From structural design to delivery: mRNA therapeutics for cancer immunotherapy.

mRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority in expressing all sequence-known proteins in vivo. In particular, with a small dosage of delivered mRNA, antigen-presenting cells (APCs) can synthesize mutant neo-antigens and multi-antigens and present epitopes to T lymphocytes to elicit antitumor effects. In addition, expressing receptors like chimeric antigen receptor (CAR), T-cell receptor (TCR), CD134, and immune-modulating factors including cytokines, interferons, and antibodies in specific cells can enhance immunological response against tumors. With the maturation of in vitro transcription (IVT) technology, large-scale and pure mRNA encoding specific proteins can be synthesized quickly. However, the clinical translation of mRNA-based anticancer strategies is restricted by delivering mRNA into target organs or cells and the inadequate endosomal escape efficiency of mRNA. Recently, there have been some advances in mRNA-based cancer immunotherapy, which can be roughly classified as modifications of the mRNA structure and the development of delivery systems, especially the lipid nanoparticle platforms. In this review, the latest strategies for overcoming the limitations of mRNA-based cancer immunotherapies and the recent advances in delivering mRNA into specific organs and cells are summarized. Challenges and opportunities for clinical applications of mRNA-based cancer immunotherapy are also discussed.

High-Energy Earth-Abundant Cathodes with Enhanced Cationic/Anionic Redox for Sustainable and Long-Lasting Na-Ion Batteries.

Layered iron/manganese-based oxides are a class of promising cathode materials for sustainable batteries due to their high energy densities and earth abundance. However, the stabilization of cationic and anionic redox reactions in these cathodes during cycling at high voltage remain elusive. Here, an electrochemically/thermally stable P2-Na0.67Fe0.3Mn0.5Mg0.1Ti0.1O2 cathode material with zero critical elements is designed for sodium-ion batteries (NIBs) to realize a highly reversible capacity of ≈210 mAh g-1 at 20 mA g-1 and good cycling stability with a capacity retention of 74% after 300 cycles at 200 mA g-1, even when operated with a high charge cut-off voltage of 4.5 V versus sodium metal. Combining a suite of cutting-edge characterizations and computational modeling, it is shown that Mg/Ti co-doping leads to stabilized surface/bulk structure at high voltage and high temperature, and more importantly, enhances cationic/anionic redox reaction reversibility over extended cycles with the suppression of other undesired oxygen activities. This work fundamentally deepens the failure mechanism of Fe/Mn-based layered cathodes and highlights the importance of dopant engineering to achieve high-energy and earth-abundant cathode material for sustainable and long-lasting NIBs.

Curcumin-polydopamine nanoparticles alleviate ferroptosis by iron chelation and inhibition of oxidative stress damage.

Ferroptosis, characterized by elevated iron levels and lipid peroxidation (LPO), is a recently identified regulatory mechanism of cell death. Its substantial involvement in ischemic tissue injury, neurodegenerative disorders, and cancer positions ferroptosis inhibition as a promising strategy for managing these diverse diseases. In this study, we introduce curcumin-polydopamine nanoparticles (Cur-PDA NPs) as an innovative ferroptosis inhibitor. Cur-PDA NPs demonstrate remarkable efficacy in chelating both Fe2+ and Fe3+in vitro along with scavenging free radicals. Cur-PDA NPs were found to efficiently mitigate reactive oxygen species, reduce Fe2+ accumulation, suppress LPO, and rejuvenate mitochondrial function in PC12 cells. Thus, these NPs can act as potent therapeutic agents against ferroptosis, primarily via iron chelation and reduction of oxidative stress.

Zero Voltage-Degradation of Li2MnO3 with Ultrathin Amorphous Li─Mn─O Coating.

Manganese-based lithium-rich layered oxides (Mn-LLOs) are promising candidate cathode materials for lithium-ion batteries, however, the severe voltage decay during cycling is the most concern for their practical applications. Herein, an Mn-based composite nanostructure constructed Li2MnO3 (LMO@Li2MnO3) is developed via an ultrathin amorphous functional oxide LixMnOy coating at the grain surface. Due to the thin and universal LMO amorphous surface layer etched from the lithiation process by the high-concentration alkaline solution, the structural and interfacial stability of Li2MnO3 are enhanced apparently, showing the significantly improved voltage maintenance, cycle stability, and energy density. In particular, the LMO@Li2MnO3 cathode exhibits zero voltage decay over 200 cycles. Combining with ex situ spectroscopic and microscopic techniques, the Mn2+/4+ coexisted behavior of the amorphous LMO is revealed, which enables the stable electrochemistry of Li2MnO3. This work provides new possible routes for suppressing the voltage decay of Mn-LLOs by modifying with the composite functional unit construction.

Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy.

Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

A dysprosium(III)-based triple helical-like complex as a turn-on/off fluorescence sensor for Al(III) and 4,5-dimethyl-2-nitroaniline.

A novel triple helical-like complex [Dy2K2L3(NO3)2]·3DMF (1) based on a designed Schiff base N'1,N'3-bis((E)-3-ethoxy-2-hydroxybenzylidene)-malonohydrazide (H4L) was synthesized with good chemical and thermal stabilities. Single-crystal X-ray structural analysis showed that 1 presents a tetranuclear triple helical-like structure via the coordination mode of Dy : K : L with 2 : 2 : 3 stoichiometry. Fluorescence measurements showed that 1@EtOH has excellent fluorescence turn-on/off response ability for aluminium ions and 4,5-dimethyl-2-nitroaniline (DMNA) with outstanding selectivity, sensitivity, and anti-interference ability. The calculated limit of detection (LOD) values for 1@EtOH to Al3+ and DMNA were found to be 0.53 and 3.33 µM, respectively. Density functional theory (DFT) calculation showed that the fluorescence response mechanism can be explained by the photoinduced electron transfer (PET) mechanism; meanwhile, the inner filter effect (IFE) of DMNA can also affect the emission of 1@EtOH.

Glutamine inhibition combined with CD47 blockade enhances radiotherapy-induced ferroptosis in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a formidable cancer type that poses significant treatment challenges, including radiotherapy (RT) resistance. The metabolic characteristics of tumors present substantial obstacles to cancer therapy, and the relationship between RT and tumor metabolism in HNSCC remains elusive. Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Here, we report that after RT, glutamine levels rise in HNSCC, and the glutamine transporter protein SLC1A5 is upregulated. Notably, blocking glutamine significantly enhances the therapeutic efficacy of RT in HNSCC. Furthermore, inhibition of glutamine combined with RT triggers immunogenic tumor ferroptosis, a form of nonapoptotic regulated cell death. Mechanistically, RT increases interferon regulatory factor (IRF) 1 expression by activating the interferon signaling pathway, and glutamine blockade augments this efficacy. IRF1 drives transferrin receptor expression, elevating intracellular Fe2+ concentration, disrupting iron homeostasis, and inducing cancer cell ferroptosis. Importantly, the combination treatment-induced ferroptosis is dependent on IRF1 expression. Additionally, blocking glutamine combined with RT boosts CD47 expression and hinders macrophage phagocytosis, attenuating the treatment effect. Dual-blocking glutamine and CD47 promote tumor remission and enhance RT-induced ferroptosis, thereby ameliorating the tumor microenvironment. Our work provides valuable insights into the metabolic and immunological mechanisms underlying RT-induced ferroptosis, highlighting a promising strategy to augment RT efficacy in HNSCC.

PROTAC Prodrug-Integrated Nanosensitizer for Potentiating Radiation Therapy of Cancer.

Radiation therapy (RT) is one of the primary options for clinical cancer therapy, in particular advanced head and neck squamous cell carcinoma (HNSCC). Herein, the crucial role of bromodomain-containing protein 4 (BRD4)-RAD51 associated protein 1 (RAD51AP1) axis in sensitizing RT of HNSCC is revealed. A versatile nanosensitizer (RPB7H) is thus innovatively engineered by integrating a PROteolysis TArgeting Chimeras (PROTAC) prodrug (BPA771) and hafnium dioxide (HfO2) nanoparticles to downregulate BRD4-RAD51AP1 pathway and sensitize HNSCC tumor to RT. Upon intravenous administration, the RPB7H nanoparticles selectively accumulate at the tumor tissue and internalize into tumor cells by recognizing neuropilin-1 overexpressed in the tumor mass. HfO2 nanoparticles enhance RT effectiveness by amplifying X-ray deposition, intensifying DNA damage, and boosting oxidative stress. Meanwhile, BPA771 can be activated by RT-induced H2O2 secretion to degrade BRD4 and inactivate RAD51AP1, thus impeding RT-induced DNA damage repair. This versatile nanosensitizer, combined with X-ray irradiation, effectively regresses HNSCC tumor growth in a mouse model. The findings introduce a PROTAC prodrug-based radiosensitization strategy by targeting the BRD4-RAD51AP1 axis, may offer a promising avenue to augment RT and more effective HNSCC therapy.

Ferroelectric BaTiO3 Regulating the Local Electric Field for Interfacial Stability in Solid-State Lithium Metal Batteries.

Solid-state Li metal batteries (SSLMBs) are widely investigated since they possess promising energy density and high safety. However, the poor interfacial compatibility between the electrolyte and electrodes limits their promising development. Herein, a robust composite electrolyte (poly(vinyl ethylene carbonate) electrolyte with 3 wt % of BaTiO3, PVEC-3BTO) with excellent interfacial performance is rationally designed by incorporating ferroelectric BaTiO3 (BTO) nanoparticles into the poly(vinyl ethylene carbonate) (PVEC) electrolyte matrix. Benefiting from the high dielectric constant and ferroelectric properties of BTO, the interfacial compatibility between electrolytes and electrodes was significantly improved. The enhanced Li+ transference number (0.64) of solid electrolyte and in situ generated BaF2 inorganic interphase contribute to the enhanced cycling stability of PVEC-3BTO based Li//Li symmetrical batteries. Furthermore, the antioxidation ability of PVEC-3BTO has also been enhanced by modulating the local electric field for good pairing with high-voltage LiCoO2 material. Therefore, in this work, the mechanism of BTO for improving interfacial compatibility is revealed, and also useful methods for addressing the interface issues of SSLMBs have been provided.

Paeoniflorin confers ferroptosis resistance by regulating the gut microbiota and its metabolites in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is closely related to ferroptosis, a new type of cell death that mainly manifests as intracellular iron accumulation and lipid peroxidation. Paeoniflorin (PA) helps to improve impaired glucose tolerance, influences the distribution of the intestinal flora, and induces significant resistance to ferroptosis in several models. In this study, we found that PA improved cardiac dysfunction in mice with DCM by alleviating myocardial damage, resisting oxidative stress and ferroptosis, and changing the community composition and structure of the intestinal microbiota. Metabolomics analysis revealed that PA-treated fecal microbiota transplantation affected metabolites in DCM mice. Based on in vivo and in vitro experiments, 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor that mediates the cardioprotective and antiferroptotic effects of PA-treated fecal microbiota transplantation (FMT) in DCM mice.NEW & NOTEWORTHY This study demonstrated for the first time that paeoniflorin (PA) exerts protective effects in diabetic cardiomyopathy mice by alleviating myocardial damage, resisting ferroptosis, and changing the community composition and structure of the intestinal microbiota, and 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor in its therapeutic efficacy.

Constructing custom thermodynamics using deep learning.

One of the most exciting applications of artificial intelligence is automated scientific discovery based on previously amassed data, coupled with restrictions provided by known physical principles, including symmetries and conservation laws. Such automated hypothesis creation and verification can assist scientists in studying complex phenomena, where traditional physical intuition may fail. Here we develop a platform based on a generalized Onsager principle to learn macroscopic dynamical descriptions of arbitrary stochastic dissipative systems directly from observations of their microscopic trajectories. Our method simultaneously constructs reduced thermodynamic coordinates and interprets the dynamics on these coordinates. We demonstrate its effectiveness by studying theoretically and validating experimentally the stretching of long polymer chains in an externally applied field. Specifically, we learn three interpretable thermodynamic coordinates and build a dynamical landscape of polymer stretching, including the identification of stable and transition states and the control of the stretching rate. Our general methodology can be used to address a wide range of scientific and technological applications.

Copper-Based Single-Atom Nanozyme System Mimicking Platelet Cells for Enhancing the Outcome of Radioimmunotherapy.

Background: Radiotherapy is an indispensable part of the multidisciplinary treatment of breast cancer (BC). Due to the potential for serious side effects from ionizing radiation in the treatment of breast cancer, which can adversely affect the patient's quality of life, the radiation dose is often limited. This limitation can result in an incomplete eradication of tumors. Methods: In this study, biomimetic copper single-atom catalysts (platelet cell membrane camouflaging, PC) were synthesized with the aim of improving the therapeutic outcomes of radiotherapy for BC. Following guidance to the tumor site facilitated by the platelet cell membrane coating, PC releases a copper single-atom nanozyme (SAzyme). This SAzyme enhances therapeutic effects by generating reactive oxygen species from H2O2 and concurrently inhibiting the self-repair mechanisms of cancer cells through the consumption of intracellular glutathione (GSH) within the tumor microenvironment. PC-augmented radiotherapy induces immunogenic cell death, which triggers an immune response to eradicate tumors. Results: With the excellent biocompatibility, PC exhibited precise tumor-targeting capabilities. Furthermore, when employed in conjunction with radiotherapy, PC showed impressive tumor elimination results through immunological activation. Remarkably, the tumor suppression rate achieved with PC-enhanced radiotherapy reached an impressive 93.6%. Conclusion: Therefore, PC presents an innovative approach for designing radiosensitizers with tumor-specific targeting capabilities, aiming to enhance the therapeutic impact of radiotherapy on BC.

Lung toxicity induced by anti-HER2 antibody - drug conjugates for breast cancer.

Human epidermal growth factor receptor 2 (HER2) serves as both a prognostic indicator and a therapeutic target for breast cancer. Therefore, anti-HER2 therapy plays a crucial role in the treatment of HER2-positive cancer. Antibody-drug conjugates (ADCs) are composed of a monoclonal antibody, a chemical linker and a payload, wherein their aim is to reduce the toxicity associated with chemotherapy drugs by utilizing specific antibodies. Among the anti-HER2 ADCs currently approved for clinical use, trastuzumab emtansine(T-DM1) and trastuzumab deruxtecan (T-Dxd) have demonstrated remarkable efficacy in treating HER2-positive breast cancer. However, it is essential to emphasize the occurrence of lung toxicity during the treatment process, which can be life-threatening. In this review, we provide an overview of the new epidemiological features associated with interstitial lung disease (ILD) related to anti-HER2 ADCs in breast cancer. We also summarize the potential pathogenesis and explore the diagnosis and treatment strategies within this field.

A Numerical Study of the Dynamic Crack Behavior of Brittle Material Induced by Blast Waves.

Blast stress waves profoundly impact engineering structures, exciting and affecting the rupture process in brittle construction materials. A novel numerical model was introduced to investigate the initiation and propagation of cracks subjected to blast stress waves within the borehole-crack configuration. Twelve models were established with different crack lengths to simulate sandstone samples. The influence of crack length on crack initiation and propagation was investigated using those models. The linear equation of state was used to express the relationship between the pressure and density of the material. The major principal stress failure criterion was used to evaluate the failure of elements. A triangular pressure curve was adopted to produce the blast stress wave. The results indicated that the pre-crack length critically influenced the crack initiation and propagation mechanism by analyzing the stress history at the crack tip, crack propagation velocity, and distance. The inducement of a P-wave and S-wave is paramount in models with a short pre-crack. For long pre-crack models, Rayleigh waves significantly contribute to crack propagation.

Optimization of supraclavicular lymph node clinical target volume delineation in high-risk breast cancer: a single center experience and recommendation.

BACKGROUND: Prophylactic irradiation of supraclavicular lymph node drainage areas can improve the regional control rate of lymph node-positive or lymph node-negative disease but a locally-advanced stage breast cancer, and it can reduce breast cancer-related mortality. However, many controversies exist in the clinical target volume delineation of supraclavicular lymph node drainage in patients with breast cancer. METHODS: We retrospectively analyzed 42 patients with breast cancer and supraclavicular lymph node metastasis at our hospital between January 2017 and December 2021. Among these cases, 32 were locally advanced and 10 were stage IV at initial treatment. A patient with breast cancer who did not undergo dissection of the supraclavicular and infraclavicular lymph nodes at our hospital was selected as a standard patient. A contrast-enhanced computed tomography (CT) scan for positioning was used as a template image, and blood vessels, muscles, and bony landmarks were used as references for positioning. The metastatic supraclavicular lymph nodes were identified in all enrolled patients and projected into the template CT images. RESULTS: The metastastic pattern of supraclavicular lymph node in breast cancer was proposed: distribution along the posterolateral border of the internal jugular vein (medial supraclavicular group) and along the transverse jugular vein (lateral supraclavicular group). We theorized that the lateral and posterior borders of the clinical target volume in the supraclavicular region should include the lymph nodes in the posterior triangle of the neck (level V) in high-risk individuals. If the metastatic axillary lymph node is extensive, then the superior border of the supraclavicular region should be moved upward appropriately. CONCLUSIONS: This study analyzed patients with breast cancer and supraclavicular lymph node metastasis at initial treatment, explored the metastastic pattern of supraclavicular lymph node, and applied anatomical knowledge to further optimize the target volume delineation of supraclavicular lymph node drainage area in high-risk breast cancer.

VISTA blockade alleviates immunosuppression of MDSCs in oral squamous cell carcinoma.

V-domain Ig suppressor of T-cell activation (VISTA) is a novel immune checkpoint regulator that can inhibit T cell-mediated antitumor immunity. Although the use of anti-VISTA monoclonal antibody has demonstrated encouraging outcomes in the therapy of various malignancies, its specific impact and underlying mechanisms in oral squamous cell carcinoma (OSCC) remain to be explored. In this work, we analyzed human OSCC tissue microarrays, human peripheral blood mononuclear cells, and immunocompetent transgenic mouse models to investigate the relationship between high VISTA expression and markers of myeloid-derived immunosuppressive cells (MDSCs; CD11b, CD33, Arginase-1), tumor-associated macrophages (CD68, CD163, CD206), and T cell function (CD8, PD-L1, Granzyme B). In OSCC, we discovered that VISTA was highly expressed and stably expressed in MDSCs. Furthermore, we established a mouse OSCC orthotopic xenograft tumor model to investigate the impact of VISTA blockade on the tumor microenvironment. We found that VISTA blockade reduces the immunosuppressive microenvironment and delays tumor growth. This is achieved by suppressing the quantity and function of MDSCs while boosting the function of tumor-infiltrating T cells. Our research indicated that VISTA expressed by MDSCs has a crucial function in the progression of OSCC and that VISTA blockade therapy is a promising immune checkpoint blockade therapy.

Smart and versatile biomaterials for cutaneous wound healing.

The global increase of cutaneous wounds imposes huge health and financial burdens on patients and society. Despite improved wound healing outcomes, conventional wound dressings are far from ideal, owing to the complex healing process. Smart wound dressings, which are sensitive to or interact with changes in wound condition or environment, have been proposed as appealing therapeutic platforms to effectively facilitate wound healing. In this review, the wound healing processes and features of existing biomaterials are firstly introduced, followed by summarizing the mechanisms of smart responsive materials. Afterwards, recent advances and designs in smart and versatile materials of extensive applications for cutaneous wound healing were submarined. Finally, clinical progresses, challenges and future perspectives of the smart wound dressing are discussed. Overall, by mapping the composition and intrinsic structure of smart responsive materials to their individual needs of cutaneous wounds, with particular attention to the responsive mechanisms, this review is promising to advance further progress in designing smart responsive materials for wounds and drive clinical translation.

Self-Adaptive Nanoregulator to Mitigate Dynamic Immune Evasion of Pancreatic Cancer.

The advance of immunotherapy has shifted the paradigm of cancer management in clinics. Nevertheless, a considerable subset of pancreatic ductal adenocarcinoma (PDAC) patients marginally respond to current immunotherapy due to the occurrence of dynamic immune evasion arising from intrinsic and therapeutic stress. In this investigation, the pivotal role of pancreatic cancer-associated fibroblast (CAF)-induced fibrosis and tumor cell-mediated T-cell exhaustion in driving the dynamic immune evasion is identified. Building upon this discovery, the authors herein engineer a novel peptide-drug conjugate (PDC)-based self-adaptive nanoregulator for mitigating dynamic immune evasion of PDAC. The resulting nanoregulator can perform a two-stage morphology transformation from spherical micelle to nanofiber, and subsequently from nanofiber to spherical nanoparticles. Such kind of nanostructure design can facilitate differentialized delivery of CAF inhibitor in the extracellular matrix for intervening CAF-mediated tumor fibrosis, and indoleamine 2,3-dioxygenase 1 inhibitor to tumor cells for relieving IDO1-kynurenine axis-induced T-cell exhaustion. Antitumor study with the self-adaptive nanoregulator elicited persistent antitumor immunity and remarkable antitumor performance in both Panc02 and KPC tumor models in vivo. Taken together, the PDC-based self-adaptive nanoregulator may provide a novel avenue for enhanced PDAC immunotherapy.

Tertiary lymphoid structures and cytokines interconnections: The implication in cancer immunotherapy.

Tertiary lymphoid structures (TLSs) are organized aggregates of lymphocytes and antigen-presenting cells that develop in non-lymphoid tissues during chronic inflammation, resembling the structure and features of secondary lymphoid organs. Numerous studies have shown that TLSs may be an important source of antitumor immunity within solid tumors, facilitating T cell and B cell differentiation and the subsequent production of antitumor antibodies, which are beneficial for cancer prognosis and responses to immunotherapy. The formation of TLSs relies on the cytokine signaling network between heterogeneous cell populations, such as stromal cells, lymphocytes and cancer cells. The coordinated action of various cytokines drives the complex process of TLSs development. In this review, we will comprehensively describe the mechanisms by which various cytokines regulate TLS formation and function, and the recent advancements and therapeutic potential of exploiting these mechanisms to induce intratumoral TLSs as an emerging immunotherapeutic approach or to enhance existing immunotherapy.

Nanovesicles loaded with a TGF-ß receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy.

The immune-excluded tumors (IETs) show limited response to current immunotherapy due to intrinsic and adaptive immune resistance. In this study, it is identified that inhibition of transforming growth factor-ß (TGF-ß) receptor 1 can relieve tumor fibrosis, thus facilitating the recruitment of tumor-infiltrating T lymphocytes. Subsequently, a nanovesicle is constructed for tumor-specific co-delivery of a TGF-ß inhibitor (LY2157299, LY) and the photosensitizer pyropheophorbide a (PPa). The LY-loaded nanovesicles suppress tumor fibrosis to promote intratumoral infiltration of T lymphocytes. Furthermore, PPa chelated with gadolinium ion is capable of fluorescence, photoacoustic and magnetic resonance triple-modal imaging-guided photodynamic therapy, to induce immunogenic death of tumor cells and elicit antitumor immunity in preclinical cancer models in female mice. These nanovesicles are further armored with a lipophilic prodrug of the bromodomain-containing protein 4 inhibitor (i.e., JQ1) to abolish programmed death ligand 1 expression of tumor cells and overcome adaptive immune resistance. This study may pave the way for nanomedicine-based immunotherapy of the IETs.