S-LA) and squalene (SQ) were engineered. In the treatment of triple negative breast cancer (TNBC), the oxygen carried by SQ can be converted to reactive oxygen species (ROS). Meanwhile, glutathione (GSH) consumption during transformation from Ce6-S-S-LA to chlorin e6 (Ce6) avoided the depletion of ROS. The co-assembled (CS NPs) were encapsulated by homologous tumor cell membrane to improve the tumor targeting. The results showed that the ICD effect of CS@M NPs was confirmed by the significant release of calreticulin (CRT) and high mobility group protein B1 (HMGB1), and it significantly activated the immune system by inhibiting the hypoxia inducible factor-1alpha (HIF-1α)-CD39-CD73-adenosine a2a receptor (A2AR) pathway, which not only promoted the maturation of dendritic cells (DC) and the presentation of tumor specific antigens, but also induced effective immune infiltration of tumors. Overall, the integrated nanoplatform implements the concept of multiple advantages of tumor targeting, reactive drug release, and synergistic photodynamic therapy-immunotherapy, which can achieve nearly 90% tumor suppression rate in orthotopic TNBC models.     

Immunogenic Cell Death Inducing Metal Complexes for Cancer Therapy

Cancer is one of the deadliest diseases worldwide. Recent statistics have shown that metastases and tumor relapse are the leading causes of cancer-associated deaths. While traditional treatments are able to efficiently remove the primary tumor, secondary tumors remain poorly accessible. Capitalizing on this there is an urgent need for novel treatment modalities. Among the most promising approaches, increasing research interest has been devoted to immunogenic cell death inducing agents that are able to trigger localized cell death of the cancer cells as well as induce an immune response inside the whole organism. Preliminary studies have shown that immunogenic cell death inducing compounds could be able to overcome metastatic and relapsing tumors. Herein, the application of metal complexes as immunogenic cell death inducing compounds is systematically reviewed.     

MnOx Nanospikes as Nanoadjuvants and Immunogenic Cell Death Drugs with Enhanced Antitumor Immunity and Antimetastatic Effect

Despite the widespread applications of manganese oxide nanomaterials (MONs) in biomedicine, the intrinsic immunogenicity of MONs is still unclear. MnO_x nanospikes (NSs) as tumor microenvironment (TME)‐responsive nanoadjuvants and immunogenic cell death (ICD) drugs are proposed for cancer nanovaccine‐based immunotherapy. MnO_x NSs with large mesoporous structures show ultrahigh loading efficiencies for ovalbumin and tumor cell fragment. The combination of ICD via chemodynamic therapy and ferroptosis inductions, as well as antigen stimulations, presents a better synergistic immunopotentiation action. Furthermore, the obtained nanovaccines achieve TME‐responsive magnetic resonance/photoacoustic dual‐mode imaging contrasts, while effectively inhibiting primary/distal tumor growth and tumor metastasis.     

Engineered Bacteria Labeled with Iridium(III) Photosensitizers for Enhanced Photodynamic Immunotherapy of Solid Tumors

Despite metal-based photosensitizers showing great potential in photodynamic therapy for tumor treatment, the application of the photosensitizers is intrinsically limited by their poor cancer-targeting properties. Herein, we reported a metal-based photosensitizer-bacteria hybrid, Ir-HEcN , via covalent labeling of an iridium(III) photosensitizer to the surface of genetically engineered bacteria. Due to its intrinsic self-propelled motility and hypoxia tropism, Ir-HEcN selectively targets and penetrates deeply into tumor tissues. Importantly, Ir-HEcN is capable of inducing pyroptosis and immunogenic cell death of tumor cells under irradiation, thereby remarkably evoking anti-tumor innate and adaptive immune responses in vivo and leading to the regression of solid tumors via combinational photodynamic therapy and immunotherapy. To the best of our knowledge, Ir-HEcN is the first metal complex decorated bacteria for enhanced photodynamic immunotherapy.