Exo-atmospheric vehicles are constrained by limited maneuverability,which leads to the contradiction between evasive maneuver and precision strike.To address the problem of Integrated Evasion and Impact(IEI)decision u...Exo-atmospheric vehicles are constrained by limited maneuverability,which leads to the contradiction between evasive maneuver and precision strike.To address the problem of Integrated Evasion and Impact(IEI)decision under multi-constraint conditions,a hierarchical intelligent decision-making method based on Deep Reinforcement Learning(DRL)was proposed.First,an intelligent decision-making framework of“DRL evasion decision”+“impact prediction guidance decision”was established:it takes the impact point deviation correction ability as the constraint and the maximum miss distance as the objective,and effectively solves the problem of poor decisionmaking effect caused by the large IEI decision space.Second,to solve the sparse reward problem faced by evasion decision-making,a hierarchical decision-making method consisting of maneuver timing decision and maneuver duration decision was proposed,and the corresponding Markov Decision Process(MDP)was designed.A detailed simulation experiment was designed to analyze the advantages and computational complexity of the proposed method.Simulation results show that the proposed model has good performance and low computational resource requirement.The minimum miss distance is 21.3 m under the condition of guaranteeing the impact point accuracy,and the single decision-making time is 4.086 ms on an STM32F407 single-chip microcomputer,which has engineering application value.展开更多
Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor i...Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact mo...BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.展开更多
High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their inve...High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma,demonstrating positive cor-relations between PES1 and programmed death-ligand 1(PD-L1)expression(51.72%for PES1 and 58.62%for PD-L1),as well as associations with lymph node metastasis and tumor invasion depth.However,the relationship between PES1 and PD-L1 remains incompletely defined.To further address this gap,we ana-lyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+T cell infiltration,along-side a positive correlation with PD-L1 expression.Based on prior findings,we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms.While these pathways require experimental validation,our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.展开更多
Ovarian cancer(OC),a highly lethal gynaecological malignancy,is often diagnosed at advanced stages,resulting in a poor prognosis.Sialylation,an important form of glycosylation,significantly contributes to the progress...Ovarian cancer(OC),a highly lethal gynaecological malignancy,is often diagnosed at advanced stages,resulting in a poor prognosis.Sialylation,an important form of glycosylation,significantly contributes to the progression of various solid tumours,including OC.Aberrant sialylation promotes tumour progression and metastasis by altering the structure and function of glycoproteins.Although its role in several solid tumours is well documented,the role of abnormal sialylation in OC and its potential as a therapeutic target remain poorly understood.This review highlights sialylation as a key regulator of the progression,metastasis,and drug resistance of OC.A deeper understanding of altered sialylation can contribute to the identification of novel therapeutic strategies for OC.展开更多
The discovery of glycosylated RNA molecules,known as glycoRNAs,introduces a novel dimension to cellular biology.This commentary explores the transformative findings surrounding glycoRNAs,emphasizing their unique roles...The discovery of glycosylated RNA molecules,known as glycoRNAs,introduces a novel dimension to cellular biology.This commentary explores the transformative findings surrounding glycoRNAs,emphasizing their unique roles in cancer progression and the therapeutic opportunities they present.GlycoRNAs,through interactions with lectins and immune receptors,may contribute to tumor immune evasion.Moreover,the therapeutic potential of this emerging knowledge includes interventions targeting glycoRNA synthesis and modulation of associated signaling pathways.By highlighting these critical insights,this commentary aims to encourage the development of innovative strategies that could improve cancer prognosis and treatment.展开更多
Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the up...Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the upstream regulatory mechanisms linking neural inputs to immune evasion and metabolic reprogramming remain incompletely understood.We systematically summarize current evidence from molecular,cellular,and immunological studies to elucidate how neurotransmitter-dependent mechanisms drive dynamic changes in the tumor microenvironment through the regulation of tumor cells and immune cells,and map the complex interaction networks between the nervous system and tumor progression.We propose a unifying“neuro-metabolic-immune axis”framework that highlights the dual role of neurotransmitters in suppressing anti-tumor immunity and facilitating tumor adaptation.By mapping this axis,we reveal new insights into tumor ecology and identify neural pathways as promising therapeutic targets.Targeting these pathways may enhance immunotherapy and disrupt tumor-supportive metabolism,offering new directions in precision oncology.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)are effective cancer treatments;however,a significant proportion of colorectal cancer(CRC)patients exhibit limited re-sponses to ICI therapy.KAT6A has been strongly associa...BACKGROUND Immune checkpoint inhibitors(ICIs)are effective cancer treatments;however,a significant proportion of colorectal cancer(CRC)patients exhibit limited re-sponses to ICI therapy.KAT6A has been strongly associated with cancer initiation and progression.AIM To examine the role of KAT6A in CRC progression and immune evasion.METHODS The functional role of KAT6A was evaluated through genetic knockdown,pharmacological inhibition(WM-3835),and CRISPR/dCas9-mediated epigenetic editing in CRC cells.T cell-mediated apoptosis was assessed using co-culture models,and H3K23pr was measured via chromatin immunoprecipitation assays.PD-L1 expression at mRNA and protein levels was analyzed under KAT6A knockdown conditions.RESULTS KAT6A suppression reduced CRC cell proliferation,invasion,and migration.Pharmacological or epigenetic disruption of KAT6A phenocopied these effects,with dose-dependent reductions in H3K23pr(28.4%residual at 10μM)and PD-L1 expression.KAT6A knockdown enhanced T cell-mediated apoptosis,evidenced by increased expression of granzyme B and perforin.Mechanistically,KAT6A loss decreased H3K23pr and reduced RNA polymerase II occupancy on the PD-L1 promoter,leading to suppressed PD-L1 transcription.CRISPR/dCas9-mediated H3K23pr editing at the PD-L1 promoter directly modulated immune evasion,confirming its causal role.Overexpression of PD-L1 mitigated the inhibitory effects of KAT6A knockdown on CRC progression and immune evasion.CONCLUSION KAT6A drives CRC progression and immune evasion by promoting histone H3 propionylation to epigenetically activate PD-L1 expression.Targeting KAT6A or its downstream H3K23pr-PD-L1 axis represents a promising therapeutic strategy to overcome ICI resistance in CRC.展开更多
Cold tumors,defined by insufficient immune cell infiltration and a highly immunosuppressive tumor microenvironment(TME),exhibit limited responsiveness to conventional immunotherapies.This reviewsystematically summariz...Cold tumors,defined by insufficient immune cell infiltration and a highly immunosuppressive tumor microenvironment(TME),exhibit limited responsiveness to conventional immunotherapies.This reviewsystematically summarizes the mechanisms of immune evasion and the therapeutic strategies for cold tumors as revealed by multiomics technologies.By integrating genomic,transcriptomic,proteomic,metabolomic,and spatialmulti-omics data,the review elucidates key immune evasionmechanisms,including activation of the WNT/β-catenin pathway,transforming growth factor-β(TGF-β)–mediated immunosuppression,metabolic reprogramming(e.g.,lactate accumulation),and aberrant expression of immune checkpoint molecules.Furthermore,this review proposes multi-dimensional therapeutic strategies,such as targeting immunosuppressive pathways(e.g.,programmed death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitors combined with TGF-βblockade),reshaping the TME through chemokine-based therapies,oncolytic viruses,and vascular normalization,and metabolic interventions(e.g.,inhibition of lactate dehydrogenase A(LDHA)or glutaminase(GLS)).In addition,personalized neoantigen vaccines and engineered cell therapies(e.g.,T cell receptor-engineered T(TCR-T)and natural killer(NK)cells)show promising potential.Emerging evidence also highlights the role of epigenetic regulation(e.g.,histone deacetylase(HDAC)inhibitors)and N6-Methyladenosine(m6A)RNA modifications in reversing immune evasion.Despite the promising insights offered by multi-omics integration in guiding precision immunotherapy,challenges remain in clinical translation,including data heterogeneity,target-specific toxicity,and limitations in preclinical models.Future efforts should focus on coupling dynamic multi-omics technologies with intelligent therapeutic design to convert cold tumors into immunologically active(“hot”)microenvironments,ultimately facilitating breakthroughs in personalized immunotherapy.展开更多
BACKGROUND Tumor-associated macrophages(TAMs)have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma(HCC).Nevertheless,a comprehensive quantitative analysis of TAMs in...BACKGROUND Tumor-associated macrophages(TAMs)have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma(HCC).Nevertheless,a comprehensive quantitative analysis of TAMs in HCC remained insufficient.Therefore,the objective of this study was to employ bibliometric methods to investigate the development trends and research frontiers pertaining to this field.AIM To determine the knowledge structure and current research hotspots by bibliometric analysis of scholarly papers pertaining to TAMs in HCC.METHODS The present study employed the Web of Science Core Collection to identify all papers related to TAMs in HCC research.Utilizing the Analysis Platform of Bibliometrics,CiteSpace 6.2.R4,and Vosviewer 1.6.19,the study conducted a comprehensive analysis encompassing multiple dimensions such as publication quantity,countries of origin,affiliated institutions,publishing journals,contributing authors,co-references,author keywords,and emerging frontiers within this research domain.RESULTS A thorough examination was undertaken on 818 papers within this particular field,published between January 1,1985 to September 1,2023,which has witnessed a substantial surge in scholarly contributions since 2012,with a notable outbreak in 2019.China was serving as the central hub in this field,with Fudan University leading in terms of publications and citations.Chinese scholars have taken the forefront in driving the research expansion within this field.Hepatology emerged as the most influential journal in this field.The study by Qian and Pollard in 2010 received the highest number of co-citations.It was observed that the citation bursts of references coincided with the outbreak of publications.Notably,“tumor microenvironment”,“immunotherapy”,“prognostic”,“inflammation”,and“polarization”,etc.emerged as frequently occurring keywords in this field.Of particular interest,“immune evasion”,“immune infiltration”,and“cancer genome atlas”were identified as emerging frontiers in recent research.CONCLUSION The field of TAMs in HCC exhibited considerable potential,as evidenced by the promising prospects of immunotherapeutic interventions targeting TAMs for the amelioration of HCC.The emerging frontiers in this field primarily revolved around modulating the immunosuppressive characteristics of TAMs within a liver-specific immune environment,with a focus on how to counter immune evasion and reduce immune infiltration.展开更多
Candida albicans(C.albicans)represents one of the most prevalent opportunistic fungal pathogens in cancer patients.Although the association between C.albicans and cancer has been recognized for decades,the causal rela...Candida albicans(C.albicans)represents one of the most prevalent opportunistic fungal pathogens in cancer patients.Although the association between C.albicans and cancer has been recognized for decades,the causal relationship,whether C.albicans infection is a consequence of cancer or a direct contributor to cancer development-remains a subject of intensive investigation.Recently,the complex interplay between microbes and cancer has garnered significant attention within the scientific community,with growing interest in elucidating the underlying molecular mechanisms.This review systematically examines the biological characteristics of C.albicans,its multifaceted interactions with the host,and its relationship with the intestinal microbiota.Additionally,it provides a comprehensive analysis of the association between C.albicans and the development of various malignancies,with particular emphasis on digestive tract cancers.The review also identifies critical knowledge gaps and apparent contradictions in existing research,highlighting potential avenues for breakthroughs that will advance the efficient and accurate screening,diagnosis,and treatment of cancer.展开更多
Aiming at the missile avoidance problem of the unmanned aerial vehicle(UAV)in complex obstacle environments,this work proposes a collision-avoidance method based on receding horizon optimization.The proposed method ge...Aiming at the missile avoidance problem of the unmanned aerial vehicle(UAV)in complex obstacle environments,this work proposes a collision-avoidance method based on receding horizon optimization.The proposed method generated a specific trajectory for the UAV to effectively induce the proportional navigation missile to successfully intercept the obstacle,thereby accomplishing the evasive maneuver.The evasive maneuver was divided into two distinct stages,namely the collision-inducing phase and the fast departure phase.The obstacle potential field-based target selection algorithm was employed to identify the most appropriate target obstacle,while the induced trajectory was determined through a combination of receding horizon optimization and the hp-adaptive pseudo-spectral method.Simulation experiments were carried out under three different types of obstacle environments and one multiobstacle environment,and the simulation results show that the method proposed in this paper greatly improves the success rate of UAV evasive maneuvers,proving the effectiveness of this method.展开更多
Vehicle collision avoidance(CA)has been widely studied to improve road traffic safety.However,most evasion assistance control methods face challenges in effectively coordinating collision avoidance safety and human-ma...Vehicle collision avoidance(CA)has been widely studied to improve road traffic safety.However,most evasion assistance control methods face challenges in effectively coordinating collision avoidance safety and human-machine interaction conflict.This paper introduces a novel multi-mode evasion assistance control(MEAC)method for intelligent distributed-drive electric vehicles.A reference safety area is established considering the vehicle safety and stability requirements,which serves as a guiding principle for evading obstacles.The proposed method includes two control modes:Shared-EAC(S-EAC)and Emergency-EAC(E-EAC).In S-EAC,an integrated human-machine authority allocation mechanism is designed to mitigate conflicts between human drivers and the control system during collision avoidance.The E-EAC mode is tailored for situations where the driver has no collision avoidance behavior and utilizes model predictive control to generate additional yaw moments for collision avoidance.Simulation and experimental results indicate that the proposed method reduces human-machine conflict and assists the driver in safe collision avoidance in the S-EAC mode under various driver conditions.In addition,it enhances the vehicle responsiveness and reduces the extent of emergency steering in the E-EAC mode while improving the safety and stability during the collision avoidance process.展开更多
1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demons...1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.展开更多
Glycosylphosphatidylinositol(GPI)anchoring represents a fundamental post-translational modification in eukaryotic cells.In fungi,this modification facilitates diverse biological functions through protein targeting to ...Glycosylphosphatidylinositol(GPI)anchoring represents a fundamental post-translational modification in eukaryotic cells.In fungi,this modification facilitates diverse biological functions through protein targeting to the cell wall,yet research on its roles in plant pathogenic fungi remains limited.This study elucidates the function of GPI anchoring in the maize fungal pathogen Cochlibolus heterostrophus.The research demonstrates widespread accumulation of GPI-anchored proteins in hyphae,appressorium and infection hyphae of C.heterostrophus.Deletion of ChGPI7,encoding a crucial enzyme in GPI anchor biosynthesis,substantially reduced vegetative growth,conidiation,and virulence through impaired appressorium formation and invasive growth.The ΔChgpi7 mutants exhibited marked deficiencies in cell wall integrity,leading to decreased stress resistance.Both ChGPI7 deletion and hydro fluoric acid(HF)pyridine treatment eliminated cell wall GPI-anchored proteins and exposed chitin,indicating that GPI-anchored proteins shield chitin from host immune recognition.Analysis identified 124 predicted GPI-anchored proteins in C.heterostrophus,including the putative cell wall glycoprotein ChFEM1.The deletion of ChFEM1 similarly reduced virulence and compromised infection structures and cell wall integrity.Additionally,ChGPI7 influenced both the cell wall localization and protein abundance of ChFEM1.These findings demonstrate that GPI anchoring mediates cell wall integrity and immune evasion during C.heterostrophus infection.展开更多
In practical combat scenarios,Hypersonic Glide Vehicles(HGV)face the challenge of evading Successive Pursuers from the Same Direction while satisfying the Homing Constraint(SPSDHC).To address this problem,this paper p...In practical combat scenarios,Hypersonic Glide Vehicles(HGV)face the challenge of evading Successive Pursuers from the Same Direction while satisfying the Homing Constraint(SPSDHC).To address this problem,this paper proposes a parameterized evasion guidance algorithm based on reinforcement learning.The three-player optimal evasion strategy is firstly analyzed and approximated by parametrization.The switching acceleration command of HGV optimal evasion strategy considering the upper limit of missile acceleration command is analyzed based on the optimal control theory.The terminal miss of HGV in the case of evading two missiles is analyzed,which means that the three-player optimal evasion strategy is a linear combination of two one-toone strategies.Then,a velocity control algorithm is proposed to increase the terminal miss by actively controlling the flight speed of the HGV based on the parametrized evasion strategy.The reinforcement learning method is used to implement the strategy in real time and a reward function is designed by deducing homing strategy for the HGV to approach the target,which ensures that the HGV satisfies the homing constraint.Experimental results demonstrate the feasibility and robustness of the proposed parameterized evasion strategy,which enables the HGV to generate maximum terminal miss and satisfy homing constraint when facing single or double missiles.展开更多
Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive imm...Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive immunity evasion have been established,but how HBV evades the innate surveillance is less clear.There are three types of host cells involving in the innate immune responses against HBV infection:Hepatocytes,hepatic nonparenchymal cells and conventional innate immune cells.Among these,hepatocytes are the only target cells that are susceptible to HBV infection and the only confirmed site where HBV replication takes place.This review focuses on the hepatocyte-intrinsic innate immunity;one of the earliest host defense responses.After entering hepatocytes,the viral components can be sensed by the cellular pattern recognition receptors.This triggers downstream antiviral responses capable of inhibiting viral replication and even degrading the viral DNA genome directly or indirectly.However,HBV has evolved a variety of sophisticated strategies to evade intracellular immune defense,resulting in the establishment of infection.Here,we provide insights into the mechanisms of the intrinsic innate immune response of hepatocytes and how HBV escapes these defense mechanisms.Hopefully,this will lay the foundation for the development of novel anti-HBV therapies.展开更多
Modern medicine faces the formidable challenge of cancer because of its ability to evade immune surveillance and cultivate resistance to conventional therapies. Cancer cells, when overexpressed with CD47, send a “don...Modern medicine faces the formidable challenge of cancer because of its ability to evade immune surveillance and cultivate resistance to conventional therapies. Cancer cells, when overexpressed with CD47, send a “don’t eat me” signal to macrophages, successfully shielding them from immune destruction. Similarly, tyrosine kinase inhibitors (TKIs) have revolutionized cancer treatment by targeting oncogenic pathways, but their effectiveness is often compromised by resistance and minimal residual disease. This review explores a novel combination of CD47-SIRP-blockade and TKIs, addressing the limitations of monotherapies in cancer treatment. Disrupting the CD47-SIRPα interaction stimulates macrophage-mediated phagocytosis and revives exhausted T cells, while TKIs simultaneously target tumor growth drivers. Confirmation from preclinical studies indicates that this combination is capable of enhancing anti-tumor immunity and remodeling tumor microenvironments for enhanced therapeutic outcomes. However, hematotoxicity and tumor heterogeneity present challenges in the path to clinical translation. This review presents current findings, identifies key research areas, and proposes future directions to enhance this combinatorial approach. In the midst of a new era in cancer treatment, immune modulation combined with targeted therapies promises to offer more effective, less toxic, and personalized treatment options. This combination approach has the potential to significantly improve cancer treatment strategies by overcoming current therapeutic limitations.展开更多
African swine fever virus(ASFV)pB318L is an important protein for viral replication that acts as a membrane-bound trans-geranylgeranyl-diphosphate synthase(GGPPS)catalyzing the condensation of isopentenyl diphosphate(...African swine fever virus(ASFV)pB318L is an important protein for viral replication that acts as a membrane-bound trans-geranylgeranyl-diphosphate synthase(GGPPS)catalyzing the condensation of isopentenyl diphosphate(IPP)with allylic diphosphates.Recently we solved the crystal structure pB318L lacking N-terminal transmembrane region and performed a preliminary structural analysis.In this study,structure-based mutagenesis study and geranylgeranyl pyrophosphate(GGPP)production assay further revealed the key residues for the GGPPS activity.Structural comparison showed pB318L displays a strong similarity to typical GGPPSs instead of protein prenyltransferases.The phylogenetic analysis indicated pB318L may share a common ancestor with the GGPPSs from Brassicaceae plants rather than from its natural host.The subcellular localization analysis showed pB318L is localized in both nucleus and cytoplasm(including the endoplasmic reticulum membrane and mitochondria outer membrane).A unique N-terminal nuclear localization signal(NLS)following the transmembrane region was discovered in pB318L and the NLS was confirmed to be required for the nuclear import.We further revealed the NLS plays an essential role in the interaction with nuclear transporter karyopherin subunit alpha 1(KPNA1).Their interaction may suppress signal transducers and activators of transcription 1(STAT1)translocation and subsequently competitively inhibit nuclear import of IFNstimulated gene factor 3(ISGF3)complex.Our biochemical,structural and cellular analyses provide novel insights to pB318L that acts as an essential GGPPS that promotes viral replication and as a nuclear import protein that may be involved in immune evasion of ASFV.展开更多
The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid ...The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors.In response to low oxygen availability,the Hypoxia Inducible Factors(HIF-1/2/3α)act as metabolic mediators,producing extracellular metabolites in the tumor microenvironment that influence the immune cells.The modulation of lactate and adenosine on immune evasion has been widely described;however,under hypoxic conditions,it has been barely addressed.Evidence has demonstrated an interplay between cancer and the immune cells,and the present review explores thefindings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context.Moreover,new insights based on systemic oxygen administration are discussed,which might counterbalance the effect mediated by lactate and adenosine,to recover anti-tumor immunity.Thus,the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.展开更多
基金co-supported by the National Natural Science Foundation of China(No.62103432)the China Postdoctoral Science Foundation(No.284881)the Young Talent fund of University Association for Science and Technology in Shaanxi,China(No.20210108)。
文摘Exo-atmospheric vehicles are constrained by limited maneuverability,which leads to the contradiction between evasive maneuver and precision strike.To address the problem of Integrated Evasion and Impact(IEI)decision under multi-constraint conditions,a hierarchical intelligent decision-making method based on Deep Reinforcement Learning(DRL)was proposed.First,an intelligent decision-making framework of“DRL evasion decision”+“impact prediction guidance decision”was established:it takes the impact point deviation correction ability as the constraint and the maximum miss distance as the objective,and effectively solves the problem of poor decisionmaking effect caused by the large IEI decision space.Second,to solve the sparse reward problem faced by evasion decision-making,a hierarchical decision-making method consisting of maneuver timing decision and maneuver duration decision was proposed,and the corresponding Markov Decision Process(MDP)was designed.A detailed simulation experiment was designed to analyze the advantages and computational complexity of the proposed method.Simulation results show that the proposed model has good performance and low computational resource requirement.The minimum miss distance is 21.3 m under the condition of guaranteeing the impact point accuracy,and the single decision-making time is 4.086 ms on an STM32F407 single-chip microcomputer,which has engineering application value.
基金supported by the National Key Research and Development Program of China(No.2022YFE0102100)the National Natural Science Foundation of China(Nos.U22A20307 and 81930041)。
文摘Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.
基金Supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBJC00001the Key Discipline Special Project of Tianjin Municipal Health Commission,No.TJWJ2022XK016.
文摘BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
文摘High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma,demonstrating positive cor-relations between PES1 and programmed death-ligand 1(PD-L1)expression(51.72%for PES1 and 58.62%for PD-L1),as well as associations with lymph node metastasis and tumor invasion depth.However,the relationship between PES1 and PD-L1 remains incompletely defined.To further address this gap,we ana-lyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+T cell infiltration,along-side a positive correlation with PD-L1 expression.Based on prior findings,we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms.While these pathways require experimental validation,our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.
基金supported by Hubei Provincial Natural Science Foundation of China(No.2023AFB670).
文摘Ovarian cancer(OC),a highly lethal gynaecological malignancy,is often diagnosed at advanced stages,resulting in a poor prognosis.Sialylation,an important form of glycosylation,significantly contributes to the progression of various solid tumours,including OC.Aberrant sialylation promotes tumour progression and metastasis by altering the structure and function of glycoproteins.Although its role in several solid tumours is well documented,the role of abnormal sialylation in OC and its potential as a therapeutic target remain poorly understood.This review highlights sialylation as a key regulator of the progression,metastasis,and drug resistance of OC.A deeper understanding of altered sialylation can contribute to the identification of novel therapeutic strategies for OC.
基金funded by the Korea Health Technology R&D Project through the Bio and Medical Technology Development Program of the National Research Foundation,supported by the Ministry of Science and ICT(RS-2023-00210847)and the Ministry of Education(RS-2024-00463331),Republic of Korea.
文摘The discovery of glycosylated RNA molecules,known as glycoRNAs,introduces a novel dimension to cellular biology.This commentary explores the transformative findings surrounding glycoRNAs,emphasizing their unique roles in cancer progression and the therapeutic opportunities they present.GlycoRNAs,through interactions with lectins and immune receptors,may contribute to tumor immune evasion.Moreover,the therapeutic potential of this emerging knowledge includes interventions targeting glycoRNA synthesis and modulation of associated signaling pathways.By highlighting these critical insights,this commentary aims to encourage the development of innovative strategies that could improve cancer prognosis and treatment.
基金Supported by the National Natural Science Foundation of China,No.82272719the Natural Science Foundation of Guangdong Province,No.2023A1515012724 and No.2024A1515013249the Science and Technology Projects in Guangzhou,No.2024A04J5205.
文摘Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment,profoundly influencing key processes such as tumor immune evasion,metabolic reprogramming,and metastasis.However,the upstream regulatory mechanisms linking neural inputs to immune evasion and metabolic reprogramming remain incompletely understood.We systematically summarize current evidence from molecular,cellular,and immunological studies to elucidate how neurotransmitter-dependent mechanisms drive dynamic changes in the tumor microenvironment through the regulation of tumor cells and immune cells,and map the complex interaction networks between the nervous system and tumor progression.We propose a unifying“neuro-metabolic-immune axis”framework that highlights the dual role of neurotransmitters in suppressing anti-tumor immunity and facilitating tumor adaptation.By mapping this axis,we reveal new insights into tumor ecology and identify neural pathways as promising therapeutic targets.Targeting these pathways may enhance immunotherapy and disrupt tumor-supportive metabolism,offering new directions in precision oncology.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)are effective cancer treatments;however,a significant proportion of colorectal cancer(CRC)patients exhibit limited re-sponses to ICI therapy.KAT6A has been strongly associated with cancer initiation and progression.AIM To examine the role of KAT6A in CRC progression and immune evasion.METHODS The functional role of KAT6A was evaluated through genetic knockdown,pharmacological inhibition(WM-3835),and CRISPR/dCas9-mediated epigenetic editing in CRC cells.T cell-mediated apoptosis was assessed using co-culture models,and H3K23pr was measured via chromatin immunoprecipitation assays.PD-L1 expression at mRNA and protein levels was analyzed under KAT6A knockdown conditions.RESULTS KAT6A suppression reduced CRC cell proliferation,invasion,and migration.Pharmacological or epigenetic disruption of KAT6A phenocopied these effects,with dose-dependent reductions in H3K23pr(28.4%residual at 10μM)and PD-L1 expression.KAT6A knockdown enhanced T cell-mediated apoptosis,evidenced by increased expression of granzyme B and perforin.Mechanistically,KAT6A loss decreased H3K23pr and reduced RNA polymerase II occupancy on the PD-L1 promoter,leading to suppressed PD-L1 transcription.CRISPR/dCas9-mediated H3K23pr editing at the PD-L1 promoter directly modulated immune evasion,confirming its causal role.Overexpression of PD-L1 mitigated the inhibitory effects of KAT6A knockdown on CRC progression and immune evasion.CONCLUSION KAT6A drives CRC progression and immune evasion by promoting histone H3 propionylation to epigenetically activate PD-L1 expression.Targeting KAT6A or its downstream H3K23pr-PD-L1 axis represents a promising therapeutic strategy to overcome ICI resistance in CRC.
基金The 75th Batch of China Postdoctoral Science Foundation projects(No.2024M754279)Natural Science Foundation of Jiangsu Province(No.BK20240738)+2 种基金Basic Science(Natural Science)Research Project in Universities of Jiangsu Province(No.24KJB360004)Jiangsu Province Chinese Medicine Science and Technology Development Plan Youth Talent Project(No.QN202206)Nanjing University of ChineseMedicine Luo Linxiu Teacher Development Fund Project(No.LLX202310).
文摘Cold tumors,defined by insufficient immune cell infiltration and a highly immunosuppressive tumor microenvironment(TME),exhibit limited responsiveness to conventional immunotherapies.This reviewsystematically summarizes the mechanisms of immune evasion and the therapeutic strategies for cold tumors as revealed by multiomics technologies.By integrating genomic,transcriptomic,proteomic,metabolomic,and spatialmulti-omics data,the review elucidates key immune evasionmechanisms,including activation of the WNT/β-catenin pathway,transforming growth factor-β(TGF-β)–mediated immunosuppression,metabolic reprogramming(e.g.,lactate accumulation),and aberrant expression of immune checkpoint molecules.Furthermore,this review proposes multi-dimensional therapeutic strategies,such as targeting immunosuppressive pathways(e.g.,programmed death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitors combined with TGF-βblockade),reshaping the TME through chemokine-based therapies,oncolytic viruses,and vascular normalization,and metabolic interventions(e.g.,inhibition of lactate dehydrogenase A(LDHA)or glutaminase(GLS)).In addition,personalized neoantigen vaccines and engineered cell therapies(e.g.,T cell receptor-engineered T(TCR-T)and natural killer(NK)cells)show promising potential.Emerging evidence also highlights the role of epigenetic regulation(e.g.,histone deacetylase(HDAC)inhibitors)and N6-Methyladenosine(m6A)RNA modifications in reversing immune evasion.Despite the promising insights offered by multi-omics integration in guiding precision immunotherapy,challenges remain in clinical translation,including data heterogeneity,target-specific toxicity,and limitations in preclinical models.Future efforts should focus on coupling dynamic multi-omics technologies with intelligent therapeutic design to convert cold tumors into immunologically active(“hot”)microenvironments,ultimately facilitating breakthroughs in personalized immunotherapy.
基金Supported by the Sanming Project of Medicine in Shenzhen,No.SZZYSM202111002Shenzhen Medical Research Fund,No.B2302008+1 种基金Shenzhen Science and Technology Program,No.JCYJ20220531091809022,No.JSGG20210802093208023,No.JCYJ20220818103402006,and No.ZDSYS201606081515458Traditional Chinese Medicine Bureau of Guangdong Province,No.20231286.
文摘BACKGROUND Tumor-associated macrophages(TAMs)have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma(HCC).Nevertheless,a comprehensive quantitative analysis of TAMs in HCC remained insufficient.Therefore,the objective of this study was to employ bibliometric methods to investigate the development trends and research frontiers pertaining to this field.AIM To determine the knowledge structure and current research hotspots by bibliometric analysis of scholarly papers pertaining to TAMs in HCC.METHODS The present study employed the Web of Science Core Collection to identify all papers related to TAMs in HCC research.Utilizing the Analysis Platform of Bibliometrics,CiteSpace 6.2.R4,and Vosviewer 1.6.19,the study conducted a comprehensive analysis encompassing multiple dimensions such as publication quantity,countries of origin,affiliated institutions,publishing journals,contributing authors,co-references,author keywords,and emerging frontiers within this research domain.RESULTS A thorough examination was undertaken on 818 papers within this particular field,published between January 1,1985 to September 1,2023,which has witnessed a substantial surge in scholarly contributions since 2012,with a notable outbreak in 2019.China was serving as the central hub in this field,with Fudan University leading in terms of publications and citations.Chinese scholars have taken the forefront in driving the research expansion within this field.Hepatology emerged as the most influential journal in this field.The study by Qian and Pollard in 2010 received the highest number of co-citations.It was observed that the citation bursts of references coincided with the outbreak of publications.Notably,“tumor microenvironment”,“immunotherapy”,“prognostic”,“inflammation”,and“polarization”,etc.emerged as frequently occurring keywords in this field.Of particular interest,“immune evasion”,“immune infiltration”,and“cancer genome atlas”were identified as emerging frontiers in recent research.CONCLUSION The field of TAMs in HCC exhibited considerable potential,as evidenced by the promising prospects of immunotherapeutic interventions targeting TAMs for the amelioration of HCC.The emerging frontiers in this field primarily revolved around modulating the immunosuppressive characteristics of TAMs within a liver-specific immune environment,with a focus on how to counter immune evasion and reduce immune infiltration.
文摘Candida albicans(C.albicans)represents one of the most prevalent opportunistic fungal pathogens in cancer patients.Although the association between C.albicans and cancer has been recognized for decades,the causal relationship,whether C.albicans infection is a consequence of cancer or a direct contributor to cancer development-remains a subject of intensive investigation.Recently,the complex interplay between microbes and cancer has garnered significant attention within the scientific community,with growing interest in elucidating the underlying molecular mechanisms.This review systematically examines the biological characteristics of C.albicans,its multifaceted interactions with the host,and its relationship with the intestinal microbiota.Additionally,it provides a comprehensive analysis of the association between C.albicans and the development of various malignancies,with particular emphasis on digestive tract cancers.The review also identifies critical knowledge gaps and apparent contradictions in existing research,highlighting potential avenues for breakthroughs that will advance the efficient and accurate screening,diagnosis,and treatment of cancer.
基金Natural Science Foundation of Heilongjiang Province of China(Grant No.YQ2022F012)the Fundamental Research Funds for the Central Universities(Grant No.HIT.OCEF.2023010)to provide fund for conducting experiments.
文摘Aiming at the missile avoidance problem of the unmanned aerial vehicle(UAV)in complex obstacle environments,this work proposes a collision-avoidance method based on receding horizon optimization.The proposed method generated a specific trajectory for the UAV to effectively induce the proportional navigation missile to successfully intercept the obstacle,thereby accomplishing the evasive maneuver.The evasive maneuver was divided into two distinct stages,namely the collision-inducing phase and the fast departure phase.The obstacle potential field-based target selection algorithm was employed to identify the most appropriate target obstacle,while the induced trajectory was determined through a combination of receding horizon optimization and the hp-adaptive pseudo-spectral method.Simulation experiments were carried out under three different types of obstacle environments and one multiobstacle environment,and the simulation results show that the method proposed in this paper greatly improves the success rate of UAV evasive maneuvers,proving the effectiveness of this method.
基金Supported by National Key Research and Development Program of China(Grant Nos.2022YFE0117100 and 2021YFB250120101)National Natural Science Foundation of China(Grant No.52325212)+1 种基金Shanghai Municipal Automotive Industry Science,Technology Development Foundation(Grant No.2203)the SAIC Motor Corporation Limited(Grant No.2023023).
文摘Vehicle collision avoidance(CA)has been widely studied to improve road traffic safety.However,most evasion assistance control methods face challenges in effectively coordinating collision avoidance safety and human-machine interaction conflict.This paper introduces a novel multi-mode evasion assistance control(MEAC)method for intelligent distributed-drive electric vehicles.A reference safety area is established considering the vehicle safety and stability requirements,which serves as a guiding principle for evading obstacles.The proposed method includes two control modes:Shared-EAC(S-EAC)and Emergency-EAC(E-EAC).In S-EAC,an integrated human-machine authority allocation mechanism is designed to mitigate conflicts between human drivers and the control system during collision avoidance.The E-EAC mode is tailored for situations where the driver has no collision avoidance behavior and utilizes model predictive control to generate additional yaw moments for collision avoidance.Simulation and experimental results indicate that the proposed method reduces human-machine conflict and assists the driver in safe collision avoidance in the S-EAC mode under various driver conditions.In addition,it enhances the vehicle responsiveness and reduces the extent of emergency steering in the E-EAC mode while improving the safety and stability during the collision avoidance process.
文摘1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.
基金supported by the Fundamental Research Funds for the Central Universities,China(2021ZKPY007).
文摘Glycosylphosphatidylinositol(GPI)anchoring represents a fundamental post-translational modification in eukaryotic cells.In fungi,this modification facilitates diverse biological functions through protein targeting to the cell wall,yet research on its roles in plant pathogenic fungi remains limited.This study elucidates the function of GPI anchoring in the maize fungal pathogen Cochlibolus heterostrophus.The research demonstrates widespread accumulation of GPI-anchored proteins in hyphae,appressorium and infection hyphae of C.heterostrophus.Deletion of ChGPI7,encoding a crucial enzyme in GPI anchor biosynthesis,substantially reduced vegetative growth,conidiation,and virulence through impaired appressorium formation and invasive growth.The ΔChgpi7 mutants exhibited marked deficiencies in cell wall integrity,leading to decreased stress resistance.Both ChGPI7 deletion and hydro fluoric acid(HF)pyridine treatment eliminated cell wall GPI-anchored proteins and exposed chitin,indicating that GPI-anchored proteins shield chitin from host immune recognition.Analysis identified 124 predicted GPI-anchored proteins in C.heterostrophus,including the putative cell wall glycoprotein ChFEM1.The deletion of ChFEM1 similarly reduced virulence and compromised infection structures and cell wall integrity.Additionally,ChGPI7 influenced both the cell wall localization and protein abundance of ChFEM1.These findings demonstrate that GPI anchoring mediates cell wall integrity and immune evasion during C.heterostrophus infection.
基金supported by the National Natural Science Foundation of China(No.62103014)。
文摘In practical combat scenarios,Hypersonic Glide Vehicles(HGV)face the challenge of evading Successive Pursuers from the Same Direction while satisfying the Homing Constraint(SPSDHC).To address this problem,this paper proposes a parameterized evasion guidance algorithm based on reinforcement learning.The three-player optimal evasion strategy is firstly analyzed and approximated by parametrization.The switching acceleration command of HGV optimal evasion strategy considering the upper limit of missile acceleration command is analyzed based on the optimal control theory.The terminal miss of HGV in the case of evading two missiles is analyzed,which means that the three-player optimal evasion strategy is a linear combination of two one-toone strategies.Then,a velocity control algorithm is proposed to increase the terminal miss by actively controlling the flight speed of the HGV based on the parametrized evasion strategy.The reinforcement learning method is used to implement the strategy in real time and a reward function is designed by deducing homing strategy for the HGV to approach the target,which ensures that the HGV satisfies the homing constraint.Experimental results demonstrate the feasibility and robustness of the proposed parameterized evasion strategy,which enables the HGV to generate maximum terminal miss and satisfy homing constraint when facing single or double missiles.
基金Supported by Shenzhen Medical Research Fund,No.D2301010Shenzhen Science and Technology Program,No.RCYX20231211090346060。
文摘Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive immunity evasion have been established,but how HBV evades the innate surveillance is less clear.There are three types of host cells involving in the innate immune responses against HBV infection:Hepatocytes,hepatic nonparenchymal cells and conventional innate immune cells.Among these,hepatocytes are the only target cells that are susceptible to HBV infection and the only confirmed site where HBV replication takes place.This review focuses on the hepatocyte-intrinsic innate immunity;one of the earliest host defense responses.After entering hepatocytes,the viral components can be sensed by the cellular pattern recognition receptors.This triggers downstream antiviral responses capable of inhibiting viral replication and even degrading the viral DNA genome directly or indirectly.However,HBV has evolved a variety of sophisticated strategies to evade intracellular immune defense,resulting in the establishment of infection.Here,we provide insights into the mechanisms of the intrinsic innate immune response of hepatocytes and how HBV escapes these defense mechanisms.Hopefully,this will lay the foundation for the development of novel anti-HBV therapies.
文摘Modern medicine faces the formidable challenge of cancer because of its ability to evade immune surveillance and cultivate resistance to conventional therapies. Cancer cells, when overexpressed with CD47, send a “don’t eat me” signal to macrophages, successfully shielding them from immune destruction. Similarly, tyrosine kinase inhibitors (TKIs) have revolutionized cancer treatment by targeting oncogenic pathways, but their effectiveness is often compromised by resistance and minimal residual disease. This review explores a novel combination of CD47-SIRP-blockade and TKIs, addressing the limitations of monotherapies in cancer treatment. Disrupting the CD47-SIRPα interaction stimulates macrophage-mediated phagocytosis and revives exhausted T cells, while TKIs simultaneously target tumor growth drivers. Confirmation from preclinical studies indicates that this combination is capable of enhancing anti-tumor immunity and remodeling tumor microenvironments for enhanced therapeutic outcomes. However, hematotoxicity and tumor heterogeneity present challenges in the path to clinical translation. This review presents current findings, identifies key research areas, and proposes future directions to enhance this combinatorial approach. In the midst of a new era in cancer treatment, immune modulation combined with targeted therapies promises to offer more effective, less toxic, and personalized treatment options. This combination approach has the potential to significantly improve cancer treatment strategies by overcoming current therapeutic limitations.
基金supported by the grants from the National Natural Science Foundation of China to Heng Zhang(31970152)the Strategic Priority Research Program of CAS to Yu-Hui Dong(XDB37040302)the CAS Emergency Research Project on African Swine Fever to Yu-Hui Dong(Grant KJZDSW-L06-01).
文摘African swine fever virus(ASFV)pB318L is an important protein for viral replication that acts as a membrane-bound trans-geranylgeranyl-diphosphate synthase(GGPPS)catalyzing the condensation of isopentenyl diphosphate(IPP)with allylic diphosphates.Recently we solved the crystal structure pB318L lacking N-terminal transmembrane region and performed a preliminary structural analysis.In this study,structure-based mutagenesis study and geranylgeranyl pyrophosphate(GGPP)production assay further revealed the key residues for the GGPPS activity.Structural comparison showed pB318L displays a strong similarity to typical GGPPSs instead of protein prenyltransferases.The phylogenetic analysis indicated pB318L may share a common ancestor with the GGPPSs from Brassicaceae plants rather than from its natural host.The subcellular localization analysis showed pB318L is localized in both nucleus and cytoplasm(including the endoplasmic reticulum membrane and mitochondria outer membrane).A unique N-terminal nuclear localization signal(NLS)following the transmembrane region was discovered in pB318L and the NLS was confirmed to be required for the nuclear import.We further revealed the NLS plays an essential role in the interaction with nuclear transporter karyopherin subunit alpha 1(KPNA1).Their interaction may suppress signal transducers and activators of transcription 1(STAT1)translocation and subsequently competitively inhibit nuclear import of IFNstimulated gene factor 3(ISGF3)complex.Our biochemical,structural and cellular analyses provide novel insights to pB318L that acts as an essential GGPPS that promotes viral replication and as a nuclear import protein that may be involved in immune evasion of ASFV.
文摘The tumor microenvironment(TME)is characterized by a symbiosis between cancer cells and the immune cells.The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors.In response to low oxygen availability,the Hypoxia Inducible Factors(HIF-1/2/3α)act as metabolic mediators,producing extracellular metabolites in the tumor microenvironment that influence the immune cells.The modulation of lactate and adenosine on immune evasion has been widely described;however,under hypoxic conditions,it has been barely addressed.Evidence has demonstrated an interplay between cancer and the immune cells,and the present review explores thefindings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context.Moreover,new insights based on systemic oxygen administration are discussed,which might counterbalance the effect mediated by lactate and adenosine,to recover anti-tumor immunity.Thus,the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.
