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Currently, the understanding of the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway's involvement in efficient immunotherapy mainly revolves around the role of mitochondria or nucleus modulation. Nonetheless, the role of endoplasmic reticulum (ER) stress in activating the cGAS‐STING mechanism to boost immunity against tumors remains essentially unexplored. Herein, novel findings demonstrating that ER stress can be used as a strategy for stimulating the cGAS‐STING pathway, thereby augmenting the immune response against cancer, are presented. To accomplish this objective, ER‐targeting p‐methylbenzene sulfonamide‐tailored IR780 (p‐780) is synthesized and it is loaded into CaO2 nanoparticles, which are further functionalized with distearoyl phosphoethanolamine‐polyethylene glycol（DSPE‐PEG）‐biotin to form PEG/CaO2@p‐780 NPs. The disruption of calcium homeostasis, coupled with the heightened levels of reactive oxygen species (ROS) mediated by p‐780, along with hyperpyrexia, collectively contributes to the amplification of endoplasmic reticulum (ER) stress. This cascade of events effectively triggers the cGAS‐STING pathway and, in parallel, facilitates the degradation of the programmed cell death 1 ligand 1 (PD‐L1) protein. In addition, oxygen released through CaO2 decomposition is expected to promote p‐780–mediated phototherapy, while reversing the immunosuppressive tumor microenvironment associated with hypoxia. Furthermore, DSPE‐PEG‐biotin facilitates tumor site‐specific drug delivery through active targeting mediated by the biotin receptor. Collectively, PEG/CaO2@p‐780 nanoparticles successfully activate systemic antitumor immunity by enhancing ER stress. [ABSTRACT FROM AUTHOR]

Chemo‐immunotherapy has shown great success in boosting systemic anti‐tumor effects in the clinic. However, cancer cells can escape the maximum impact of chemotherapy through intracellular symbiotic bacteria and abnormally activated macropinocytosis, while cancer immune evasion is largely facilitated by the programmed cell death 1 ligand 1 (PD‐L1) protein and tumor‐secreted exosomes. To efficiently sensitize chemo‐immunotherapy, the clinical mitoxantrone (MTO) is therefore rationally coordinated with Cu2+ to develop nanoscale metal‐organic frameworks (MTO‐Cu), then loaded with the macropinocytosis and exosome secretion inhibitor amiloride (AMI) and modified with targeted chondroitin sulfate (CS) to form CS/MTO‐Cu@AMI nanoadjuvant. Notably, the coordinated Cu2+ effectively triggers cuproptosis‐induced mitochondrial dysfunction, which activates AMPK pathway‐mediated PD‐L1 protein degradation, deprives energy supply for macropinocytosis and exosome release, and amplifies oxidative stress for deactivating intracellular bacteria, thus efficiently sensitizing chemo‐immunotherapy. Meanwhile, AMI suppresses macropinocytosis and exosome secretion to act synergistically with Cu2+‐caused chemo‐immunotherapy potentiation. Moreover, damaged dsDNA during CS/MTO‐Cu@AMI treatment activates the cGAS‐STING pathway, further evoking the anti‐tumor immunity. Additionally, the attached CS endows CS/MTO‐Cu@AMI with specific tumor targeting and hyaluronidase‐responsive charge reversal property, while MTO‐Cu endows this nanoadjuvant with pH/GSH dual‐responsive release behavior. Therefore, CS/MTO‐Cu@AMI efficiently sensitizes chemotherapy and activates systemic antitumor immunity in vitro and in vivo, providing an innovative solution to potentiate cancer chemo‐immunotherapy. [ABSTRACT FROM AUTHOR]

Induction of immunogenic cell death (ICD) in tumor combined with immune checkpoint blockade (ICB) therapy is widely developed to improve the efficacy of cancer immunotherapy. However, the current ICD induced based on apoptosis, i.e., immunogenic apoptosis, is often restricted in immunogenicity owing to the inflammatory quenching that occurs early in apoptosis. Recently, pyroptosis is demonstrated to be a more efficient ICD form, i.e., immunogenic pyroptosis. The cell contents released during pyroptosis can powerfully activate tumor immunogenicity. Herein, first, it is demonstrated that lower doses of epigenetic drug decitabine can increase GSDME expression in prostate cancer (PCa) RM‐1 cells and successfully induce an apoptosis‐pyroptosis transition after photodynamic therapy (PDT). Subsequently, a microenvironment dual‐responsive nano‐drug equipped with PD‐L1 blocking peptide (TSD@LSN‐D) is developed for self‐synergistic cancer immunotherapy. The poorly immunogenic RM‐1 PCa model confirm that the powerful antitumor immune response evoked by TSD@LSN‐D not only can effectively inhibit the primary tumor but also form a long‐term immune memory to prevent PCa recurrence and metastasis. To the best of authors' knowledge, this work presents the first concept that promotes the apoptosis–pyroptosis transition after tumor PDT through epigenetic modulation. Furthermore, the powerful combination of immunogenic pyroptosis with ICB opens a new platform for PCa immunotherapy. [ABSTRACT FROM AUTHOR]

Protein preorganization is ubiquitous in nature and enables subtle structural rearrangements and precise function executions, making it an attractive approach for generating functional peptide materials. Here, a phosphorylation‐dependent pre‐organization approach to optimize the therapeutic outcomes of a self‐assembling peptide targeting programmed cell death ligand 1 (PD‐L1) is reported. Upon incorporating the imaging probe cyanine 5.5 (Cy5.5) and therapeutic drug 10‐hydroxycamptothecin (HCPT), three phosphorylated precursors (1P, 2P, and 3P) containing identical peptide sequences with different tyrosine phosphorylation sites are constructed. The presence of a phosphate group can stabilize the self‐assembling peptide in a well‐defined, preorganized state. Moreover, variations in the phosphorylation sites lead to different preorganized secondary structures, dephosphorylation rates, and PD‐L1 binding affinities. Responding to alkaline phosphatase dephosphorylation, subtle structural transformation to more ordered states, an increase in binding affinity against PD‐L1, and rapid cellular internalization are observed. Compared with the unphosphorylated control (0P), the preorganization of 1P, 2P, and 3P can optimize tumor retention and resultant therapeutic performance, of which 3P maximizes the final therapeutic outcomes, leading to a 70.3% tumor inhibition rate. This study highlights the great potential to control the subtle structural transformation and therapeutic effects of self‐assembling peptides by preparing their preorganized entities. [ABSTRACT FROM AUTHOR]

To address urgent tasks in the treatment of advanced deep‐seated tumors, a 980 nm absorbing agent with aggregation‐induced emission tendency, namely TPE‐BT‐BBTD, which simultaneously possesses the longest absorption wavelength among all the reported AIE molecules is developed. The functionality of deep near‐infrared‐II fluorescence imaging (NIR‐II FLI) and outstanding photothermal performance is well‐tailored for advanced pancreatic cancer treatment. With the covalent attachment of the programmed death‐ligand 1 (αPD‐L1) antibody, αPD‐L1@TPE‐BT‐BBTD nanoparticles show precise tumor targeting and excellent immunosuppression reversal ability. Following local photothermal therapy, immunogenic tumor vaccination is induced to trigger the infiltration of cytotoxic T lymphocytes (CTLs) in tumors. With the decreased FoxP3+ Treg cells and M2‐like macrophages that are reversed by αPD‐L1, CTLs activity is further enhanced with more production of granzyme B (GrB), which much accurately leads to tumor apoptosis and effectively suppressed spontaneous metastases. Overall, αPD‐L1@TPE‐BT‐BBTD nanoparticles based NIR‐II FLI‐mediated photo‐immunotherapy is able to significantly improve the control of primary tumor and metastasis in the treatment of advanced deep‐seated tumors. [ABSTRACT FROM AUTHOR]

Inosine is proven to promote the proliferation and function of CD8+ cytotoxic lymphocytes (CD8+ T) under glucose restriction and enhance the efficacy of programmed cell death protein ligand‐1 (PD‐L1) blockade therapy. However, systemic administration of high frequencies and large doses of inosine and anti‐PD‐L1 antibody (aPDL1) is required, which inevitably reduces bioavailability and causes severe immunological side effects. Therefore, it is crucial to develop a drug delivery system to achieve gradient release of inosine and aPDL1 for local immunotherapy. In this study, an inosine‐based supramolecular hydrogel, inosine‐phenylenediboronic‐isoguanosine (IPBisoG), is successfully developed following a simple one‐pot procedure. Both in vitro and in vivo studies demonstrate that the biocompatible and biodegradable IPBisoG hydrogel displays excellent stability and self‐healing properties. Furthermore, the IPBisoG hydrogel is shown to achieve the gradual and sequential release of inosine and aPDL1. Inosine, which enhances the proliferation and function of CD8+ T cells, together with aPDL1, the blocker of the immunosuppressive pathway in tumor microenvironment, can highly enhance the in vivo efficacy of PD‐L1 blockade therapy. The employment of IPBisoG hydrogel is also shown to trigger systemic immune responses. These results demonstrate that IPBisoG hydrogel can be a promising platform for tumor‐local immunotherapy in the future. [ABSTRACT FROM AUTHOR]

The clinical outcomes of programmed cell death protein‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) blockade are usually limited by the multiple immune evasion mechanism of the tumor, as well as the immune storm caused by "off‐target" effects of the PD‐1/PD‐L1 antibody. Here, a previously unknown strategy is proposed to synergize the "Ca2+ interference" mediated M2‐like tumor‐associated macrophages (TAM) re‐education and Ca2+‐activating locally PD‐L1 depletion for immunotherapy. The authors discover that calcium‐containing nanoparticles can induce significant "Ca2+ interference" effect and simultaneously reset TAM toward the M1 phenotype through activation of multiple inflammation‐related signaling pathways, as well as NLRP3 inflammasomes, and promoting in situ tumor‐associated antigen release. In addition, a circular aptamer‐DNAzyme conjugate (cAD) is designed with a tumor‐targeting ability and its catalytic shear activity can be specifically activated by Ca2+, which reduces potential autoimmune‐like disorders of PD‐L1 antibody. By simply integrating the ultra‐high pH‐sensitive calcium peroxide nanoparticles with cAD into one nanosystem, it is demonstrated that the nanosystem not only arrest primary tumor progression and lung metastasis but also provides a long‐term immunological memory, which can protect against tumor rechallenge. Therefore, this work provides an attractive strategy for boosting tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Stress response to radiation sensitizes immunologically nonresponsive tumors to cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) therapy. The combination of radiotherapy (RT) and CTLA‐4 immune checkpoint blockade therapy has been clinically adopted and has yielded outstanding cooperative effects from restricted local lethality to systemic immune response. However, this combination therapy induces resistance caused by T cell depletion and increased programmed death‐ligand 1 (PD‐L1) expression in tumor cells. Hence, suppressing PD‐L1 expression through RT coupled with anti‐CTLA‐4 therapy can directly and efficiently address tumor resistance. Herein, metal‐phenolic network is incorporated into a triple combination therapy. Hafnium, a radiosensitizer used in clinical studies, is coordinated with polyphenols to constitute the principal structure of nanopumps (AHSC NPs). AHSC NPs embedded with atovaquone and sabutoclax could alleviate hypoxia and accelerate the activation of the apoptosis signaling pathway. Clinical/preclinical materials and approaches are employed as foundations and innovatively incorporate AHSC NPs to furnish a research basis and reference value for the integration of nanotechnology into clinical trials. [ABSTRACT FROM AUTHOR]

Here, a novel strategy to selectively degrade membrane proteins of programmed cell death‐ligand 1 (PD‐L1) in cancer cells is reported. 4T1 cells show high levels of extracellular alkaline phosphatase (ALP) and membrane proteins of PD‐L1. Therefore, peptide derivatives capable of responding to ALP and binding to PD‐L1 are designed. Enzyme‐instructed self‐assembly (EISA) by ALP and surface‐induced self‐assembly by PD‐L1 of Comp. 3 leads to the selective formation of nanomaterials around PD‐L1 on the cell membrane, which is similar to attaching a hydrophobic label to the surface of PD‐L1 to simulate its partial denaturation state. When taken up by cells, PD‐L1 could be further degraded by the proteasome pathway in the cytoplasm. This process does not occur in the normal cell line, LO2 cells, which express relatively low levels of ALP. In addition to concentration and time dependence, the selective knock‐out of PD‐L1 by the strategy is reversible by simply removing Comp. 3. In vivo studies reveal that Comp. 3 inhibits tumor growth in a tumor‐bearing mouse model. The study offers a novel platform for the precise degradation of membrane proteins using EISA, which might ultimately lead to the development of novel nanomedicines to treat diseases. [ABSTRACT FROM AUTHOR]

Overcoming innate or adaptive resistance to immune checkpoint inhibitor therapy in solid tumors with limited T‐cell responses remains challenging. Increasing evidence has indicated that epigenetic alterations, especially overexpression of DNA methyltransferase and immunosuppressive adenosine, are major obstacles to T cell activation. Here, a tumor microenvironment (TME) inspired prodrug nanomicelle (AOZN) composed of the epigenetic modulator γ‐oryzanol (Orz), the adenosine inhibitor α, β‐methylene adenosine 5′ diphosphate (AMPCP), and GSH‐activable crosslinker, is rationally designed. High glutathione redox triggers Orz and AMPCP release in the TME. The released Orz act as a DNA methyltransferases inhibitor to upregulate gasdermin D (GSDMD) expression and AMPCP converted procaspase‐1 into active caspase‐1 by increasing ATP levels. Active caspase‐1 elicited GSDMD cleavage and induced pyroptosis in tumor cells. Furthermore, it is demonstrated that Orz and AMPCP likely have a synergistic effect in combating the immunosuppressive TME. Moreover, Orz enhances programmed death‐ligand 1 (PD‐L1) expression and sensitize tumors to anti‐PD‐L1 therapy. Thus, the AOZNs nano‐formulation drastically improves the hydrophobic properties of Orz with advantages of safe, affordable, readily available, and efficiency in regressing tumor growth, enhancing PD‐L1 responsive rate and prolonging survival of the B16F10 melanoma‐bearing mouse model. As a result, AOZNs provides a promising strategy for enhancing cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Despite the potential of drug‐loaded scaffolds for tumor recurrence and metastasis (TRM) postoperation, their therapeutic benefits are limited by marked immunosuppressive tumor microenvironment (ITME) and drug‐related untargeted toxicity. Herein, an innovative implantable bioresponsive nanoarray is developed to overcome the above limitations. Chemotherapeutics doxorubicin (DOX) and the epigenetic modulator JQ1 are coloaded into tumor‐targeting nanoparticles (HP‐DOX/JQ1 NPs), which are then linked up through a bio‐responsive linker to construct the nanoarray loading with another part of JQ1 (DOX/JQ1‐IBRN). Under high level of H2O2 in TME, the implanted DOX/JQ1‐IBRN disaggregates and release JQ1 while generating small‐sized HP‐DOX/JQ1 NPs for realizing ITME modulation and tumor‐targeting therapy. JQ1 selectively blocks programmed death‐ligand 1 (PD‐L1) mediated immune evasion and reduces regulatory T cells (Tregs)/‐disruptive effect to facilitate immunopositivity. HP‐DOX/JQ1 NPs destroy residual tumor precisely and trigger gasdermin E (GSDME)‐dependent pyroptosis, further enhancing the number and functions of tumor‐infiltrating T lymphocytes for antitumor immunity. It is demonstrated that DOX/JQ1‐IBRN prevents post‐surgical TRM and prolongs survival in multiple murine tumor models with negligible toxicity. This cooperation in tumor accurate pyroptosis and ITME conversion through the implantable nanoarray (a simple, valid, and safe scaffold) is expected to provide crucial insights for post‐surgical treatment. [ABSTRACT FROM AUTHOR]

The clinical application of antitumor immunotherapy still faces severe challenges related to efficacy. Here, a light‐triggered core–shell nanosystem is designed to boost antitumor immune response via controlled release of anti‐PD‐L1 (αPD‐L1) antibodies and enhanced antigen presentation. The nanosystem (AZ‐P@P) is constructed via integrating gold nanorods (AuNRs) as a photothermal core and zeolitic imidazolate framework‐8 (ZIF‐8) as a shell for aPD‐L1 delivery, and further PEGylating. In the nanosystem, the ZIF‐8 shell protects αPD‐L1 antibody from the complex physiological environment and hyperthermia. Once accumulated at the tumor site, AZ‐P@P under near‐infrared (NIR) light‐triggered heating induces tumor cell deaths releasing tumor‐derived protein antigens (TDPAs) and adenosine triphosphate (ATP). Thereafter, the released ATP degrades the ZIF‐8 shell to expose the AuNRs, which can promote intratumoral T cell infiltration by capturing TDPAs and transporting them to dendritic cells (DCs). Concurrently, a large amount of αPD‐L1 is released in situ to reinvigorate T cell activity. Mechanistic studies reveal that AZ‐P@P promotes the maturation of DCs and the infiltration of activated T cells, thus eliciting a robust antitumor immunity. It is demonstrated that AZ‐P@P triggered by NIR light can significantly destroy primary tumors and suppress metastasis. This multiple immunoregulatory system provides a promising tool for tumor treatment. [ABSTRACT FROM AUTHOR]

Inosine-Based Supramolecular Hydrogel for Highly Efficient PD-L1 Blockade Therapy via Mediating CD8+ T Cells (Adv. Funct. Keywords: CD8 + T cells; immunotherapy; inosine; programmed cell death protein ligand-1; supramolecular hydrogels EN CD8 + T cells immunotherapy inosine programmed cell death protein ligand-1 supramolecular hydrogels 1 1 1 08/18/22 20220815 NES 220815 B Tumor Immunotherapeutic Gels b In article number 2204273, Dunfang Zhang, Hang Zhao, and co-workers demonstrate that an inosine-based supramolecular hydrogel, IPBisoG, can achieve the gradual and sequential release of inosine and aPDL1. CD8 + T cells, immunotherapy, inosine, programmed cell death protein ligand-1, supramolecular hydrogels. [Extracted from the article]