Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

A synthetic KLHL20 ligand to validate CUL3KLHL20 as a potent E3 ligase for targeted protein degradation.

Targeted protein degradation (TPD) has risen as a promising therapeutic modality. Leveraging the catalytic nature of the ubiquitin-proteasome enzymatic machinery, TPD exhibits higher potency to eliminate disease-causing target proteins such as oncogenic transcription factors that may otherwise be difficult to abrogate by conventional inhibitors. However, there are challenges that remain. Currently, nearly all degraders engage CUL4CRBN or CUL2VHL as the E3 ligase for target ubiquitination. While their immediate efficacies are evident, the narrowed E3 ligase options make TPD vulnerable to potential drug resistance. In addition, E3 ligases show differential tissue expression and have intrinsic limitations in accessing varying types of disease-relevant targets. As the success of TPD is closely associated with the ability of E3 ligases to efficiently polyubiquitinate the target of interest, the long-term outlook of TPD drug development will depend on whether E3 ligases such as CUL4CRBN and CUL2VHL are accessible to the targets of interest. To overcome these potential caveats, a broad collection of actionable E3 ligases is required. Here, we designed a macrocyclic degrader engaging CUL3KLHL20 for targeting BET proteins and validated CUL3KLHL20 as an E3 ligase system suitable for TPD. This work thus contributes to the expansion of usable E3 ligases for potential drug development.

A Prion-like Domain in Transcription Factor EBF1 Promotes Phase Separation and Enables B Cell Programming of Progenitor Chromatin.

Establishment of B-lineage-specific gene expression requires the binding of transcription factors to inaccessible chromatin of progenitors. The transcription factor EBF1 can bind genomic regions prior to the detection of chromatin accessibility in a manner dependent on EBF1's C-terminal domain (CTD) and independent of cooperating transcription factors. Here, we studied the mechanism whereby the CTD enables this pioneering function. The CTD of EBF1 was dispensable for initial chromatin targeting but stabilized occupancy via recruitment of the chromatin remodeler Brg1. We found that the CTD harbors a prion-like domain (PLD) with an ability of liquid-liquid phase separation, which was enhanced by interaction of EBF1 with the RNA-binding protein FUS. Brg1 also partitioned into phase-separated FUS condensates and coincided with EBF1 and FUS foci in pro-B cells. Heterologous PLDs conferred pioneering function on EBF1ΔCTD. Thus, the phase separation ability of EBF1 facilitates Brg1-mediated chromatin opening and the transition of naive progenitor chromatin to B-lineage-committed chromatin.

EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.

GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.

Mitochondrial fission is a tightly regulated process involving multiple proteins and cell signaling. Despite extensive studies on mitochondrial fission factors, our understanding of the regulatory mechanisms remains limited. This study shows the critical role of a mitochondrial GTPase, GTPBP8, in orchestrating mitochondrial fission in mammalian cells. Depletion of GTPBP8 resulted in drastic elongation and interconnectedness of mitochondria. Conversely, overexpression of GTPBP8 shifted mitochondrial morphology from tubular to fragmented. Notably, the induced mitochondrial fragmentation from GTPBP8 overexpression was inhibited in cells either depleted of the mitochondrial fission protein Drp1 (also known as DNM1L) or carrying mutated forms of Drp1. Importantly, downregulation of GTPBP8 caused an increase in oxidative stress, modulating cell signaling involved in the increased phosphorylation of Drp1 at Ser637. This phosphorylation hindered the recruitment of Drp1 to mitochondria, leading to mitochondrial fission defects. By contrast, GTPBP8 overexpression triggered enhanced recruitment and assembly of Drp1 at mitochondria. In summary, our study illuminates the cellular function of GTPBP8 as a pivotal modulator of the mitochondrial division apparatus, inherently reliant on its influence on Drp1.

scAMAC: self-supervised clustering of scRNA-seq data based on adaptive multi-scale autoencoder.

Cluster assignment is vital to analyzing single-cell RNA sequencing (scRNA-seq) data to understand high-level biological processes. Deep learning-based clustering methods have recently been widely used in scRNA-seq data analysis. However, existing deep models often overlook the interconnections and interactions among network layers, leading to the loss of structural information within the network layers. Herein, we develop a new self-supervised clustering method based on an adaptive multi-scale autoencoder, called scAMAC. The self-supervised clustering network utilizes the Multi-Scale Attention mechanism to fuse the feature information from the encoder, hidden and decoder layers of the multi-scale autoencoder, which enables the exploration of cellular correlations within the same scale and captures deep features across different scales. The self-supervised clustering network calculates the membership matrix using the fused latent features and optimizes the clustering network based on the membership matrix. scAMAC employs an adaptive feedback mechanism to supervise the parameter updates of the multi-scale autoencoder, obtaining a more effective representation of cell features. scAMAC not only enables cell clustering but also performs data reconstruction through the decoding layer. Through extensive experiments, we demonstrate that scAMAC is superior to several advanced clustering and imputation methods in both data clustering and reconstruction. In addition, scAMAC is beneficial for downstream analysis, such as cell trajectory inference. Our scAMAC model codes are freely available at https://github.com/yancy2024/scAMAC.

Chronic viral infection impairs immune memory to a different pathogen.

Chronic viral infections cause T cell dysfunction in both animal models and human clinical settings, thereby affecting the ability of the host immune system to clear viral pathogens and develop proper virus-specific immune memory. However, the impact of chronic viral infections on the host's immune memory to other pathogens has not been well described. In this study, we immunized mice with recombinant Listeria monocytogenes expressing OVA (Lm-OVA) to generate immunity to Lm and allow analysis of OVA-specific memory T (Tm) cells. We then infected these mice with lymphocytic choriomeningitis virus (LCMV) strain Cl-13 which establishes a chronic infection. We found that chronically infected mice were unable to protect against Listeria re-challenge. OVA-specific Tm cells showed a progressive loss in total numbers and in their ability to produce effector cytokines in the context of chronic LCMV infection. Unlike virus-specific T cells, OVA-specific Tm cells from chronically infected mice did not up-regulate the expression of inhibitory receptors, a hallmark feature of exhaustion in virus-specific T cells. Finally, OVA-specific Tm cells failed to mount a robust recall response after bacteria re-challenge both in the chronically infected and adoptively transferred naïve hosts. These results show that previously established bacteria-specific Tm cells become functionally impaired in the setting of an unrelated bystander chronic viral infection, which may contribute to poor immunity against other pathogens in the host with chronic viral infection.

Dimensionality reduction approach for many-objective epistasis analysis.

In epistasis analysis, single-nucleotide polymorphism-single-nucleotide polymorphism interactions (SSIs) among genes may, alongside other environmental factors, influence the risk of multifactorial diseases. To identify SSI between cases and controls (i.e. binary traits), the score for model quality is affected by different objective functions (i.e. measurements) because of potential disease model preferences and disease complexities. Our previous study proposed a multiobjective approach-based multifactor dimensionality reduction (MOMDR), with the results indicating that two objective functions could enhance SSI identification with weak marginal effects. However, SSI identification using MOMDR remains a challenge because the optimal measure combination of objective functions has yet to be investigated. This study extended MOMDR to the many-objective version (i.e. many-objective MDR, MaODR) by integrating various disease probability measures based on a two-way contingency table to improve the identification of SSI between cases and controls. We introduced an objective function selection approach to determine the optimal measure combination in MaODR among 10 well-known measures. In total, 6 disease models with and 40 disease models without marginal effects were used to evaluate the general algorithms, namely those based on multifactor dimensionality reduction, MOMDR and MaODR. Our results revealed that the MaODR-based three objective function model, correct classification rate, likelihood ratio and normalized mutual information (MaODR-CLN) exhibited the higher 6.47% detection success rates (Accuracy) than MOMDR and higher 17.23% detection success rates than MDR through the application of an objective function selection approach. In a Wellcome Trust Case Control Consortium, MaODR-CLN successfully identified the significant SSIs (P < 0.001) associated with coronary artery disease. We performed a systematic analysis to identify the optimal measure combination in MaODR among 10 objective functions. Our combination detected SSIs-based binary traits with weak marginal effects and thus reduced spurious variables in the score model. MOAI is freely available at https://sites.google.com/view/maodr/home.

Transcription factor PbNAC71 regulates xylem and vessel development to control plant height.

Dwarfism is an important agronomic trait in fruit breeding programs. However, the germplasm resources required to generate dwarf pear (Pyrus spp.) varieties are limited. Moreover, the mechanisms underlying dwarfism remain unclear. In this study, "Yunnan" quince (Cydonia oblonga Mill.) had a dwarfing effect on "Zaosu" pear. Additionally, the dwarfism-related NAC transcription factor gene PbNAC71 was isolated from pear trees comprising "Zaosu" (scion) grafted onto "Yunnan" quince (rootstock). Transgenic Nicotiana benthamiana and pear OHF-333 (Pyrus communis) plants overexpressing PbNAC71 exhibited dwarfism, with a substantially smaller xylem and vessel area relative to the wild-type controls. Yeast one-hybrid, dual-luciferase, chromatin immunoprecipitation-qPCR, and electrophoretic mobility shift assays indicated that PbNAC71 downregulates PbWalls are thin 1 expression by binding to NAC-binding elements in its promoter. Yeast two-hybrid assays showed that PbNAC71 interacts with the E3 ubiquitin ligase PbRING finger protein 217 (PbRNF217). Furthermore, PbRNF217 promotes the ubiquitin-mediated degradation of PbNAC71 by the 26S proteasome, thereby regulating plant height as well as xylem and vessel development. Our findings reveal a mechanism underlying pear dwarfism and expand our understanding of the molecular basis of dwarfism in woody plants.

CD8+ T cells in fetal membranes display a unique phenotype, and their activation is involved in the pathophysiology of spontaneous preterm birth.

Preterm labor/birth is the leading cause of perinatal mortality and morbidity worldwide. Previous studies demonstrated that T cells were crucial for maintaining maternal-fetal immune tolerance during the first trimester of pregnancy; however, their phenotypes and functions in labor and delivery remain largely unknown. We recruited three cohorts of women at delivery for T-cell immunophenotyping in the placentas, fetal membranes, umbilical cord blood, and maternal peripheral blood. Our data showed a differential enrichment of T cells during the third trimester of human pregnancy, with CD4+ T cells being more observable within the umbilical cord blood, whereas CD8+ T cells became relatively more abundant in fetal membranes. CD4+ and CD8+ T cells derived from fetal membranes were dominated by effector memory T cells and exhibited extensive expression of activation markers but decreased expression of homing receptor. In comparison with term births, fetal membrane CD8+ T cells, especially the central memory subset, were significantly increased in frequency and showed more profound activation in spontaneous preterm birth patients. Finally, using an allogeneic mouse model, we found that T-cell-activation-induced preterm birth could be alleviated by the depletion of CD8+ T but not CD4+ T cells in vivo. Collectively, we showed that CD8+ T cells in fetal membranes displayed a unique phenotype, and their activation was involved in the pathophysiology of spontaneous preterm birth, which provides novel insights into the immune mechanisms of preterm birth and potential targets for the prevention of this syndrome. © 2023 The Pathological Society of Great Britain and Ireland.

Dissipative coupling-induced phonon lasing.

Phonon lasers, as the counterpart of photonic lasers, have been intensively studied in a large variety of systems; however, (all) most of them are based on the directly coherent pumping. Intuitively, dissipation is unfavorable for lasing. Here, we experimentally demonstrate a mechanism of generating phonon lasing from the dissipative coupling in a multimode optomechanical system. By precisely engineering the dissipations of two membranes and tuning the intensity modulation of the cavity light, the two-membrane-in-the-middle system exhibits non-Hermitian characteristics and the cavity-mediated interaction between two nanomechanical resonators becomes purely dissipative. The level attraction and damping repulsion are clearly exhibited as the signature of dissipative coupling. After the exceptional point, a non-Hermitian phase transition, where eigenvalues and the corresponding eigenmodes coalesce, two phonon modes are simultaneously excited into the self-sustained oscillation regime by increasing the interaction strength over a critical value (threshold). In distinct contrast to conventional phonon lasers, the measurement of the second-order phonon correlation reveals the oscillatory and biexponential phases in the nonlasing regime as well as the coherence phase in the lasing regime. Our study provides a method to study phonon lasers in a non-Hermitian open system and could be applied to a wide range of disciplines, including optics, acoustics, and quantum many-body physics.

Electron delocalization triggers nonradical Fenton-like catalysis over spinel oxides.

Nonradical Fenton-like catalysis offers opportunities to overcome the low efficiency and secondary pollution limitations of existing advanced oxidation decontamination technologies, but realizing this on transition metal spinel oxide catalysts remains challenging due to insufficient understanding of their catalytic mechanisms. Here, we explore the origins of catalytic selectivity of Fe-Mn spinel oxide and identify electron delocalization of the surface metal active site as the key driver of its nonradical catalysis. Through fine-tuning the crystal geometry to trigger Fe-Mn superexchange interaction at the spinel octahedra, ZnFeMnO4 with high-degree electron delocalization of the Mn-O unit was created to enable near 100% nonradical activation of peroxymonosulfate (PMS) at unprecedented utilization efficiency. The resulting surface-bound PMS* complex can efficiently oxidize electron-rich pollutants with extraordinary degradation activity, selectivity, and good environmental robustness to favor water decontamination applications. Our work provides a molecule-level understanding of the catalytic selectivity and bimetallic interactions of Fe-Mn spinel oxides, which may guide the design of low-cost spinel oxides for more selective and efficient decontamination applications.

Stretchable and Breathable Electroluminescent Displays Based on Ultrathin Nanocomposite Designs.

Stretchable electroluminescent devices represent an emerging optoelectronic technology for future wearables. However, their typical construction on sub-millimeter-thick elastomers has limited moisture permeability, leading to discomfort during long-term skin attachment. Although breathable textile displays may partially address this issue, they often have distinct visual appearances with discrete emissions from fibers or fiber junctions. This study introduces a convenient procedure to create stretchable, permeable displays with continuous luminous patterns. The design utilizes ultrathin nanocomposite devices embedded in a porous elastomeric microfoam to achieve high moisture permeability. These displays also exhibit excellent deformability, low-voltage operation, and excellent durability. Additionally, the device is decorated with fluorinated silica nanoparticles to achieve self-cleaning and washable capabilities. The practical implementation of these nanocomposite devices is demonstrated by creating an epidermal counter display that allows intimate integration with the human body. These developments provide an effective design of stretchable and breathable displays for comfortable wearing.

Glass Disorder Modulated Luminescence in Zero-Dimensional Antimony-Chloride Coplanar Dimers for Optical Anti-counterfeiting.

Zero-dimensional metal halides have received wide attention due to their structural diversity, strong quantum confinement, and associated excellent photoluminescence properties. A reversible and tunable luminescence would be desirable for applications such as anti-counterfeiting, information encryption, and artificial intelligence. Yet, these materials are underexplored, with little known about their luminescence tuning mechanisms. Here we report a pyramidal coplanar dimer, (TBA)Sb2Cl7 (TBA = tetrabutylammonium), showing broadband emission wavelength tuning (585-650 nm) by simple thermal treatment. We attribute the broad color change to structural disorder induced by varying the heat treatment temperatures. Increasing the heating temperature transitions the material from long-range ordered crystalline phase to highly disordered glassy phase. The latter exhibits stronger electron-phonon coupling, enhancing the self-trapped exciton emission efficiency. The work provides a new material platform for manifold optical anti-counterfeiting applications and sheds light on the emission color tuning mechanisms for further design of stimuli-responsive materials.

Lithiophilic Chemistry Facilitated Ultrathin Lithium for Scalable Prelithiation.

Prelithiation plays a crucial role in advancing the development of high-energy-density batteries, and ultrathin lithium (UTL) has been proven to be a promising anode prelithiation reagent. However, there remains a need to explore an adjustable, efficient, and cost-effective method for manufacturing UTL. In this study, we introduce a method for producing UTL with adjustable thicknesses ranging from 1.5 to 10 µm through blade coating of molten lithium on poly(vinylidene fluoride)-modified copper current collectors. By employing the transfer-printing method, prelithiated graphite and Si-C composite electrodes are prepared, which exhibit significantly improved initial Coulombic efficiencies of 99.60% and 99.32% in half-cells, respectively. Moreover, the energy densities of Li(NiCoMn)1/3O2 and LiFePO4 full cells assembled with the prelithiated graphite electrodes increase by 13.1% and 23.6%, respectively.

Revisiting the Reactivity of the Dismissed Hydrogen Atom Transfer Catalyst Succinimide-N-oxyl.

Phthalimide-N-oxyl (PINO) and related radicals are promising catalysts for C-H functionalization reactions. To date, only a small number of N-oxyl derivatives have demonstrated improved activities over PINO. We postulate that the lack of success in identifying superior catalysts is associated not only with challenges in the design and synthesis of new structures, but also the way catalysts are evaluated and utilized. Catalyst evaluation typically relies on the use of chemical oxidants to generate N-oxyl radicals from their parent N-hydroxy compounds. Herein we provide an example where a potential-controlled electrochemical analysis reveals that succinimide-N-oxyl (SINO) compares favorably to PINO as a hydrogen atom transfer (HAT) catalyst-in contrast to previous claims based on other approaches. Our efforts to understand the basis for the greater reactivity of SINO relative to PINO have underscored that the HAT kinetics are significantly influenced by factors beyond changes in thermodynamics. This is perhaps best illustrated by the similar reactivity of tetrachloro-PINO and SINO despite the latter engaging in substantially more exergonic reactions. The key role of HAT transition state (TS) polarization prompted the design and initial characterization of a chlorinated SINO derivative, which we found to be the most reactive N-oxyl HAT catalyst reported to date.

Bismuth: An Epitaxy-like Conversion Mechanism Enabled by Intercalation-Conversion Chemistry for Stable Aqueous Chloride-Ion Storage.

The exploitation of new anion battery systems based on high-abundance oceanic elements (e.g., F-, Cl-, and Br-) is a strong supplement to the current metal cation (e.g., Li+, Na+) battery technologies. Bismuth (Bi), the rare anion-specific anode species nearest to practical application for chloride ion storage, is plagued by volume expansion and structure collapse due to limited control of its conversion behavior. Here, we reveal that a unique epitaxy-like conversion mechanism in the monocrystalline Bi nanospheres (R3m group) can drastically inhibit grain pulverization and capacity fading, which is enabled by Cl- intercalation in their interlayer space. The Bi nanosphere anode can self-evolve and transform into a rigid BiOCl nanosheet-interlaced structure after the initial conversion reaction. With this epitaxy-like conversion mechanism, the Bi anode exhibits a record-high capacity of 249 mAh g-1 (∼1.2 mAh cm-2) at 0.25 C and sustains more than 1400 h with 20% capacity loss. Pairing this anode with a Prussian blue cathode, the full battery can deliver an ultrahigh desalination capacity of 127.1 m gCl gBi-1. Our study milestones the understanding of conversion-type anode structures, which is an essential step toward the commercialization of aqueous batteries.

Tunneling Interpenetrative Lithium Ion Conduction Channels in Polymer-in-Ceramic Composite Solid Electrolytes.

Polymer-in-ceramic composite solid electrolytes (PIC-CSEs) provide important advantages over individual organic or inorganic solid electrolytes. In conventional PIC-CSEs, the ion conduction pathway is primarily confined to the ceramics, while the faster routes associated with the ceramic-polymer interface remain blocked. This challenge is associated with two key factors: (i) the difficulty in establishing extensive and uninterrupted ceramic-polymer interfaces due to ceramic aggregation; (ii) the ceramic-polymer interfaces are unresponsive to conducting ions because of their inherent incompatibility. Here, we propose a strategy by introducing polymer-compatible ionic liquids (PCILs) to mediate between ceramics and the polymer matrix. This mediation involves the polar groups of PCILs interacting with Li+ ions on the ceramic surfaces as well as the interactions between the polar components of PCILs and the polymer chains. This strategy addresses the ceramic aggregation issue, resulting in uniform PIC-CSEs. Simultaneously, it activates the ceramic-polymer interfaces by establishing interpenetrating channels that promote the efficient transport of Li+ ions across the ceramic phase, the ceramic-polymer interfaces, and the intervening pathways. Consequently, the obtained PIC-CSEs exhibit high ionic conductivity, exceptional flexibility, and robust mechanical strength. A PIC-CSE comprising poly(vinylidene fluoride) (PVDF) and 60 wt % PCIL-coated Li3Zr2Si2PO12 (LZSP) fillers showcasing an ionic conductivity of 0.83 mS cm-1, a superior Li+ ion transference number of 0.81, and an elongation of ∼300% at 25 °C could be produced on meter-scale. Its lithium metal pouch cells show high energy densities of 424.9 Wh kg-1 (excluding packing films) and puncture safety. This work paves the way for designing PIC-CSEs with commercial viability.

Anomalous thermodynamic cost of clock synchronization.

Clock synchronization is critically important in positioning, navigation and timing systems. While its performance has been intensively studied in a wide range of disciplines, much less is known for the fundamental thermodynamics of clock synchronization‒what limits the precision and how to optimize the energy cost for clock synchronization. Here, we report the first experimental investigation of two stochastic autonomous clocks synchronization, unveiling the thermodynamic relation between the entropy cost and clock synchronization in an open cavity optomechanical system. Two interacting clocks are synchronized spontaneously owing to the disparate decay rates of hybrid modes by engineering the controllable cavity-mediated dissipative coupling. The measured dependence of the degree of synchronization on the overall entropy cost exhibits an unexpected non-monotonic characteristic, while the relation between the degree of synchronization and the entropy cost for the synchronization is monotonically decreasing. The investigation of transient dynamics of clock synchronization exposes a trade-off between energy and time consumption. Our results demonstrate the possibility of clock synchronization in an effective linear system, reveal the fundamental relation between clock synchronization and thermodynamics, and have a great potential for precision measurements, distributed quantum networks, and biological science.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.