BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor prognosis.The BRAF^(V600E) mutation is closely related to the formation of...BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor prognosis.The BRAF^(V600E) mutation is closely related to the formation of an immunosuppressive microenvironment.However,the correlation between BRAF^(V600E) mutation and changes in local immune microenvironment of CRC is not clear.AIM To explore the effect and mechanism of BRAF^(V600E) mutant on the immune microenvironment of CRC.METHODS Thirty patients with CRC were included in this study:20 in a control group and 10 in a treatment group.The density of microvessels and microlymphatic vessels,and M2 subtype macrophages in tumor tissues were detected by immunohistochemistry.Screening and functional analysis of exosomal long noncoding RNAs(lncRNAs)were performed by transcriptomics.The proliferation and migration of human umbilical vein endothelial cells(HUVECs)and human lymphatic endothelial cells(HLECs)were detected by CCK-8 assay and scratch test,respectively.The tube-forming ability of endothelial cells was detected by tube formation assay.The macrophage subtypes were obtained by flow cytometry.The expression of vascular endothelial growth factor(VEGF)-A,basic fibroblast growth factor(bFGF),transforming growth factor(TGF)-β1,VEGF-C,claudin-5,occludin,zonula occludens(ZO)-1,fibroblast activation protein,andα-smooth muscle actin was assessed by western blot analysis.The levels of cytokines interleukin(IL)-6,TGF-β1,and VEGF were assessed by enzyme-linked immunosorbent assay.RESULTS BRAF^(V600E) mutation was positively correlated with the increase of preoperative serum carbohydrate antigen 19-9(P<0.05),and with poor tumor tissue differentiation in CRC(P<0.01).Microvascular density and microlymphatic vessel density in BRAF^(V600E) mutant CRC tissues were higher than those in BRAF wildtype CRC(P<0.05).The number of CD163+M2 macrophages in BRAF^(V600E) mutant CRC tumor tissue was markedly increased(P<0.05).Compared with exosomes from CRC cells with BRAF gene silencing,the expression of 13 lncRNAs and 192 mRNAs in the exosomes from BRAF^(V600E) mutant CRC cells was upregulated,and the expression of 22 lncRNAs and 236 mRNAs was downregulated(P<0.05).The biological functions and signaling pathways predicted by differential lncRNA target genes and differential mRNAs were closely related to angiogenesis,tumor cell proliferation,differentiation,metabolism,and changes in the microenvironment.The proliferation,migration,and tube formation ability of HUVECs and HLECs induced by exosomes in the 1627 cell group(HT29 cells with BRAF gene silencing)was greatly reduced compared with the HT29 cell group(P<0.05).Compared with the HT29 cell group,the expression levels of VEGF-A,bFGF,TGF-β1,and VEGF-C in the exosomes derived from 1627 cells were reduced.The expression of ZO-1 in HUVECs,and claudin-5,occludin,and ZO-1 in HLECs of the 1627 cell group was higher.Compared with the 1627 cell group,the exosomes of the HT29 cell group promoted the expression of CD163 in macrophages(P<0.05).IL-6 secretion by macrophages in the HT29 cell group was markedly elevated(P<0.05),whereas TGF-β1 was decreased(P<0.05).The levels of IL-6,TGF-β1,and VEGF secreted by fibroblasts in the 1627 cell group decreased,compared with the HT29 cell group(P<0.05).CONCLUSION BRAF^(V600E) mutant CRC cells can reach the tumor microenvironment by releasing exosomal lncRNAs,and induce the formation of an immunosuppressive microenvironment.展开更多
The interaction of lactate metabolism with immunity plays a crucial role in the remodeling of the immune microenvironment and even in the heterogeneous progression of hepatocellular carcinoma(HCC).The intratumor-accum...The interaction of lactate metabolism with immunity plays a crucial role in the remodeling of the immune microenvironment and even in the heterogeneous progression of hepatocellular carcinoma(HCC).The intratumor-accumulated lactate served a vital role in the inefficacy of antitumor immune responses,the aggressiveness of tumor cells,and immunotherapy.1 Furthermore,lactate generated from the tumor microenvironment can be used as fuel for the proliferation and infiltration of immunosuppressive cells.2 Previous studies regarding the taxonomies of HCC,solely from the perspective of lactate3 or tumor immune microenvironment4 may introduce the potential for bias in the comprehension of HCC heterogeneity.Thus,deciphering the crosstalk properties between lactate and immune is imperative.展开更多
The deficiency in immunogenicity and the presence of immunosuppression within the tumor microenvironment significantly hindered the efficacy of immunotherapy.Consequently,a nanoformulation containing metal sulfide of ...The deficiency in immunogenicity and the presence of immunosuppression within the tumor microenvironment significantly hindered the efficacy of immunotherapy.Consequently,a nanoformulation containing metal sulfide of FeS and GSDMD plasmid(NP_(FeS/GD))had been developed to effectively augment antitumor immune responses through dual activation of immunogenic PANoptosis and ferroptosis,as well as reprogramming immunosuppressive effects via H_(2)S amplification.The bioactive NP_(FeS/GD)exhibited controlled release of GSDMD plasmid,H_(2)S,and Fe^(2+)in response to the tumor microenvironment.Fe^(2+),H2S,and the expression of GSDMD protein could effectively elicit highly immunogenic PANoptosis and ferroptosis.Furthermore,releasing H_(2)S could mitigate the overexpression of indoleamine 2,3-dioxygenase1(IDO1)induced by immunogenic PANoptotic and ferroptotic cell death and disrupt the activity of IDO1.Consequently,NP_(FeS/GD)effectively triggered the antitumor innate and adaptive immune responses through induction of PANoptotic and ferroptotic cell death and reshaped the tumor immunosuppressive microenvironment to enhance antitumor immunotherapy for metastasis inhibition.This study unveiled the significant potential of immunogenic PANoptosis and ferroptosis in H_(2)S gas therapy for enhancing tumor immunotherapy,offering novel insights and ideas for the rational design of nanomedicine to enhance tumor immunogenicity while reprogramming the tumor immunosuppressive microenvironment.展开更多
Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is develope...Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into it.Moreover,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues.At the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T cells.The exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive microenvironment.Overall,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.展开更多
Tumor metastasis is responsible for most mortality in cancer patients,and remains a challenge in clinical cancer treatment.Platelets can be recruited and activated by tumor cells,then adhere to circulating tumor cells...Tumor metastasis is responsible for most mortality in cancer patients,and remains a challenge in clinical cancer treatment.Platelets can be recruited and activated by tumor cells,then adhere to circulating tumor cells(CTCs)and assist tumor cells extravasate in distant organs.Therefore,nanoparticles specially hitchhiking on activated platelets are considered to have excellent targeting ability for primary tumor,CTCs and metastasis in distant organs.However,the activated tumor-homing platelets will release transforming growth factor-β(TGF-β),which promotes tumor metastasis and forms immunosuppressive microenvironment.Therefore,a multitalent strategy is needed to balance the accurate tumor tracking and alleviate the immunosuppressive signals.In this study,a fucoidan-functionalized micelle(FD/DOX)was constructed,which could efficiently adhere to activated platelets through P-selectin.Compared with the micelle without P-selectin targeting effect,FD/DOX had increased distribution in both tumor tissue and metastasis niche,and exhibited excellent anti-tumor and anti-metastasis efficacy on 4 T1 spontaneous metastasis model.In addition,due to the contribution of fucoidan,FD/DOXtreatment was confirmed to inhibit the expression of TGF-β,thereby stimulating anti-tumor immune response and reversing the immunosuppressive microenvironment.The fucoidan-functionalized activated platelets-hitchhiking micelle was promising for the metastatic cancer treatment.展开更多
Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is i...Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.展开更多
The immunosuppressive tumor microenvironment(TME)undermines the efficacy of many cancer therapies.This study investigated the immunomodulatory and anti-tumor activity of Azvudine(FNC),alone or in combination with anti...The immunosuppressive tumor microenvironment(TME)undermines the efficacy of many cancer therapies.This study investigated the immunomodulatory and anti-tumor activity of Azvudine(FNC),alone or in combination with anti-PD-1 blockade.We established syngeneic tumor models in immunocompetent mice.Single-cell RNA sequencing,flow cytometry,and immunological assays were employed to analyze immune cell reconstitution and functional changes following FNC administration.FNC demonstrated dose-and time-dependent tumor inhibition.It significantly expanded memory T cells,natural killer(NK)cells,and CD8+cytotoxic T lymphocytes,while reducing the abundance of myeloid-derived suppressor cells(MDSCs).Flow cytometry confirmed these immunological shifts,showing enhanced infiltration of effector immune cells within the TME.Moreover,FNC induced hallmark features of immunogenic cell death(ICD),including the release of damage-associated molecular patterns such as high-mobility group box 1(HMGB1)and calreticulin.When combined with anti-PD-1 therapy,FNC produced a synergistic anti-tumor effect,leading to durable tumor remission in all treated mice.FNC remodels the TME by mitigating immunosuppression and amplifying anti-tumor immunity,offering a promising strategy to augment existing immunotherapies.Further clinical evaluation is warranted to ascertain the translational potential of FNC in diverse oncologic settings.展开更多
Ovarian cancer remains a leading cause of gynecological cancer mortality1,and patients with advanced stage ovarian cancer frequently develop malignant ascites that foster immunosuppressive microenvironments and therap...Ovarian cancer remains a leading cause of gynecological cancer mortality1,and patients with advanced stage ovarian cancer frequently develop malignant ascites that foster immunosuppressive microenvironments and therapeutic resistance2,3.Although ascites have traditionally been considered detrimental,we report a paradoxical role in which they enhance the cytotoxicity ofγδT cells—a unique T cell subset that can be allogenically transferred for cancer treatment4,5—toward ovarian cancer.展开更多
Cancer remains one of the major threats to public health.Traditional chemotherapy,radiotherapy,and other anti-tumor therapies have numerous limitations in clinical treatment.Notwithstanding the considerable advances m...Cancer remains one of the major threats to public health.Traditional chemotherapy,radiotherapy,and other anti-tumor therapies have numerous limitations in clinical treatment.Notwithstanding the considerable advances made in recent years with regard to immunotherapy in both basic research and clinical practice,there remains scope for further improvement,particularly with respect to its efficacy against solid tumors.With advancements in nanotechnology,tumor nanovaccines hold immense potential for preventing tumor recurrence and treating metastatic tumors.Nevertheless,the considerable heterogeneity of tumor immunogenicity presents a number of significant challenges in the development of nanometrescale vaccines targeting solid tumors.Recent findings indicate that immune checkpoint inhibitor(ICI)therapy can improve the immunosuppressive microenvironment within tumors,while nanovaccines can also augment tumor sensitivity toward ICIs.Consequently,combining tumor nanovaccine with ICI therapy holds promise for effectively eradicating tumors or controlling their recurrence and metastasis during cancer treatment.This review delves into the mechanism behind combining tumor nanovaccine with ICI while focusing on factors influencing this combined therapy approach.Moreover,it offers an overview of the current research status regarding the combination of tumor nanovaccines with chemotherapy,radiotherapy,photothermal therapy,and sonodynamic therapy,as well as prospects for future developments in this field.展开更多
Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In ou...Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In our design,Mn^(2+)functionalized COF was employed as a bioactive CpG carrier,which could simultaneously engineer and polarize macrophages to the antitumor phenotype,via the synergistic interaction of CpG and Mn^(2+).In the in vitro experiments,the engineered macrophages were found to secret high levels of antitumor cytokines for efficient TNBC cell inhibition.In the in vivo antitumor model,bioactive COF-engineered macrophages were found to relieve the hypoxia tumor microenvironment,enabling prevention of immune cell depletion during ACT.Thus,we realized efficient TNBC therapy and metastasis inhibition with the engineered macrophages in a long-term therapy model.This work provides a promising strategy for metastatic TNBC treatment and highlights the importance of bioactive COF in biomedicine.展开更多
Obesity usually exacerbates the immunosuppressive tumor microenvironment(ITME),hindering CD8+T cell infiltration and function,which further represents a significant barrier to the efficacy of immunotherapy.Herein,a mu...Obesity usually exacerbates the immunosuppressive tumor microenvironment(ITME),hindering CD8+T cell infiltration and function,which further represents a significant barrier to the efficacy of immunotherapy.Herein,a multifunctional liposomal system(CR-Lip)for encapsulating celastrol(CEL)was utilized to remodel obesity-related ITME and improve cancer immunotherapy,wherein Ginsenoside Rg3(Rg3)was detected interspersed in the phospholipid bilayer and its glycosyl exposed on the surface of the liposome.CR-Lip had a relatively uniform size(116.5 nm),facilitating favorable tumor tissue accumulation through the interaction between Rg3 and glucose transporter 1 overexpressed in obese tumor cells.Upon reaching the tumor region,CR-Lip was found to induce the immunogenic cell death(ICD)of HFD tumor cells.Notably,the level of PHD3 in HFD tumor cells was effectively boosted by CR-Lip to effectively block metabolic reprogramming and increase the availability of major free fatty acids fuel sources.In vivo,experiments studies revealed that the easy-obtained nano platform stimulated enhanced the production of various cytokines in tumor tissues,DC maturation,CD8+T-cell infiltration,and synergistic anticancer therapeutic potency with aPD-1(tumor inhibition rate=82.1%)towards obesity-related melanoma.Consequently,this study presented an efficacious approach to tumor immunotherapy in obese mice by encompassing tumor eradication,inducing ICD,and reprogramming metabolism.Furthermore,it offered a unique insight into a valuable attempt at the immunotherapy of obesity-associated related tumors.展开更多
Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resi...Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.展开更多
Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and po...Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.展开更多
Bothβ-catenin and STAT3 drive colorectal cancer(CRC)growth,progression,and immune evasion,and their co-overexpression is strongly associated with a poor prognosis.However,current small molecule inhibitors have limite...Bothβ-catenin and STAT3 drive colorectal cancer(CRC)growth,progression,and immune evasion,and their co-overexpression is strongly associated with a poor prognosis.However,current small molecule inhibitors have limited efficacy due to the reciprocal feedback activation between STAT3 andβ-catenin.Inspired by the PRO-teolysis TArgeting Chimera(PROTAC),a promising pharmacological modality for the selective degradation of proteins,we developed a strategy of nanoengineered peptide PROTACs(NP-PROTACs)to degrade bothβ-catenin and STAT3 effectively.The NP-PROTACs were engineered by coupling the peptide PROTACs with DSPE-PEG via disulfide bonds and self-assembled into nanoparticles.Notably,the dual degradation ofβ-catenin and STAT3 mediated by NP-PROTACs led to a synergistic antitumor effect compared to single-target treatment.Moreover,NP-PROTACs treatment enhanced CD103^(+)dendritic cell infiltration and T-cell cytotoxicity,alleviating the immunosuppressive microenvironment induced byβ-catenin/STAT3 in CRC.These results highlight the potential of NP-PROTACs in facilitating the simultaneous degradation of two pathogenic proteins,thereby providing a novel avenue for cancer therapy.展开更多
Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during c...Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.展开更多
The intrinsic oncogenic mechanisms and properties of the tumor microenvironment(TME)have been extensively investigated.Primary features of the TME include metabolic reprogramming,hypoxia,chronic inflammation,and tumor...The intrinsic oncogenic mechanisms and properties of the tumor microenvironment(TME)have been extensively investigated.Primary features of the TME include metabolic reprogramming,hypoxia,chronic inflammation,and tumor immunosuppression.Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME.Specifically,hypoxic adaptation,metabolic dysregulation,and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation,thereby promoting the progression of tumor events.This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME,with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells.The available findings suggest that components of the TME collectively contribute to the progression of tumor events.The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.展开更多
Cancer immunotherapy has veered the paradigm of cancer treatment.Despite recent advances in immunotherapy for improved antitumor efficacy,the complicated tumor microenvironment(TME)is highly immunosuppressive,yielding...Cancer immunotherapy has veered the paradigm of cancer treatment.Despite recent advances in immunotherapy for improved antitumor efficacy,the complicated tumor microenvironment(TME)is highly immunosuppressive,yielding both astounding and unsatisfactory clinical successes.In this regard,clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME.Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME.The immunosuppressive TME may even dampen the efficacy of antitumor immunity.Recently,some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment(TIME)for robust immunotherapeutic responses.In this review,we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy,especially those unique classes associated with the immunosuppressive effect.The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation.After introducing the various strategies,we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.展开更多
The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for immunotherapy.Despite constructive progresses have been made with anti-program...The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for immunotherapy.Despite constructive progresses have been made with anti-programmed death-1(anti-PD1)checkpoint blockade for immunotherapy,the efficacy of PD1/PD-L1 therapy deserves to be improved.Here,we constructed a novel transfersomes based nanovaccine complexed microneedles to enhance anti-PD1 immunotherapy via transdermal immunization for skin tumor therapy.Transfersomes were functionalized with DCs targeting moietyαCD40,co-encapsulated with antigens and adjuvant poly I:C.Moreover,transdermal administration promoted accumulation in tumor-draining lymph nodes(tdLN),which could facilitate cellular uptake,activate DCs maturation and enhance Th1 immune responses.Using a mouse melanoma model,combined therapy of such nanovaccine complexed microneedles with pembrolizumab(αPD1)was able to enhance cytotoxic T lymphocytes activation,promote infiltration and reduce regulatory T cells frequency in tdLN and tumor tissues,which achieved reversion of the immunosuppressive microenvironment into immune activation.This study highlighted the potential of transfersomes based nanovaccines complexed microneedles as an attractive platform for tumor immunotherapy.展开更多
The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes(CTLs)allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy...The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes(CTLs)allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy.Nanobiotechnology-engineered autologous tumor vaccines(ATVs)that were camouflaged by tumor cell membrane(TCM)were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells,consequently realizing the sequential immunotherapy.PDE5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical practice.Immediately afterwards,phosphodiesterase-5(PDE5)and programmed cell death 1 ligand 1(PD-L1)dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of NSCLC.Systematic studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor(i.e.,L-arginine)exerted robust anti-tumor effects through increasing inducible nitric oxide synthase(iNOS)expression,blockading PDE5 pathway and activating systematic immune responses,which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous models.The pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.展开更多
Various therapeutic modalities have been engineered for lung cancer treatment,but their clinic application is severely impeded by the poor therapy efficiency and immunosuppressive microenvironment.Herein,we fabricated...Various therapeutic modalities have been engineered for lung cancer treatment,but their clinic application is severely impeded by the poor therapy efficiency and immunosuppressive microenvironment.Herein,we fabricated a library of small molecule redox-labile nanoparticles(NPs)(i.e.,diPTX-2C NPs,diPTX-2S NPs,and diPTX-2Se NPs)by the self-assembly of dimer paclitaxel(PTX)prodrug,and then utilized these NPs with the traditional Chinese medicine(TCM)Qi-Yu-San-Long-Fang(Q)for effective chemoimmunotherapy on Lewis lung carcinoma(LLC)-bearing mice models.Under the high concentration of glutathione(GSH)and H_(2)O_(2),diPTX-2Se NPs could specifically release PTX in cancer cells and exert a higher selectivity and toxicity than normal cells.In LLC tumor-bearing mice,oral administration of Q not only effectively downregulated programmed death ligand-1(PD-L1)expression,but also remodeled the immunosuppressive tumor immune microenvironment via the increase of CD4^(+)T and CD8^(+)T cell proportion and the repolarization of M2 into M1 macrophages in tumor tissues,collectively achieving superior synergistic treatment outcomes in combination with intravenous PTX prodrug NPs.Besides,we found that the combination regimen also demonstrated excellent chemoimmunotherapeutic performances on low-dose small established tumor and high-dose large established tumor models.This study may shed light on the potent utilization of Chinese and Western-integrative strategy for efficient tumor chemoimmunotherapy.展开更多
基金The study was reviewed and approved by the Hebei General Hospital Institutional Review Board(approval No.202134).
文摘BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor prognosis.The BRAF^(V600E) mutation is closely related to the formation of an immunosuppressive microenvironment.However,the correlation between BRAF^(V600E) mutation and changes in local immune microenvironment of CRC is not clear.AIM To explore the effect and mechanism of BRAF^(V600E) mutant on the immune microenvironment of CRC.METHODS Thirty patients with CRC were included in this study:20 in a control group and 10 in a treatment group.The density of microvessels and microlymphatic vessels,and M2 subtype macrophages in tumor tissues were detected by immunohistochemistry.Screening and functional analysis of exosomal long noncoding RNAs(lncRNAs)were performed by transcriptomics.The proliferation and migration of human umbilical vein endothelial cells(HUVECs)and human lymphatic endothelial cells(HLECs)were detected by CCK-8 assay and scratch test,respectively.The tube-forming ability of endothelial cells was detected by tube formation assay.The macrophage subtypes were obtained by flow cytometry.The expression of vascular endothelial growth factor(VEGF)-A,basic fibroblast growth factor(bFGF),transforming growth factor(TGF)-β1,VEGF-C,claudin-5,occludin,zonula occludens(ZO)-1,fibroblast activation protein,andα-smooth muscle actin was assessed by western blot analysis.The levels of cytokines interleukin(IL)-6,TGF-β1,and VEGF were assessed by enzyme-linked immunosorbent assay.RESULTS BRAF^(V600E) mutation was positively correlated with the increase of preoperative serum carbohydrate antigen 19-9(P<0.05),and with poor tumor tissue differentiation in CRC(P<0.01).Microvascular density and microlymphatic vessel density in BRAF^(V600E) mutant CRC tissues were higher than those in BRAF wildtype CRC(P<0.05).The number of CD163+M2 macrophages in BRAF^(V600E) mutant CRC tumor tissue was markedly increased(P<0.05).Compared with exosomes from CRC cells with BRAF gene silencing,the expression of 13 lncRNAs and 192 mRNAs in the exosomes from BRAF^(V600E) mutant CRC cells was upregulated,and the expression of 22 lncRNAs and 236 mRNAs was downregulated(P<0.05).The biological functions and signaling pathways predicted by differential lncRNA target genes and differential mRNAs were closely related to angiogenesis,tumor cell proliferation,differentiation,metabolism,and changes in the microenvironment.The proliferation,migration,and tube formation ability of HUVECs and HLECs induced by exosomes in the 1627 cell group(HT29 cells with BRAF gene silencing)was greatly reduced compared with the HT29 cell group(P<0.05).Compared with the HT29 cell group,the expression levels of VEGF-A,bFGF,TGF-β1,and VEGF-C in the exosomes derived from 1627 cells were reduced.The expression of ZO-1 in HUVECs,and claudin-5,occludin,and ZO-1 in HLECs of the 1627 cell group was higher.Compared with the 1627 cell group,the exosomes of the HT29 cell group promoted the expression of CD163 in macrophages(P<0.05).IL-6 secretion by macrophages in the HT29 cell group was markedly elevated(P<0.05),whereas TGF-β1 was decreased(P<0.05).The levels of IL-6,TGF-β1,and VEGF secreted by fibroblasts in the 1627 cell group decreased,compared with the HT29 cell group(P<0.05).CONCLUSION BRAF^(V600E) mutant CRC cells can reach the tumor microenvironment by releasing exosomal lncRNAs,and induce the formation of an immunosuppressive microenvironment.
基金supported by the Major Science and Technology projects of Henan Province,China(No.221100310100).
文摘The interaction of lactate metabolism with immunity plays a crucial role in the remodeling of the immune microenvironment and even in the heterogeneous progression of hepatocellular carcinoma(HCC).The intratumor-accumulated lactate served a vital role in the inefficacy of antitumor immune responses,the aggressiveness of tumor cells,and immunotherapy.1 Furthermore,lactate generated from the tumor microenvironment can be used as fuel for the proliferation and infiltration of immunosuppressive cells.2 Previous studies regarding the taxonomies of HCC,solely from the perspective of lactate3 or tumor immune microenvironment4 may introduce the potential for bias in the comprehension of HCC heterogeneity.Thus,deciphering the crosstalk properties between lactate and immune is imperative.
基金supported by the National Natural Science Foundation of China(52103164 and 82172073)the Yong Elite Scientist Sponsorship Program by CAST(No.YESS20200177,China)+1 种基金the Fundamental Research Funds for the Central Universities(JUSRP123079 and JUSRP123078,China)the Guangdong Basic and Applied Basic Research Foundation(2021A1515220033,China).
文摘The deficiency in immunogenicity and the presence of immunosuppression within the tumor microenvironment significantly hindered the efficacy of immunotherapy.Consequently,a nanoformulation containing metal sulfide of FeS and GSDMD plasmid(NP_(FeS/GD))had been developed to effectively augment antitumor immune responses through dual activation of immunogenic PANoptosis and ferroptosis,as well as reprogramming immunosuppressive effects via H_(2)S amplification.The bioactive NP_(FeS/GD)exhibited controlled release of GSDMD plasmid,H_(2)S,and Fe^(2+)in response to the tumor microenvironment.Fe^(2+),H2S,and the expression of GSDMD protein could effectively elicit highly immunogenic PANoptosis and ferroptosis.Furthermore,releasing H_(2)S could mitigate the overexpression of indoleamine 2,3-dioxygenase1(IDO1)induced by immunogenic PANoptotic and ferroptotic cell death and disrupt the activity of IDO1.Consequently,NP_(FeS/GD)effectively triggered the antitumor innate and adaptive immune responses through induction of PANoptotic and ferroptotic cell death and reshaped the tumor immunosuppressive microenvironment to enhance antitumor immunotherapy for metastasis inhibition.This study unveiled the significant potential of immunogenic PANoptosis and ferroptosis in H_(2)S gas therapy for enhancing tumor immunotherapy,offering novel insights and ideas for the rational design of nanomedicine to enhance tumor immunogenicity while reprogramming the tumor immunosuppressive microenvironment.
基金the National Natural Science Foundation of China(82173762,China)111 Project(B18035,China)+2 种基金the Fundamental of Research Funds for the Central Universities(China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,China)Project of Chengdu Science and Technology Bureau(2020-GH03-00003-HZ)。
文摘Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into it.Moreover,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues.At the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T cells.The exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive microenvironment.Overall,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.
基金supported by National Natural Science Foundation of China(81974499 and 81690261)Sichuan Science and Technology Program(2018RZ0136)。
文摘Tumor metastasis is responsible for most mortality in cancer patients,and remains a challenge in clinical cancer treatment.Platelets can be recruited and activated by tumor cells,then adhere to circulating tumor cells(CTCs)and assist tumor cells extravasate in distant organs.Therefore,nanoparticles specially hitchhiking on activated platelets are considered to have excellent targeting ability for primary tumor,CTCs and metastasis in distant organs.However,the activated tumor-homing platelets will release transforming growth factor-β(TGF-β),which promotes tumor metastasis and forms immunosuppressive microenvironment.Therefore,a multitalent strategy is needed to balance the accurate tumor tracking and alleviate the immunosuppressive signals.In this study,a fucoidan-functionalized micelle(FD/DOX)was constructed,which could efficiently adhere to activated platelets through P-selectin.Compared with the micelle without P-selectin targeting effect,FD/DOX had increased distribution in both tumor tissue and metastasis niche,and exhibited excellent anti-tumor and anti-metastasis efficacy on 4 T1 spontaneous metastasis model.In addition,due to the contribution of fucoidan,FD/DOXtreatment was confirmed to inhibit the expression of TGF-β,thereby stimulating anti-tumor immune response and reversing the immunosuppressive microenvironment.The fucoidan-functionalized activated platelets-hitchhiking micelle was promising for the metastatic cancer treatment.
基金Supported by the Zhejiang Provincial Natural Science Foundation of China,No.LTGC23H200005 and No.LQ19H160017the Medical Science and Technology Project of Zhejiang Province,China,No.2022RC167.
文摘Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.
文摘The immunosuppressive tumor microenvironment(TME)undermines the efficacy of many cancer therapies.This study investigated the immunomodulatory and anti-tumor activity of Azvudine(FNC),alone or in combination with anti-PD-1 blockade.We established syngeneic tumor models in immunocompetent mice.Single-cell RNA sequencing,flow cytometry,and immunological assays were employed to analyze immune cell reconstitution and functional changes following FNC administration.FNC demonstrated dose-and time-dependent tumor inhibition.It significantly expanded memory T cells,natural killer(NK)cells,and CD8+cytotoxic T lymphocytes,while reducing the abundance of myeloid-derived suppressor cells(MDSCs).Flow cytometry confirmed these immunological shifts,showing enhanced infiltration of effector immune cells within the TME.Moreover,FNC induced hallmark features of immunogenic cell death(ICD),including the release of damage-associated molecular patterns such as high-mobility group box 1(HMGB1)and calreticulin.When combined with anti-PD-1 therapy,FNC produced a synergistic anti-tumor effect,leading to durable tumor remission in all treated mice.FNC remodels the TME by mitigating immunosuppression and amplifying anti-tumor immunity,offering a promising strategy to augment existing immunotherapies.Further clinical evaluation is warranted to ascertain the translational potential of FNC in diverse oncologic settings.
基金supported by the National Natural Science Foundation of China(Grant No.82274034)the Peking University Medicine plus X Pilot Program-Platform Construction Project(Grant No.2024YXXLHPT004).
文摘Ovarian cancer remains a leading cause of gynecological cancer mortality1,and patients with advanced stage ovarian cancer frequently develop malignant ascites that foster immunosuppressive microenvironments and therapeutic resistance2,3.Although ascites have traditionally been considered detrimental,we report a paradoxical role in which they enhance the cytotoxicity ofγδT cells—a unique T cell subset that can be allogenically transferred for cancer treatment4,5—toward ovarian cancer.
基金financially supported by the Key Scientific Research Project of Henan Provincial Universities in 2024(No.24A350013)the Project of Basic Research Fund of Henan Institute of Medical and Pharmaceutical Sciences(No.2024BP0202)+1 种基金the Key Scientific and Technological Project of Henan Province(No.242102311213)the Henan Province Postdoctoral Program(No.343915)。
文摘Cancer remains one of the major threats to public health.Traditional chemotherapy,radiotherapy,and other anti-tumor therapies have numerous limitations in clinical treatment.Notwithstanding the considerable advances made in recent years with regard to immunotherapy in both basic research and clinical practice,there remains scope for further improvement,particularly with respect to its efficacy against solid tumors.With advancements in nanotechnology,tumor nanovaccines hold immense potential for preventing tumor recurrence and treating metastatic tumors.Nevertheless,the considerable heterogeneity of tumor immunogenicity presents a number of significant challenges in the development of nanometrescale vaccines targeting solid tumors.Recent findings indicate that immune checkpoint inhibitor(ICI)therapy can improve the immunosuppressive microenvironment within tumors,while nanovaccines can also augment tumor sensitivity toward ICIs.Consequently,combining tumor nanovaccine with ICI therapy holds promise for effectively eradicating tumors or controlling their recurrence and metastasis during cancer treatment.This review delves into the mechanism behind combining tumor nanovaccine with ICI while focusing on factors influencing this combined therapy approach.Moreover,it offers an overview of the current research status regarding the combination of tumor nanovaccines with chemotherapy,radiotherapy,photothermal therapy,and sonodynamic therapy,as well as prospects for future developments in this field.
基金supported by the National Natural Science Foundation of China(No.22304073)the Dongguan Science and Technology of Social Development Program(No.20231800935782)。
文摘Triple-negative breast cancer(TNBC)is one of the most lethal diseases and lack of feasible therapeutic methods.Herein,we developed a bioactive covalent organic framework(COF)for adoptive cell therapy(ACT)of TNBC.In our design,Mn^(2+)functionalized COF was employed as a bioactive CpG carrier,which could simultaneously engineer and polarize macrophages to the antitumor phenotype,via the synergistic interaction of CpG and Mn^(2+).In the in vitro experiments,the engineered macrophages were found to secret high levels of antitumor cytokines for efficient TNBC cell inhibition.In the in vivo antitumor model,bioactive COF-engineered macrophages were found to relieve the hypoxia tumor microenvironment,enabling prevention of immune cell depletion during ACT.Thus,we realized efficient TNBC therapy and metastasis inhibition with the engineered macrophages in a long-term therapy model.This work provides a promising strategy for metastatic TNBC treatment and highlights the importance of bioactive COF in biomedicine.
基金support from the Public Platform of Pharmaceutical Research Center,Academy of Chinese Medical Science,Zhejiang Chinese Medical University.This work was supported by the National Natural Science Foundation of China(82174095)the Natural Science Foundation of Zhejiang Province(LZ22H290001,China)the Zhejiang Province Traditional Chinese Medicine Science and Technology Project(2023ZL362).
文摘Obesity usually exacerbates the immunosuppressive tumor microenvironment(ITME),hindering CD8+T cell infiltration and function,which further represents a significant barrier to the efficacy of immunotherapy.Herein,a multifunctional liposomal system(CR-Lip)for encapsulating celastrol(CEL)was utilized to remodel obesity-related ITME and improve cancer immunotherapy,wherein Ginsenoside Rg3(Rg3)was detected interspersed in the phospholipid bilayer and its glycosyl exposed on the surface of the liposome.CR-Lip had a relatively uniform size(116.5 nm),facilitating favorable tumor tissue accumulation through the interaction between Rg3 and glucose transporter 1 overexpressed in obese tumor cells.Upon reaching the tumor region,CR-Lip was found to induce the immunogenic cell death(ICD)of HFD tumor cells.Notably,the level of PHD3 in HFD tumor cells was effectively boosted by CR-Lip to effectively block metabolic reprogramming and increase the availability of major free fatty acids fuel sources.In vivo,experiments studies revealed that the easy-obtained nano platform stimulated enhanced the production of various cytokines in tumor tissues,DC maturation,CD8+T-cell infiltration,and synergistic anticancer therapeutic potency with aPD-1(tumor inhibition rate=82.1%)towards obesity-related melanoma.Consequently,this study presented an efficacious approach to tumor immunotherapy in obese mice by encompassing tumor eradication,inducing ICD,and reprogramming metabolism.Furthermore,it offered a unique insight into a valuable attempt at the immunotherapy of obesity-associated related tumors.
基金supported by the National Key R&D Program of China(Grant No.2022YFC3401404)the National Natural Science Foundation of China(Grant Nos.32170935 and 31930066).
文摘Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.
基金This study was supported by National Natural Science Foundation of China(82173762)111 Project(B18035,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,2022YFS0334).
文摘Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.
基金supported by National Natural Science Foundation of China,China(No.82322073,82173846,82304790,82304533)Ori-ental Scholars of Shanghai Universities,China(TP2022081)+13 种基金Jiangxi Province Thousand Talents Program,China(jxsq2023102168)Young Talent Lifting Project of China Association of Chinese Medicine,China[CACM-(2021-QNRC2-A08)]Shanghai Rising-Star Program,China(22QA1409100)2021 Shanghai Science and Technology Innovation Action Plan,China(21S11902800)China Postdoctoral Innovative Talent Support Program,China(BX20220213)Shanghai Sailing Pro-gram,China(22YF1445000,23YF1442600)Three-year Action Plan for Shanghai TCM Development and Inheritance Program,China[ZY(2021-2023)-0401ZY(2021-2023)-0208]Organizational Key Research and Development Program of Shanghai University of Tradi-tional Chinese Medicine,China(2023YZZ02)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine,China(ZYYCXTD-D-202004)CAMS Innovation Fund for Medical Sciences(CIFMS),China(2023-I2M-3-009)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources,China(2060302)High level Key Discipline of National Administration of Traditional Chinese Med-icine,China(No.zyyzdxk-2023071)Innovation team of high-level local universities in Shanghai:Strategic Innovation Team of TCM Chemical Biology,China.
文摘Bothβ-catenin and STAT3 drive colorectal cancer(CRC)growth,progression,and immune evasion,and their co-overexpression is strongly associated with a poor prognosis.However,current small molecule inhibitors have limited efficacy due to the reciprocal feedback activation between STAT3 andβ-catenin.Inspired by the PRO-teolysis TArgeting Chimera(PROTAC),a promising pharmacological modality for the selective degradation of proteins,we developed a strategy of nanoengineered peptide PROTACs(NP-PROTACs)to degrade bothβ-catenin and STAT3 effectively.The NP-PROTACs were engineered by coupling the peptide PROTACs with DSPE-PEG via disulfide bonds and self-assembled into nanoparticles.Notably,the dual degradation ofβ-catenin and STAT3 mediated by NP-PROTACs led to a synergistic antitumor effect compared to single-target treatment.Moreover,NP-PROTACs treatment enhanced CD103^(+)dendritic cell infiltration and T-cell cytotoxicity,alleviating the immunosuppressive microenvironment induced byβ-catenin/STAT3 in CRC.These results highlight the potential of NP-PROTACs in facilitating the simultaneous degradation of two pathogenic proteins,thereby providing a novel avenue for cancer therapy.
基金partially supported by the National Natural Science Foundation of China(51802209,22077093,51761145041,51525203)the National Research Programs from Ministry of Science and Technology(MOST)of China(2016YFA0201200)+3 种基金the Natural Science Foundation of Jiangsu Province(BK20180848)the Jiangsu Social Development Project(BE2019658)Collaborative Innovation Center of Suzhou Nano Science and Technologythe 111 Program from the Ministry of Education of China.
文摘Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.
基金Grants from the Liaoning Nature Science Foundation of China,Grant/Award Number:2022JH2/101300042National Natural Science Foundation of China,Grant/Award Numbers:81672877,82173194。
文摘The intrinsic oncogenic mechanisms and properties of the tumor microenvironment(TME)have been extensively investigated.Primary features of the TME include metabolic reprogramming,hypoxia,chronic inflammation,and tumor immunosuppression.Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME.Specifically,hypoxic adaptation,metabolic dysregulation,and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation,thereby promoting the progression of tumor events.This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME,with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells.The available findings suggest that components of the TME collectively contribute to the progression of tumor events.The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.
基金the financial support from the National Natural Science Foundation of China(81773283 and 81701684)
文摘Cancer immunotherapy has veered the paradigm of cancer treatment.Despite recent advances in immunotherapy for improved antitumor efficacy,the complicated tumor microenvironment(TME)is highly immunosuppressive,yielding both astounding and unsatisfactory clinical successes.In this regard,clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME.Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME.The immunosuppressive TME may even dampen the efficacy of antitumor immunity.Recently,some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment(TIME)for robust immunotherapeutic responses.In this review,we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy,especially those unique classes associated with the immunosuppressive effect.The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation.After introducing the various strategies,we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.
基金work was supported by the National Natural Science Foundation of China(No.31670972)the Taishan Scholar Program,China.
文摘The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for immunotherapy.Despite constructive progresses have been made with anti-programmed death-1(anti-PD1)checkpoint blockade for immunotherapy,the efficacy of PD1/PD-L1 therapy deserves to be improved.Here,we constructed a novel transfersomes based nanovaccine complexed microneedles to enhance anti-PD1 immunotherapy via transdermal immunization for skin tumor therapy.Transfersomes were functionalized with DCs targeting moietyαCD40,co-encapsulated with antigens and adjuvant poly I:C.Moreover,transdermal administration promoted accumulation in tumor-draining lymph nodes(tdLN),which could facilitate cellular uptake,activate DCs maturation and enhance Th1 immune responses.Using a mouse melanoma model,combined therapy of such nanovaccine complexed microneedles with pembrolizumab(αPD1)was able to enhance cytotoxic T lymphocytes activation,promote infiltration and reduce regulatory T cells frequency in tdLN and tumor tissues,which achieved reversion of the immunosuppressive microenvironment into immune activation.This study highlighted the potential of transfersomes based nanovaccines complexed microneedles as an attractive platform for tumor immunotherapy.
基金This work was supported by the National Natural Science Foundation of China(82022033,81873048,81771836 and 82004006)Sichuan Provincial Science Fund for applied basic research of China(2020YJ0108)Sichuan Provincial Science Fund for Distinguished Young Scholars of China(2020JDJQ0065).
文摘The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes(CTLs)allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy.Nanobiotechnology-engineered autologous tumor vaccines(ATVs)that were camouflaged by tumor cell membrane(TCM)were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells,consequently realizing the sequential immunotherapy.PDE5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical practice.Immediately afterwards,phosphodiesterase-5(PDE5)and programmed cell death 1 ligand 1(PD-L1)dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of NSCLC.Systematic studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor(i.e.,L-arginine)exerted robust anti-tumor effects through increasing inducible nitric oxide synthase(iNOS)expression,blockading PDE5 pathway and activating systematic immune responses,which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous models.The pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.
基金supported by the Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine(CACM),China(Grant No.:2022-QNRC2-B12)the Key Project of Anhui Province Department of Education,China(Grant Nos.:2023AH030070,2024AH051040,and 2022AH050528)+1 种基金Anhui Province Key Laboratory,China(Grant Nos.:KFKT202305,2024ZYFBAHKLA11,and 2024ZYFBAHKLA15)Greater Health Research Institute of Hefei Comprehensive National Science Center,China(Grant No.:2023CXMMTCM005).
文摘Various therapeutic modalities have been engineered for lung cancer treatment,but their clinic application is severely impeded by the poor therapy efficiency and immunosuppressive microenvironment.Herein,we fabricated a library of small molecule redox-labile nanoparticles(NPs)(i.e.,diPTX-2C NPs,diPTX-2S NPs,and diPTX-2Se NPs)by the self-assembly of dimer paclitaxel(PTX)prodrug,and then utilized these NPs with the traditional Chinese medicine(TCM)Qi-Yu-San-Long-Fang(Q)for effective chemoimmunotherapy on Lewis lung carcinoma(LLC)-bearing mice models.Under the high concentration of glutathione(GSH)and H_(2)O_(2),diPTX-2Se NPs could specifically release PTX in cancer cells and exert a higher selectivity and toxicity than normal cells.In LLC tumor-bearing mice,oral administration of Q not only effectively downregulated programmed death ligand-1(PD-L1)expression,but also remodeled the immunosuppressive tumor immune microenvironment via the increase of CD4^(+)T and CD8^(+)T cell proportion and the repolarization of M2 into M1 macrophages in tumor tissues,collectively achieving superior synergistic treatment outcomes in combination with intravenous PTX prodrug NPs.Besides,we found that the combination regimen also demonstrated excellent chemoimmunotherapeutic performances on low-dose small established tumor and high-dose large established tumor models.This study may shed light on the potent utilization of Chinese and Western-integrative strategy for efficient tumor chemoimmunotherapy.
