Mechanisms and applications of antitumor immunotherapy of responsive drug-loaded nanoparticles in breast cancer

During the chemotherapy of tumors,the cytotoxic effect of drugs is vital to kill tumor cells,and the delivery of a chemotherapeutic agent is of great importance for optimal therapeutic effects.The high in vivo clearance rate and low delivery efficiency of conventional chemotherapeutic agents affect the therapeutic effect.In recent years,the responsive drug delivery nanosystem has received increasing concern owing to its excellent biocompatibility,stable delivery performance,and controlled drug release strategies.To lucidly explain the cytocidal and immunotherapeutic effects of such responsive nanosystems in breast cancer,this review discusses the various stimuli and responses of drug-loaded liposomal nanosystems.The light/magnetic response of drug-loaded bionic membranes nanosystems and the heat/magnetic response of drug-loaded iron oxide nanosystems are also elaborated.Their cancer cell-killing efficacy and antitumor immunotherapeutic effects are also scrutinized.

Zinc Ion-Induced Immune Responses in Antitumor Immunotherapy

Zinc has emerged as a crucial metal in the field of antitumor immunotherapy.Despite its recognized significance,the specific molecular mechanisms behind zinc ion-mediated antitumor immune responses remain inadequately elucidated.Herein,we present a comprehensive analysis of the effects of zinc ions on immune regulation in antitumor immunotherapy.Zinc ions overload within tumor cells results in the generation of reactive oxygen species(ROS)through two mechanisms:the leakage of electrons from aerobic respiration in mitochondria and the oxidation of reduced nicotinamide adenine dinucleotide phosphate(NADPH)by NADPH oxidase 1(NOX1).The accumulation of ROS and the resulting damage to mitochondrial DNA(mtDNA)activate multiple signaling pathways,leading to the production of high levels of interferons and inflammatory cytokines.Besides,excessive zinc ions induce tumor cell pyroptosis through two pathways:the caspase-1/GSDMD-dependent canonical pathway and the caspase-3/GSDME-dependent alternative pathway,leading to the exposure of many damage-associated molecular patterns(DAMPs).As a result,strong systemic antitumor immunity is triggered,leading to the inhibition of tumor growth.This study unveils the intricate network of signaling pathways mediated by zinc ions in the tumor microenvironment(TME).Such findings not only lay a solid foundation for the development of zinc-based antitumor drugs but also advance the field of zinc-based metalloimmunotherapy.

Nanotandem-rocket releases messenger to disrupt metabolic communication for antitumor immunotherapy

Metabolic communication between intracellular metabolism and extracellular microenvironment is responsible for celluar metabolism balance and cell survival.Tumor cells adaptively regulate metabolic communication to promote hyperproliferation and immunosuppression.Herein,nanotandem-rockets(hyaluronic acid modified Mg_(5)(CO_(3))_(4)(OH)_(2)(H-MCH))are developed for stepwisely disrupting metabolic communication to activate antitumor immunity.Benefiting from the nanotandem-rocket structure,H-MCH nanoplates successively disrupt the extracellular metabolite transport and intracellular carbohydrate metabolism.Theoretical simulation together with metabolomic analysis discloses the underlying mechanism of H-MCH nanotandem-rockets.The extra-/intra-celluar interruption of metabolic communication provides H-MCH nanotandem-rockets with high efficiency in tumor eradication.Moreover,the interference of metabolic communication reverses immunosuppression to facilitate the intratumoral infiltration of immune cells.With H-MCH nanotandem-rockets as an in situ vaccine,systemic antitumor immunity and immune memory effect are fabricated to eliminate tumor metastasis and recurrence.Different from traditional metabolic poisons(e.g.,arsenic or cyanide),the structure of nanotandem-rockets endows chemical messengers with selective regulation to tumor metabolic communication,but with minimal influence to normal tissues.The nanotandem-rockets provide a powerful paltform to augment the regulating actitiy of chemical messengers in metabolic communication.We expect our discovery of disrupting tumor metabolic communication with chemical messengers will be a powerful strategy for tumor therapy with vast practical applications.

Sonosensitized Aggregation-Induced Emission Dots with Capacities of Immunogenic Cell Death Induction and Multivalent Blocking of Programmed Cell Death-Ligand 1 for Amplified Antitumor Immunotherapy

The combination of immunogenic cell death(ICD)induction and immune checkpoint blockade has emerged as a major direction of cancer immunotherapy.Among currently available ICD inducers,sonosensitizers that produce reactive oxygen species(ROS)under an external trigger to evoke ICD of tumor cells have shown great promise.However,a highly efficient sonosensitizer-based ICD inducer with an aggregationinduced emission(AIE)characteristic has yet to be developed.Herein,a novel AIE sonosensitizer with a twisted molecular structure,very small energy gap between the singlet and triplet excited states(ΔE_(ST)),and efficient ROS generation ability,which can serve as an effective ICD inducer,is reported for sonodynamic processes in cancer immunotherapy.Furthermore,an AIE sonosensitizer-based nanosystem with surface modification of anti-PD-L1 peptide is constructed for boosting antitumor immunotherapy.In this system,AIE sonosensitizer-mediated sonodynamic therapy can successfully convert a hypoimmunogenic cold tumor to a hot one and further facilitate the multivalent blocking of programed death ligand(PD-L1)by anti-PD-L1 peptides.Such an advanced nanosystem could effectively initiate the activation of antitumoral immune reactions and modulation of an immunosuppressive microenvironment,contributing to systemic antitumor effects to further inhibit the growth of distant tumors.

Emerging role of metabolic reprogramming in tumor immune evasion and immunotherapy

Mounting evidence has revealed that the therapeutic efficacy of immunotherapies is restricted to a small portion of cancer patients.A deeper understanding of how metabolic reprogramming in the tumor microenvironment(TME)regulates immunity remains a major challenge to tumor eradication.It has been suggested that metabolic reprogramming in the TME may affect metabolism in immune cells and subsequently suppress immune function.Tumor cells compete with infiltrating immune cells for nutrients and metabolites.Notably,the immunosuppressive TME is characterized by catabolic and anabolic processes that are critical for immune cell function,and elevated inhibitory signals may favor cancer immune evasion.The major energy sources that supply different immune cell subtypes also undergo reprogramming.We herein summarize the metabolic remodeling in tumor cells and different immune cell subtypes and the latest advances underlying the use of metabolic checkpoints in antitumor immunotherapies.In this context,targeting both tumor and immune cell metabolic reprogramming may enhance therapeutic efficacy.