Chemotherapy Induces Cancer-Fighting B Cells.

Tumor-infiltrating B cells are heterogeneous, and their roles in tumor immunity are controversial. In this issue of Cell, Lu and colleagues demonstrate that chemotherapy-induced complement signals promote the generation of ICOSL+B cells, which enhance tumor-specific T cell responses.

Author Correction: Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling.

High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

Tuning commensurability in twisted van der Waals bilayers.

Moiré superlattices based on van der Waals bilayers1-4 created at small twist angles lead to a long wavelength pattern with approximate translational symmetry. At large twist angles (θt), moiré patterns are, in general, incommensurate except for a few discrete angles. Here we show that large-angle twisted bilayers offer distinctly different platforms. More specifically, by using twisted tungsten diselenide bilayers, we create the incommensurate dodecagon quasicrystals at θt = 30° and the commensurate moiré crystals at θt = 21.8° and 38.2°. Valley-resolved scanning tunnelling spectroscopy shows disparate behaviours between moiré crystals (with translational symmetry) and quasicrystals (with broken translational symmetry). In particular, the K valley shows rich electronic structures exemplified by the formation of mini-gaps near the valence band maximum. These discoveries demonstrate that bilayers with large twist angles offer a design platform to explore moiré physics beyond those formed with small twist angles.

Electrostatic moiré potential from twisted hexagonal boron nitride layers.

Moiré superlattices host a rich variety of correlated electronic phases. However, the moiré potential is fixed by interlayer coupling, and it is dependent on the nature of carriers and valleys. In contrast, it has been predicted that twisted hexagonal boron nitride (hBN) layers can impose a periodic electrostatic potential capable of engineering the properties of adjacent functional layers. Here, we show that this potential is described by a theory of electric polarization originating from the interfacial charge redistribution, validated by its dependence on supercell sizes and distance from the twisted interfaces. This enables controllability of the potential depth and profile by controlling the twist angles between the two interfaces. Employing this approach, we further demonstrate how the electrostatic potential from a twisted hBN substrate impedes exciton diffusion in semiconductor monolayers, suggesting opportunities for engineering the properties of adjacent functional layers using the surface potential of a twisted hBN substrate.

SNX27 suppresses SARS-CoV-2 infection by inhibiting viral lysosome/late endosome entry.

After binding to its cell surface receptor angiotensin converting enzyme 2 (ACE2), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell through directly fusing with plasma membrane (cell surface pathway) or undergoing endocytosis traveling to lysosome/late endosome for membrane fusion (endocytic pathway). However, the endocytic entry regulation by host cell remains elusive. Recent studies show ACE2 possesses a type I PDZ binding motif (PBM) through which it could interact with a PDZ domain-containing protein such as sorting nexin 27 (SNX27). In this study, we determined the ACE2-PBM/SNX27-PDZ complex structure, and, through a series of functional analyses, we found SNX27 plays an important role in regulating the homeostasis of ACE2 receptor. More importantly, we demonstrated SNX27, together with retromer complex (the core component of the endosomal protein sorting machinery), prevents ACE2/virus complex from entering lysosome/late endosome, resulting in decreased viral entry in cells where the endocytic pathway dominates. The ACE2/virus retrieval mediated by SNX27-retromer could be considered as a countermeasure against invasion of ACE2 receptor-using SARS coronaviruses.

Quantifying Strain in Moiré Superlattice.

In twisted van der Waals (vdW) bilayers, intrinsic strain associated with the moiré superlattice and unintentionally introduced uniaxial strain may be present simultaneously. Both strains are able to lift the degeneracy of the E2g phonon modes in Raman spectra. Because of the different rotation symmetry of the two types of strain, the corresponding Raman intensity exhibits a distinct polarization dependence. We compare a 2.5° twisted MoS2 bilayer, in which the maximal intrinsic moiré strain is anticipated, and a natural MoS2 bilayer with an intentionally introduced uniaxial strain. By analyzing the frequency shift of the E2g doublet and their polarization dependence, we can not only determine the direction of unintentional uniaxial strain in the twisted bilayer but also quantify both strain components. This simple strain characterization method based on far-field Raman spectra will facilitate the studies of electronic properties of moiré superlattices under the influence of combined intrinsic and external strains.

Omnidirectional broadband phase modulation by total internal reflection.

Phase modulation plays a crucial role in shaping optical fields and physical optics. However, traditional phase modulation techniques are highly dependent on angles and wavelengths, limiting their applicability in smart optical systems. Here, we propose a first-principle theory for achieving constant phase modulation independent of incident angle and wavelength. By utilizing a hyperbolic metamaterial and engineering-specific optical parameters, different reflective phase jumps are achieved and tailored for both transverse electric (TE) and transverse magnetic (TM) waves. The aimed reflection phase difference between TE and TM waves can be thus achieved omnidirectionally and achromatically. As an example, we propose a perfect omnidirectional broadband reflection quarter wave plate. This work provides fundamental insights into manipulating optical phases through optical parameter engineering.

Genetically Programmable Fusion Cellular Vesicles for Cancer Immunotherapy.

Herein, we report that genetically programmable fusion cellular vesicles (Fus-CVs) displaying high-affinity SIRPα variants and PD-1 can activate potent antitumor immunity through both innate and adaptive immune effectors. Dual-blockade of CD47 and PD-L1 with Fus-CVs significantly increases the phagocytosis of cancer cells by macrophages, promotes antigen presentation, and activates antitumor T-cell immunity. Moreover, the bispecific targeting design of Fus-CVs ensures better targeting on tumor cells, but less on other cells, which reduces systemic side effects and enhances therapeutic efficacies. In malignant melanoma and mammary carcinoma models, we demonstrate that Fus-CVs significantly improve overall survival of model animals by inhibiting post-surgery tumor recurrence and metastasis. The Fus-CVs are suitable for protein display by genetic engineering. These advantages, integrated with other unique properties inherited from source cells, make Fus-CVs an attractive platform for multi-targeting immune checkpoint blockade therapy.

Omnidirectional polarization beam splitter for white light.

As a key element in optical systems, a broadband and omnidirectional polarization beam splitter has been long desired. Here, based on anisotropic metamaterials, a perfect polarizing beam splitter is theoretically designed for the extremely broad frequency and angle bands without energy loss. When an electromagnetic wave is incident on the beam splitter, the transverse magnetic-polarized component suffers total reflection, while the transverse electric-polarized component is completely transmitted within the incident angle range [-90°, 90°] for the white light. This study provides a new approach to design an efficient polarizing beam splitter and may promote the development and applications of anisotropic metamaterials.

Ferritin nanoparticle-based SpyTag/SpyCatcher-enabled click vaccine for tumor immunotherapy.

Recently, tumor neoantigens have been attractive for development of personal therapeutic vaccines. However, how to instantly deliver multiple neoantigens for efficient anti-tumor immunity is still challenging. Here, we established a SpyCatcher-modified ferritin nanoparticle platform, which permits convenient and stable covalent conjugation with tumor specific antigens containing SpyTag in a click-link manner. These ferritin nanoparticles are rapidly drained to lymph nodes and target dendritic cells, especially CD8α+ population, upon subcutaneous immunization. Ferritin nanoparticles carrying HPV16 oncogene E7 peptide antigen or MC38 tumor derived mutant neoantigens elicit about 2-3 folds enhanced antigen-specific cytotoxic T lymphocyte (CTL) response than soluble peptide antigens and significantly suppress the growth of E7-related or MC38 tumors. The anti-tumor effect was further enhanced in combination with PD-1 checkpoint blockade. Together, our study provides a ferritin nanoparticle-based, SpyTag/SpyCatcher-enabled click vaccine platform, especially for personalized tumor immunotherapy.

Association between time of discharge from ICU and hospital mortality: a systematic review and meta-analysis.

BACKGROUND: Epidemiological studies have provided inconsistent results on whether intensive care unit (ICU) discharge at night and on weekends is associated with an increased risk of mortality. This systematic review and meta-analysis aimed to determine whether ICU discharge time was associated with hospital mortality. METHODS: The PubMed, Embase, and Scopus databases were searched to identify cohort studies that investigated the effects of discharge from the ICU on weekends and at night on hospital mortality, with adjustments for the disease severity at ICU admission or discharge. The primary meta-analysis focused on the association between nighttime ICU discharge and hospital mortality. The secondary meta-analysis examined the association between weekend ICU discharge and hospital mortality. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS: We included 14 studies that assessed outcomes for nighttime versus daytime discharges among 953,312 individuals. Of these 14 studies, 5 evaluated outcomes for weekend versus weekday discharges (n = 70,883). The adjusted OR for hospital mortality was significantly higher among patients discharged during the nighttime, compared to patients discharged during the daytime (OR 1.31, 95% CI 1.25-1.38, P < 0.0001), and the studies exhibited low heterogeneity (I 2 = 33.8%, P = 0.105). There was no significant difference in the adjusted ORs for hospital mortality between patients discharged during the weekend or on weekdays (OR 1.03, 95% CI 0.88-1.21, P = 0.68), although there was significant heterogeneity between the studies in the weekday/weekend analysis (I 2 = 72.5%, P = 0.006). CONCLUSIONS: Nighttime ICU discharge is associated with an increased risk of hospital mortality, while weekend ICU discharge is not. Given the methodological limitations and heterogeneity among the included studies, these conclusions should be interpreted with caution, and should be tested in further studies.

[Impact of extracorporeal carbon dioxide removal combined with continuous renal replacement therapy on diaphragmatic function in patients with acute respiratory distress syndrome].

OBJECTIVE: To investigate the effects of extracorporeal carbon dioxide removal (ECCO2R) combined with continuous renal replacement therapy (CRRT) on respiratory efficiency and diaphragm function in patients with acute respiratory distress syndrome (ARDS) received mechanical ventilation. METHODS: A prospective randomized controlled study was conducted. Sixty patients with mild to moderate ARDS admitted to the department of respiratory and critical care medicine of Henan Provincial People's Hospital from January 2019 to January 2021 were enrolled, and they were divided into observation group and control group according to the random number table method, with 30 cases in each group. All patients received antibiotics, anti-inflammatory, and mechanical ventilation therapy. On this basis, the observation group received ECCO2R and CRRT, while the control group received bedside CRRT. Baseline data including gender, age, etiology, acute physiology and chronic health evaluation II (APACHE II), etc., were recorded. Arterial blood gas analysis [including arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), and oxygenation index (PaO2/FiO2)] was performed at 12 hours and 24 hours during the treatment, and respiratory mechanics parameters [including tidal volume, respiratory rate, maximum expiratory pressure (MEP), and maximum inspiratory pressure (MIP)] were recorded, and rapid shallow breathing index (RSBI) was calculated. The levels of glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and superoxide dismutase (SOD) in serum were detected by enzyme-linked immunosorbent assay (ELISA). Diaphragm thickness and diaphragm activity were measured by ultrasonography at 24 hours during the treatment. RESULTS: There were no significantly differences in age, gender, etiology, and APACHE II score between the two groups, indicating that the baseline data of the two groups were balanced and comparable. Compared with the 12 hours after treatment, the PaO2 and PaO2/FiO2 in the observation group significantly increased, PaCO2 significantly decreased, RSBI significantly decreased, MEP and MIP significantly increased, and serum GSH-Px and MDA significantly decreased, while SOD significantly increased at 24 hours during the treatment. In the control group, only PaCO2 significantly decreased. Compared with the control group, the PaCO2 significantly decreased in the observation group at 12 hours and 24 hours [mmHg (1 mmHg≈0.133 kPa): 55.05±7.57 vs. 59.49±6.95, 52.77±7.88 vs. 58.25±6.92, both P < 0.05], but no significantly differences in PaO2 and PaO2/FiO2. Compared with the control group, the observation group showed significant decreases in RSBI at 12 hours and 24 hours (times×min-1×L-1: 85.92±8.83 vs. 90.38±3.78, 75.73±3.86 vs. 90.05±3.66, both P < 0.05), significant increases in MEP and MIP [MEP (mmH2O, 1 mmH2O≈0.01 kPa): 86.64±5.99 vs. 83.88±4.18, 93.70±5.59 vs. 85.04±3.73; MIP (mmH2O): 44.19±6.66 vs. 41.17±3.13, 57.52±5.28 vs. 42.34±5.39, all P < 0.05], and significant decreases in serum GSH-Px and MDA [GSH-Px (mg/L): 78.52±8.72 vs. 82.10±3.37, 57.11±4.67 vs. 81.17±5.13; MDA (µmol/L): 7.84±1.97 vs. 8.71±0.83, 3.67±0.78 vs. 8.41±1.09, all P < 0.05], as well as a significant increase in SOD (U/L: 681.85±49.24 vs. 659.40±26.47, 782.32±40.56 vs. 676.65±51.97, both P < 0.05). Compared with the control group, the observation group showed significant increases in diaphragm thickness and diaphragm activity at 24 hours of treatment [diaphragm thickness (cm): 1.93±0.28 vs. 1.40±0.24, diaphragmatic thickening fraction: (0.22±0.04)% vs. (0.19±0.02)%, quiet breathing diaphragm displacement (cm): 1.42±0.13 vs. 1.36±0.06, deep breathing diaphragm displacement (cm): 5.11±0.75 vs. 2.64±0.59, all P < 0.05]. CONCLUSIONS: ECCO2R combined with CRRT can reduce work of breathing and oxidative stress levels in ARDS patients receiving non-invasive ventilation, and protect diaphragm function.

[Assessment of neural respiratory drive in humans].

OBJECTIVE: Assessment of neural respiratory drive is useful for diagnosis of dyspnea and respiratory failure with unknown causes. The purpose of the study was to compare the sensitivity of trandiaphragmatic pressure (Pdi) and diaphragm electromyogram (EMGdi) in assessment of neural respiratory drive. METHODS: A combined catheter with 10 electrodes and 2 balloons was used to record EMGdi and Pdi during CO2 rebreathing. Three different inspiratory maneuvers-inspiration from functional residual capacity to total lung capacity (TLC), deep inspiration from functional residual capacity against closed airway (MIP), and short sharp inspiration through the nose (Sniff) were performed. Ten healthy subjects [male 4 and female 6; age (26 ± 4) years] were studied. RESULTS: Linear relationship between EMGdi and end-tidal CO2 (r = 0.83-0.98, all P < 0.01) was better than that between Pdi and end-tidal CO2 (r = 0.48-0.96, all P < 0.01) during CO2 rebreathing, Z = -2.731, P < 0.05. The slope of linear relation between EMGdi and end-tidal CO2 (16.3-32.5) was significantly higher than that between Pdi and end-tidal CO2 (0.4-11.1), Z = -3.780, P < 0.01. The maximal EMGdi derived from TLC maneuver (211 ± 48) µV was larger than those from the MIP maneuver (161 ± 48) µV and the Sniff maneuver (145 ± 37) µV, F = 5.931, P < 0.05, whereas the maximal Pdi derived from TLC maneuver (58 ± 27) cm H2O (1 cm H2O = 0.098 kPa) was significantly lower than those from the MIP maneuver (92 ± 32) cm H2O and the Sniff maneuver (95 ± 27) cm H2O, F = 5.155, P < 0.05. CONCLUSION: EMGdi is more sensitive than Pdi in the assessment of neural respiratory drive.

Dynamically assembled nanomedicine based on host-guest molecular recognition for NIR laser-excited chemotherapy and phototheranostics.

Nanomedicines combining multimodal therapeutic modalities supply opportunities to eliminate tumors in a safe and efficient manner. However, the rigid encapsulation and covalent conjugation of different therapeutic reagents suffer from the complicated preparation process, premature drug leakage and severe adverse events. Herein, we report a self-enhanced supramolecular nanomedicine (SND) based on the host-guest molecular recognition between ß-cyclodextrin (ß-CD) and camptothecin (CPT) for trimodal synergistic chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT) using a single 670 nm near-infrared (NIR) laser. Thioketal bond and polyethylene glycol (PEG) segment are introduced into the structure of CPT-tk-PEG prodrug, thus the premature release of CPT is efficiently inhibited and the specific drug release is realized at tumor site where singlet oxygen (1O2)-generated PDT is performed. A boron dipyrromethene (BODIPY) theranostic agent is anchored onto ß-CD, endowing SND with capabilities of fluorescence imaging, PDT and PTT. Benefiting from the supramolecular assembly, not only the solubility of CPT is improved by 40 times, but also the blood circulation time and tumor accumulation of SND are greatly promoted. In vivo, SND can effectively induce the immunogenic cell death (ICD) of tumor cells, thus performing prominent inhibition against both primary and distal tumors, and even anti-metastasis effect against liver without causing obvious systemic toxicity. STATEMENT OF SIGNIFICANCE: Although nanomedicines supply opportunities to eliminate tumors in an efficient manner, they usually suffer from premature drug leakage, complicated preparation process and severe side effects owing to the rigid encapsulation or covalent conjugation. Based on the host-guest molecular recognition, we developed a self-enhanced SND for synergistic chemotherapy, photodynamic therapy and photothermal therapy. Introduction of thioketal bond in CPT prodrug avoided the premature drug release, and the specific drug release was realized in the tumor cells. Profiting from the facile supramolecular assembly strategy, SND not only displayed a primary anticancer efficacy with a low systemic toxicity, but also efficiently inhibited the growth of distal tumors, contributing a vaccine-like function to eradicate the recurrent and metastatic tumors.

Fabrication of An Immunostimulatory Supramolecular Nanomedicine for Potent Cancer Chemoimmunotherapy.

Chemoimmunotherapy can boost strong antitumor immune responses by triggering immunogenic cell death (ICD), which highlights a promising prospect in clinical applications. However, current chemoimmunotherapy shows limited efficacy due to the low delivery efficiency and insufficient immunogenicity of available chemotherapeutic drugs. A supramolecular polymeric nanomedicine (Pt-Tu@NP) is herein reported using cucurbit[7]uril-based host-guest recognition and noncovalent self-assembly. Pt-Tu@NPs have excellent biodistribution and strongly evoke the endoplasmic reticulum stress-mediated ICD of tumor cells, triggering potent antitumor immune responses by promoting dendritic cell (DC) maturation and cytotoxic T cell infiltration. The coordinated butyrate promotes a positive feedback regulation between DCs and CD8+ T cells. Pt-Tu@NPs stimulate immune cold tumors into hot ones, working in synergy with an immune checkpoint blockade to effectively suppress tumor growth and metastasis, which suggests a promising approach for cancer chemoimmunotherapy.

Poly(ethyl ethylene phosphate): Overcoming the "Polyethylene Glycol Dilemma" for Cancer Immunotherapy and mRNA Vaccination.

Polyethylene glycol conjugation (PEGylation) is the most successful strategy to promote the stability, pharmacokinetics, and efficacy of therapeutics; however, anti-PEG antibodies induced by repeated treatments raise serious concerns about the future of PEGylated therapeutics. In order to solve the "PEG dilemma", polymers with excellent water solubility and biocompatibility are urgently desired to attenuate the generation of anti-PEG antibodies. Here, poly(ethyl ethylene phosphate) (PEEP) with excellent degradability and stealth effects is used as an alternative to PEG to overcome the "PEG dilemma". PEEPylated liposomes exhibit lower immunogenicity and generate negligible anti-PEEP antibodies (IgM and IgG) after repeated treatments. In vivo studies confirm that PEEPylated liposomes loaded with oxaliplatin (PEEPlipo@OxPt) show better pharmacokinetics compared to PEGlipo@OxPt, and they exhibit potent antitumor performances, which can be further promoted with checkpoint blockade immunotherapy. In addition, PEEPylated lipid nanoparticle is also used to develop an mRNA vaccine with the ability to evoke a potent antigen-specific T cell response and achieve excellent antitumor efficacy. PEEP shows promising potentials in the development of next-generation nanomedicines and vaccines with higher safety and efficacy.

A lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection.

The respiratory system, especially the lung, is the key site of pathological injury induced by SARS-CoV-2 infection. Given the low feasibility of targeted delivery of antibodies into the lungs by intravenous administration and the short half-life period of antibodies in the lungs by intranasal or aerosolized immunization, mRNA encoding broadly neutralizing antibodies with lung-targeting capability can perfectly provide high-titer antibodies in lungs to prevent the SARS-CoV-2 infection. Here, we firstly identify a human monoclonal antibody, 8-9D, with broad neutralizing potency against SARS-CoV-2 variants. The neutralization mechanism of this antibody is explained by the structural characteristics of 8-9D Fabs in complex with the Omicron BA.5 spike. In addition, we evaluate the efficacy of 8-9D using a safe and robust mRNA delivery platform and compare the performance of 8-9D when its mRNA is and is not selectively delivered to the lungs. The lung-selective delivery of the 8-9D mRNA enables the expression of neutralizing antibodies in the lungs which blocks the invasion of the virus, thus effectively protecting female K18-hACE2 transgenic mice from challenge with the Beta or Omicron BA.1 variant. Our work underscores the potential application of lung-selective mRNA antibodies in the prevention and treatment of infections caused by circulating SARS-CoV-2 variants.

Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy.

BACKGROUND: Cancer vaccines are able to achieve tumor-specific immune editing in early-phase clinical trials. However, the infiltration of cytotoxic T cells into immune-deserted tumors is still a major limiting factor. An optimized vaccine approach to induce antigen-specific T cells that can perform robust tumor infiltration is important to accelerate their clinical translation. We previously developed a STING-activating PC7A nanovaccine that produces a strong anti-tumor T cell response on subcutaneous injection. This study systematically investigated the impact of administration methods on the performance of nanovaccines. METHODS: Tumor growth inhibition by intratumoral delivery and subcutaneous delivery of nanovaccine was investigated in TC-1 human papillomavirus-induced cancer model and B16-OVA melanoma model. Nanovaccine distribution in vivo was detected by clinical camera imaging, systemic T cell activation and tumor infiltration were tested by in vivo cytotoxicity killing assay and flow cytometry. For mechanism analysis, T cell recruitment was investigated by in vivo migration blocking assay, multiplex chemokine array, flow cytometry, RT-qPCR, chemotaxis assay and gene knockout mice. RESULTS: Nanovaccine administration was found to alter T cell production and infiltration in tumors. Intratumoral delivery of nanovaccines displayed superior antitumor effects in multiple tumor models compared with subcutaneous delivery. Mechanistic investigation revealed that intratumoral administration of the nanovaccine significantly increased the infiltration of antigen-specific T cells in TC-1 tumors, despite the lower systemic levels of T cells compared with subcutaneous injection. The inhibition of tumor growth by nanovaccines is primarily dependent on CD8+ cytotoxic T cells. Nanovaccine accumulation in tumors upregulates CXCL9 expression in myeloid cells in a STING dependent manner, leading to increased recruitment of IFNγ-expressing CD8+ T cells from the periphery, and IFNγ reciprocally stimulates CXCL9 expression in myeloid cells, resulting in positive feedback between myeloid-CXCL9 and T cell-IFNγ to promote T cell recruitment. However, the STING agonist alone could not sustain this effect in the presence of a systemic deficiency in antigen-specific T cells. CONCLUSIONS: Our results demonstrate that intratumoral administration of PC7A nanovaccine achieved stronger antitumor immunity and efficacy over subcutaneous injection. These data suggest intratumoral administration should be included in the therapeutic design in the clinical use of nanovaccine.

A Paradigm of Cancer Immunotherapy Based on 2-[18F]FDG and Anti-PD-L1 mAb Combination to Enhance the Antitumor Effect.

PURPOSE: Efforts have been devoted to select eligible candidates for PD-1/PD-L1 immune checkpoint blocker (ICB) immunotherapy. Here, we have a serendipitous finding of positron emission tomography (PET) imaging tracer 2-[18F]FDG as a potential immunomodulator. Therefore, we hypothesize that 2-[18F]FDG could induce PD-L1 expression change and create an immune-favorable microenvironment for tumor immunotherapy. EXPERIMENTAL DESIGN: We designed a series of assays to verify PD-L1 upregulation, and tested immunotherapy regimens based on 2-[18F]FDG and anti-PD-L1 mAb, as monotherapy and in combination, in fully immunocompetent mice of MC38 and CT26 models. PD-L1 expression and tumor microenvironment (TME) changes were analyzed by Western blot, transcriptomics study, and flow-cytometric analysis. RESULTS: PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 2-[18F]FDG. The activation of NF-κB/IRF3 pathway and STAT1/3-IRF1 pathway play crucial parts in modulating PD-L1 expression after DNA damage and repair. Improved αPD-L1 mAb utilization rate and significant tumor growth delay were observed when the personalized therapeutic alliance of 2-[18F]FDG stimulation and ICB was used. In addition, combination of 2-[18F]FDG with αPD-L1 mAb could reprogram a TME from "cold" to "hot," to make low immunoactivity tumors sensitive to ICB therapy. CONCLUSIONS: In summary, this promising paradigm has the potential to expand the traditional tumor theranostics. 2-[18F]FDG-based ICB immunotherapy is highly significant in enhancing antitumor effect. A research of 2-[18F]FDG-based ICB immunotherapy has been proposed to enhance the antitumor effect.