Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that meta...Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that metabolites derived from tumor cells regulate immune cell metabolism via tumor microenvironment crosstalk.However,as immunometabolic research has deepened,the leading role played by the intrinsic metabolic regulation of immune cells in the drug resistance of tumor cells has been discovered.Immune metabolites have been shown to cause immune resistance,target therapy resistance,and chemotherapy resistance,and drugs that target immune metabolism have great potential.To date,researchers have not fully explored the impact of immune-derived metabolites on tumor cells and their influence on the responsiveness to cancer drugs.In this review,we focus on the lactate,fatty acid,glucose,and nucleotide metabolic alterations that take place in T cells and macrophages and how these changes can impair anti-tumor immunity,ultimately promoting tumor cell survival and decreasing responsiveness to the corresponding therapeutic approaches.We present the current developments in drugs targeting immunometabolic pathways and propose constructive suggestions,such as precise delivery to immune cell targets to enhance efficacy and safety,offering novel perspectives for cancer drug development.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
Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabol...Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabolic pathways and signaling cascades.1 In the realm of cancer immunotherapy,metabolic interventions in immune cells have demon-strated potential to enhance therapeutic efficacy.For instance,Minogue et al.2 found that glutaric acid from tryptophan metabolism can mod-ulate the antitumor T cell response by affecting pyruvate metabolism and𝛼-ketoglutarate-dependent dioxygenases.The adjustment of glutaric acid levels in CD8^(+)T cells has been shown to promote central memory T cell development,reduce exhaustion markers,and enhance cell death.展开更多
Breast cancer cells manipulate a key nutrient to both fuel growth and disable immune defenses-a dual strategy revealed by Chinese scientists.Researchers from the Hangzhou Institute of Medicine(HIM)of the Chinese Acade...Breast cancer cells manipulate a key nutrient to both fuel growth and disable immune defenses-a dual strategy revealed by Chinese scientists.Researchers from the Hangzhou Institute of Medicine(HIM)of the Chinese Academy of Sciences and Sun Yat-Sen University discovered that tumors exploit the amino acid arginine to rewire immune cells into cancer allies.展开更多
Hyperthermia is a type of medical modality for cancer treatment using the biological effect of artificially induced heat.Even though the intrinsic effects of elevated body temperature in cancer tissues are poorly unde...Hyperthermia is a type of medical modality for cancer treatment using the biological effect of artificially induced heat.Even though the intrinsic effects of elevated body temperature in cancer tissues are poorly understood,increasing the temperature of the body has been recognized as a popular therapeutic method for tumorous lesions as well as infectious diseases since ancient times.Recently accumulated evidence has shown that hyperthermia amplifies immune responses in the body against cancer while decreasing the immune suppression and immune escape of cancer.It also shows that hyperthermia inhibits the repair of damaged cancer cells after chemotherapy or radiotherapy.These perceptions indicate that hyperthermia has potential for cancer therapy in conjunction with immunotherapy,chemotherapy,radiotherapy,and surgery.Paradoxically,the anticancer effect of hyperthermia alone has not yet been adequately exploited because deep heating techniques and devices to aggregate heat effects only in cancer tissues are difficult in practical terms.This review article focuses on the current understanding concerning cancer immunity and involvement of hyperthermia and the innate and adoptive immune system.The potential for combination therapy with hyperthermia and chemotherapy,radiotherapy,and surgery is also discussed.展开更多
Approximately 20%of colorectal cancer(CRC)patients present with metastasis at diagnosis.Among Stage I-III CRC patients who undergo surgical resection,18%typically suffer from distal metastasis within the first three y...Approximately 20%of colorectal cancer(CRC)patients present with metastasis at diagnosis.Among Stage I-III CRC patients who undergo surgical resection,18%typically suffer from distal metastasis within the first three years following initial treatment.The median survival duration after the diagnosis of metastatic CRC(mCRC)is only 9 mo.mCRC is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue,allowing cancer cells to spread from primary to distant organs;however,increa-sing evidence suggests that the mCRC process can begin early in tumor development.CRC patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological alterations.Different genomic and nongenomic events can induce subclone diversity,which leads to cancer and metastasis.Throughout the course of mCRC,metastatic cascades are associated with invasive cancer cell migration through the circulatory system,extravasation,distal seeding,dormancy,and reactivation,with each step requiring specific molecular functions.However,cancer cells presenting neoantigens can be recognized and eliminated by the immune system.In this review,we explain the biological factors that drive CRC metastasis,namely,genomic instability,epigenetic instability,the metastatic cascade,the cancer-immunity cycle,and external lifestyle factors.Despite remarkable progress in CRC research,the role of molecular classification in therapeutic intervention remains unclear.This review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.展开更多
The ability to harness innate immunity is a promising solution for improving cancer immunotherapy.Interferon(IFN)induces expression of IFN-stimulated genes(ISGs)by activating the JAK-STAT signaling pathway to promote ...The ability to harness innate immunity is a promising solution for improving cancer immunotherapy.Interferon(IFN)induces expression of IFN-stimulated genes(ISGs)by activating the JAK-STAT signaling pathway to promote innate immunity and inhibit malignant tumor growth,but the functions and mechanisms of most ISGs in cancer regulation are unknown.As an innate immune effector,ISG12a promotes the innate immune response to viral infection.In this study,ISG12a was found to be expressed at low levels in gastrointestinal cancer,represented by hepatocellular cancer(HCC)and gastric cancer(GC),and it identified as a tumor suppressor that affects clinical prognosis.ISG12a silencing accelerated the malignant transformation and epithelial–mesenchymal transition of cancer cells.Mechanistically,ISG12a promotedβ-catenin proteasomal degradation by inhibiting the degradation of ubiquitinated Axin,thereby suppressing the canonical Wnt/β-catenin signaling pathway.Notably,β-catenin was identified as a transcription factor for PD-L1.Inhibition of Wnt/β-catenin signaling by ISG12a suppressed expression of the immune checkpoint PDL1,rendering cancer cells sensitive to NK cell-mediated killing.This study reveals a mechanism underlying the anticancer effects of IFN.Some ISGs,as represented by ISG12a,may be useful in cancer therapy and prevention.The identified interrelations among innate immunity,Wnt/β-catenin signaling,and cancer immunity may provide new insight into strategies that will improve the efficiency of immunotherapy.展开更多
Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as...Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.展开更多
Transcription factor forkhead box P3(Foxp3)+regulatory T(Treg)cells are receiving increasing attention because this unique subset of T cells is characterized by exerting negative regulatory function of cellular immune...Transcription factor forkhead box P3(Foxp3)+regulatory T(Treg)cells are receiving increasing attention because this unique subset of T cells is characterized by exerting negative regulatory function of cellular immune responses.The resultant suppression of anti-tumor immunity in the tumor microenvironment(TME)is regarded as a major obstacle to immunotherapies in a plethora of cancers.Thus,an integrated understanding of the intrinsic correlation between tumors and Treg cell biology is urgently required.This review focuses on the peculiar biochemical effects of tumor metabolic environments on Tregs and how Tregs orchestrate internal metabolic switches and altered metabolic pathways and molecules to survive and function after the remodeling of homeostasis and specialization,providing new directions for immunotherapies.展开更多
Objective：To evaluate the ef icacy of autologous cytokine-induced kil er （CIK） cells transfusion combined with chemotherapy in patients suf ered from advanced colorectal cancer. Methods： Sixty untreated patients w...Objective：To evaluate the ef icacy of autologous cytokine-induced kil er （CIK） cells transfusion combined with chemotherapy in patients suf ered from advanced colorectal cancer. Methods： Sixty untreated patients with advanced colorectal cancer were randomly divided into two groups. The 30 patients in the control group received chemotherapy with the regimen of xeloda plus oxiplatin （XELOX）. The 30 patients in the trial group were treated with chemotherapy （XELOX） in combination with autologous CIK celltransfusion. T-lymphocyte subgroups were separated and measured by flow cytometry quality of life （QOL） was determined by EORTC QLQ-C30. The short-term curative ef ect was evaluated via imaging examina-tions. The patients’ median progression free survival time was estimated by Kaplan-Meier. Results：The T-lymphocyte im-mune activity was improved in patients received autologous CIK celltransfusion than those treated with chemotherapy alone. The subgroup of CD3＋CD56＋T lymphocyte was significantly increased （4.28 ± 0.45 vs 10.14 ± 1.02, P=0.01）. Short-term ef icacy evaluation revealed that there was no significant dif erence in terms of objective response rate （ORR） between the two groups, but the disease control rate （DCR） was markedly increased （86.7%vs 56.7%, P=0.020） in the group treated by chemotherapy plus CIK cells compared to the group treated with chemotherapy alone. The progression free survival time was 8.64 months （ 95%CI 6.25-9.75 months） in control group and 10.15 months （ 95%CI 7.48-12.52 months） in trial group. Compared to patients in control group, the patients in trial group had significantly longer progression-free survival （P=0.046）. The QOL assessment suggested the QOL in trial group was obviously improved than that in the control group. Compared with the control group, patients treated with autologous CIK celltransfusion scored more in the area of physical function and general health status, while the symptomatic scores in terms of pain, fatigue, nausea and vomiting and diarrhea were significantly reduced. Conclusion：Autologous CIK celltransfusion combined with chemotherapy can ef ectively enhance the immune activity of T-lymphocytes, prevent disease progression and improve the progression-free survival and QOL in patients with advanced colorectal cancer.展开更多
Objective:To investigate the correlation between immune cell infiltration pattern and clinical features and prognosis of cervical carcinoma.Methods:All cervical cancer transcript data and related clinical data were do...Objective:To investigate the correlation between immune cell infiltration pattern and clinical features and prognosis of cervical carcinoma.Methods:All cervical cancer transcript data and related clinical data were downloaded from the public database Cancer Genome Atlas(TCGA),and the relative proportions of 22 invasive immune cell types were calculated by Cibersort software.Perl was used to assess the correlation between the pattern of immune cell invasion and clinical characteristics(age,clinical stage,tumor grade)in cervical cancer,and the correlation between the pattern of immune cell invasion and survival in cervical cancer was calculated by the K-M Log-Rank method.Result:The distribution of immune cells in 306 cases of cervical cancer and 3 cases of normal tissues was assessed using Cibersort.Compared with normal tissues,the contents of resting dendritic cells,activated dendritic cells,M1 macrophages and activated CD4+memory T cells were higher;the contents of M2 macrophages,neutrophils,regulatory T cells and activated mast cells were lower in cervical cancer tissues.The contents of M1 macrophages,unactivated CD4+memory T cells,andγδT cells were positively correlated with patient age(P<0.05).The contents of follicular helper T cells,activated and unactivated natural killer(NK)cells,and naive CD4 T cells were negatively correlated with patient age(P<0.05).Those with high resting dendritic cell composition had shorter overall survival,while those with high follicular helper T cell composition had longer overall survival(P<0.05).Conclusion:Compared with normal tissues,the composition of immune cells in cervical cancer tissues has certain specificity,which can provide reference for the early screening and diagnosis of the disease.Patients in different age groups may have different immune cell infiltration patterns,which can be used as a basis to explore drug targets in clinical practice.Resting dendritic cells and follicular helper T cells in cervical cancer can be used as possible efficacy predictors of clinical immunotherapy for cervical cancer.展开更多
Lipids have been found to modulate tumor biology,including proliferation,survival,and metastasis.With the new understanding of tumor immune escape that has developed in recent years,the influence of lipids on the can...Lipids have been found to modulate tumor biology,including proliferation,survival,and metastasis.With the new understanding of tumor immune escape that has developed in recent years,the influence of lipids on the cancer—immunity cycle has also been gradually discovered.First,regarding antigen presentation,cholesterol prevents tumor antigens from being identified by antigen presenting cells.Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells,impairing antigen presentation to T cells.Prostaglandin E2(PGE2)reduce the accumulation of tumor-infiltrating dendritic cells.Regarding T-cell priming and activation,cholesterol destroys the structure of the T-cell receptor and reduces immunodetection.In contrast,cholesterol also promotes T-cell receptor clustering and relative signal transduction.PGE2 represses T-cell proliferation.Finally,regarding T-cell killing of cancer cells,PGE2 and cholesterol weaken granule-dependent cytotoxicity.Moreover,fatty acids,cholesterol,and PGE2 can improve the activity of immunosuppressive cells,increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines.Given the regulatory role of lipids in the cancer—immunity cycle,drugs that modulate fatty acids,cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy.These strategies have been studied in both preclinical and clinical studies.展开更多
Innate lymphoid cells(ILCs)are a group of innate immune cells,which constitute the first line of defense in the immune system,together with skin and mucous membrane.ILCs also play an important role in maintaining the ...Innate lymphoid cells(ILCs)are a group of innate immune cells,which constitute the first line of defense in the immune system,together with skin and mucous membrane.ILCs also play an important role in maintaining the homeostasis of the body,particularly in the complex and diverse environment of the intestine.ILCs respond to different microenvironments,maintaining homeostasis directly or indirectly through cytokines.As a result,ILCs,with complex and pleiotropic characteristics,are associated with many gastrointestinal diseases.Their ability of transition among those subgroups makes them function as both promoting and inhibiting cells,thus affecting homeostasis and disease progressing to either alleviation or deterioration.With these special characteristics,ILCs theoretically can be used in the new generation of immunotherapy as an alternative and supplement to current tumor therapy.Our review summarizes the characteristics of ILCs with respect to category,function,and the relationship with intestinal homeostasis and gastrointestinal diseases.In addition,potential tumor immunotherapies involving ILCs are also discussed to shed light on the perspectives of immunotherapy.展开更多
Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward the anaerobic and immune-...Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward the anaerobic and immune-suppressive TME,which makes them ideal natural vehicles for cancer gene therapy.Here,we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2(Il2)expression plasmid onto the surface of VNP20009,an attenuated Salmonella typhimur-ium strain with well-documented anti-cancer activity,and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella.Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Sal-monella maintained the tumor-targeting feature of bacteria,and could be effectively phagocytosed by in-tratumoral macrophages,thus leading to the expression and secretion of IL2 in TME.The detailed analysis of tumor immune microenvironment(TIME)showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME,marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME,thus leading to significant anti-tumor effects in melanoma,orthotopic hepatocellular carcinoma,and pulmonary metastasis models.More importantly,Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems.Taken together,we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effec-tive TME-targeted delivery of therapeutic gene,as well as synergistic re-activation of TIME.展开更多
As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient...As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient’s own immune system to eradicate the cancer cells.However, the limited population of patients who benefitfrom the current immunotherapies and the immune relatedadverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure,which leads to cancer immune evasion and immunity cycleblockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicityof their therapeutic cargos by spatiotemporally controllingthe biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to makeclinical translation, which are now established platforms fordiverse areas. In this perspective, we discuss the availablelipid-based nanoparticles in research and market here, thendescribe their application in cancer immunotherapy, withspecial emphasis on the T cells-activated and macrophagestargeted delivery system. Through perpetuating each step ofcancer immunity cycle, lipid-based nanoparticles can reduceimmunosuppression and promote drug delivery to triggerrobust antitumor response.展开更多
Sphingosine-1-phosphate(S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival,cell proliferation, cell migration, angiogenesis and many other cellular processes. S1 P ...Sphingosine-1-phosphate(S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival,cell proliferation, cell migration, angiogenesis and many other cellular processes. S1 P either activates S1 P receptors(S1PR1-5) through "inside-out signaling" or acts directly on intracellular targets to regulate various cellular processes. In the past two decades, much progress has been made in exploring S1 P signaling and its pathogenic roles in diseases as well as in developing modulators of S1 P signaling, including S1 P agonists, S1 P antagonists and sphingosine kinase(SphK) inhibitors.Ceramide and S1 P have been defined as reciprocal regulators of cell fate, and S1 P signaling has been shown to be crucial for the pathogenesis of various diseases, including autoimmune diseases, inflammation and cancer; therefore, targeting S1 P signaling may curtail the process of pathogenesis and serve as a potential therapeutic target for the treatment of these diseases. In this review, we describe recent advances in our understanding of S1 P signaling in cancer development(particularly in inflammationassociated cancer) as well as in innate and adaptive immunity, and we also discuss modulators of S1 P signaling in cancer treatment.展开更多
While STING(STimulator of INterferon Genes) has been shown to be essential for cytosolic DNA-triggered innate immune activation, accumulated evidence obtained from various studies suggested that an intrinsic relevance...While STING(STimulator of INterferon Genes) has been shown to be essential for cytosolic DNA-triggered innate immune activation, accumulated evidence obtained from various studies suggested that an intrinsic relevance of STING-associated signaling in tumorigenesis can be observed. Also, several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for STING, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. However, cases have also been reported where the involvement of STING shows a protective role in tumor growth. Here we summarize recent findings that have pointed towards the STING pathway as an innate immune sensing mechanism driving type I interferon production in the tumor context. Better understanding of this pathway can guide further development of novel immunotherapeutic strategies in the treatment of cancer.展开更多
Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance,preventing autoimmune responses,and minimizing tissue damage by regulating the duration and intensi...Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance,preventing autoimmune responses,and minimizing tissue damage by regulating the duration and intensity of the immune response.Furthermore,immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response.Based on substantial physiological analyses as well as preclinical and clinical studies,checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers.In the last few years,extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines(TCMs).The main advantage of TCMs and natural medicine is that they usually contain multiple active components,which can act on multiple targets at the same time,resulting in additive or synergistic effects.The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest.For example,Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals,and these antibodies can overcome the exhaustion of immune cells under tumor immune evasion.Furthermore,many other TCM molecules could also be novel and effective drug candidates for the treatment of cancers.Therefore,it is essential to assess the application of immune checkpoints in the development of new drugs and TCMs.In this review,we focus on research progress in the field of immune checkpoints based on three topics:(1)immune checkpoint targets and pathways,(2)development of novel immune checkpoint-based drugs,and(3)application of immune checkpoints in the development of TCMs.展开更多
Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response...Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts.Since flagella are key inducers of the host immune response during bacterial infection,flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy.The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects,even when more bacteria were administered to offset the difference in invasion efficiency.Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5(TLR5)signalling pathway.Indeed,we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma.Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy,thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.展开更多
AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism regulation.Metabolic changes in immune cells, such as dendritic cell (DC), macrophages, neutrophi...AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism regulation.Metabolic changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy.展开更多
基金supported by the National Key Research and Development Program of China(No.2023YFC2508500)National Natural Science Foundation of China(No.82272951)National Natural Science Foundation of China(No.82272953)。
文摘Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that metabolites derived from tumor cells regulate immune cell metabolism via tumor microenvironment crosstalk.However,as immunometabolic research has deepened,the leading role played by the intrinsic metabolic regulation of immune cells in the drug resistance of tumor cells has been discovered.Immune metabolites have been shown to cause immune resistance,target therapy resistance,and chemotherapy resistance,and drugs that target immune metabolism have great potential.To date,researchers have not fully explored the impact of immune-derived metabolites on tumor cells and their influence on the responsiveness to cancer drugs.In this review,we focus on the lactate,fatty acid,glucose,and nucleotide metabolic alterations that take place in T cells and macrophages and how these changes can impair anti-tumor immunity,ultimately promoting tumor cell survival and decreasing responsiveness to the corresponding therapeutic approaches.We present the current developments in drugs targeting immunometabolic pathways and propose constructive suggestions,such as precise delivery to immune cell targets to enhance efficacy and safety,offering novel perspectives for cancer drug development.
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 Zhejiang Provincial Natural Science Foundation of China(grant number:LGD22H090003).
文摘Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabolic pathways and signaling cascades.1 In the realm of cancer immunotherapy,metabolic interventions in immune cells have demon-strated potential to enhance therapeutic efficacy.For instance,Minogue et al.2 found that glutaric acid from tryptophan metabolism can mod-ulate the antitumor T cell response by affecting pyruvate metabolism and𝛼-ketoglutarate-dependent dioxygenases.The adjustment of glutaric acid levels in CD8^(+)T cells has been shown to promote central memory T cell development,reduce exhaustion markers,and enhance cell death.
文摘Breast cancer cells manipulate a key nutrient to both fuel growth and disable immune defenses-a dual strategy revealed by Chinese scientists.Researchers from the Hangzhou Institute of Medicine(HIM)of the Chinese Academy of Sciences and Sun Yat-Sen University discovered that tumors exploit the amino acid arginine to rewire immune cells into cancer allies.
文摘Hyperthermia is a type of medical modality for cancer treatment using the biological effect of artificially induced heat.Even though the intrinsic effects of elevated body temperature in cancer tissues are poorly understood,increasing the temperature of the body has been recognized as a popular therapeutic method for tumorous lesions as well as infectious diseases since ancient times.Recently accumulated evidence has shown that hyperthermia amplifies immune responses in the body against cancer while decreasing the immune suppression and immune escape of cancer.It also shows that hyperthermia inhibits the repair of damaged cancer cells after chemotherapy or radiotherapy.These perceptions indicate that hyperthermia has potential for cancer therapy in conjunction with immunotherapy,chemotherapy,radiotherapy,and surgery.Paradoxically,the anticancer effect of hyperthermia alone has not yet been adequately exploited because deep heating techniques and devices to aggregate heat effects only in cancer tissues are difficult in practical terms.This review article focuses on the current understanding concerning cancer immunity and involvement of hyperthermia and the innate and adoptive immune system.The potential for combination therapy with hyperthermia and chemotherapy,radiotherapy,and surgery is also discussed.
文摘Approximately 20%of colorectal cancer(CRC)patients present with metastasis at diagnosis.Among Stage I-III CRC patients who undergo surgical resection,18%typically suffer from distal metastasis within the first three years following initial treatment.The median survival duration after the diagnosis of metastatic CRC(mCRC)is only 9 mo.mCRC is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue,allowing cancer cells to spread from primary to distant organs;however,increa-sing evidence suggests that the mCRC process can begin early in tumor development.CRC patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological alterations.Different genomic and nongenomic events can induce subclone diversity,which leads to cancer and metastasis.Throughout the course of mCRC,metastatic cascades are associated with invasive cancer cell migration through the circulatory system,extravasation,distal seeding,dormancy,and reactivation,with each step requiring specific molecular functions.However,cancer cells presenting neoantigens can be recognized and eliminated by the immune system.In this review,we explain the biological factors that drive CRC metastasis,namely,genomic instability,epigenetic instability,the metastatic cascade,the cancer-immunity cycle,and external lifestyle factors.Despite remarkable progress in CRC research,the role of molecular classification in therapeutic intervention remains unclear.This review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.
基金supported by grants from the National Natural Science Foundation of China(81730064 and 81571985 to H.Z.)National Science and Technology Major Project(2017ZX10202201 and 2009ZX10004-312 to H.Z.)+2 种基金National Natural Science Foundation of China(81601383 to S.T.,31571368 and 31871324 to G.L.,81902069 to B.X.)China Postdoctoral Science Foundation(2019M652760 to B.X.)Hunan Natural Science Foundation(2018JJ3090 to H.Z.,2018JJ3091 to S.T.,2018JJ3713 and 2018RS3006 to G.L.).
文摘The ability to harness innate immunity is a promising solution for improving cancer immunotherapy.Interferon(IFN)induces expression of IFN-stimulated genes(ISGs)by activating the JAK-STAT signaling pathway to promote innate immunity and inhibit malignant tumor growth,but the functions and mechanisms of most ISGs in cancer regulation are unknown.As an innate immune effector,ISG12a promotes the innate immune response to viral infection.In this study,ISG12a was found to be expressed at low levels in gastrointestinal cancer,represented by hepatocellular cancer(HCC)and gastric cancer(GC),and it identified as a tumor suppressor that affects clinical prognosis.ISG12a silencing accelerated the malignant transformation and epithelial–mesenchymal transition of cancer cells.Mechanistically,ISG12a promotedβ-catenin proteasomal degradation by inhibiting the degradation of ubiquitinated Axin,thereby suppressing the canonical Wnt/β-catenin signaling pathway.Notably,β-catenin was identified as a transcription factor for PD-L1.Inhibition of Wnt/β-catenin signaling by ISG12a suppressed expression of the immune checkpoint PDL1,rendering cancer cells sensitive to NK cell-mediated killing.This study reveals a mechanism underlying the anticancer effects of IFN.Some ISGs,as represented by ISG12a,may be useful in cancer therapy and prevention.The identified interrelations among innate immunity,Wnt/β-catenin signaling,and cancer immunity may provide new insight into strategies that will improve the efficiency of immunotherapy.
基金supported by the National Natural Science Foundation of China(Grant nos.82473157,82460510,82203565,82103388,31960145 and 82560591)the Natural Science Foundation of Beijing(Grant no.L248059)+1 种基金Yunnan Province applied research funds(Grant nos.202201AY070001-011,202201AY070001-043,and 202301AS070018)the Science and Technology Innovation Team of tumor metabolism research at Kunming Medical University(Grant no.CXTD202102).
文摘Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.
文摘Transcription factor forkhead box P3(Foxp3)+regulatory T(Treg)cells are receiving increasing attention because this unique subset of T cells is characterized by exerting negative regulatory function of cellular immune responses.The resultant suppression of anti-tumor immunity in the tumor microenvironment(TME)is regarded as a major obstacle to immunotherapies in a plethora of cancers.Thus,an integrated understanding of the intrinsic correlation between tumors and Treg cell biology is urgently required.This review focuses on the peculiar biochemical effects of tumor metabolic environments on Tregs and how Tregs orchestrate internal metabolic switches and altered metabolic pathways and molecules to survive and function after the remodeling of homeostasis and specialization,providing new directions for immunotherapies.
基金Supported by a grant from the Key Project of National 12th Five-year Research Program of China(No.2012ZX0903016-002)
文摘Objective：To evaluate the ef icacy of autologous cytokine-induced kil er （CIK） cells transfusion combined with chemotherapy in patients suf ered from advanced colorectal cancer. Methods： Sixty untreated patients with advanced colorectal cancer were randomly divided into two groups. The 30 patients in the control group received chemotherapy with the regimen of xeloda plus oxiplatin （XELOX）. The 30 patients in the trial group were treated with chemotherapy （XELOX） in combination with autologous CIK celltransfusion. T-lymphocyte subgroups were separated and measured by flow cytometry quality of life （QOL） was determined by EORTC QLQ-C30. The short-term curative ef ect was evaluated via imaging examina-tions. The patients’ median progression free survival time was estimated by Kaplan-Meier. Results：The T-lymphocyte im-mune activity was improved in patients received autologous CIK celltransfusion than those treated with chemotherapy alone. The subgroup of CD3＋CD56＋T lymphocyte was significantly increased （4.28 ± 0.45 vs 10.14 ± 1.02, P=0.01）. Short-term ef icacy evaluation revealed that there was no significant dif erence in terms of objective response rate （ORR） between the two groups, but the disease control rate （DCR） was markedly increased （86.7%vs 56.7%, P=0.020） in the group treated by chemotherapy plus CIK cells compared to the group treated with chemotherapy alone. The progression free survival time was 8.64 months （ 95%CI 6.25-9.75 months） in control group and 10.15 months （ 95%CI 7.48-12.52 months） in trial group. Compared to patients in control group, the patients in trial group had significantly longer progression-free survival （P=0.046）. The QOL assessment suggested the QOL in trial group was obviously improved than that in the control group. Compared with the control group, patients treated with autologous CIK celltransfusion scored more in the area of physical function and general health status, while the symptomatic scores in terms of pain, fatigue, nausea and vomiting and diarrhea were significantly reduced. Conclusion：Autologous CIK celltransfusion combined with chemotherapy can ef ectively enhance the immune activity of T-lymphocytes, prevent disease progression and improve the progression-free survival and QOL in patients with advanced colorectal cancer.
基金Scientific research project of Hubei provincial health commission(No.WJ2019M118)。
文摘Objective:To investigate the correlation between immune cell infiltration pattern and clinical features and prognosis of cervical carcinoma.Methods:All cervical cancer transcript data and related clinical data were downloaded from the public database Cancer Genome Atlas(TCGA),and the relative proportions of 22 invasive immune cell types were calculated by Cibersort software.Perl was used to assess the correlation between the pattern of immune cell invasion and clinical characteristics(age,clinical stage,tumor grade)in cervical cancer,and the correlation between the pattern of immune cell invasion and survival in cervical cancer was calculated by the K-M Log-Rank method.Result:The distribution of immune cells in 306 cases of cervical cancer and 3 cases of normal tissues was assessed using Cibersort.Compared with normal tissues,the contents of resting dendritic cells,activated dendritic cells,M1 macrophages and activated CD4+memory T cells were higher;the contents of M2 macrophages,neutrophils,regulatory T cells and activated mast cells were lower in cervical cancer tissues.The contents of M1 macrophages,unactivated CD4+memory T cells,andγδT cells were positively correlated with patient age(P<0.05).The contents of follicular helper T cells,activated and unactivated natural killer(NK)cells,and naive CD4 T cells were negatively correlated with patient age(P<0.05).Those with high resting dendritic cell composition had shorter overall survival,while those with high follicular helper T cell composition had longer overall survival(P<0.05).Conclusion:Compared with normal tissues,the composition of immune cells in cervical cancer tissues has certain specificity,which can provide reference for the early screening and diagnosis of the disease.Patients in different age groups may have different immune cell infiltration patterns,which can be used as a basis to explore drug targets in clinical practice.Resting dendritic cells and follicular helper T cells in cervical cancer can be used as possible efficacy predictors of clinical immunotherapy for cervical cancer.
基金supported by the National Natural Science Foundation of China(No.81930102 to Bo Yang),the National Natural Science Foundation of China(No.82273949 to Ling Ding),the National Natural Science Foundation of China(No.82104196 to Xi Chen)。
文摘Lipids have been found to modulate tumor biology,including proliferation,survival,and metastasis.With the new understanding of tumor immune escape that has developed in recent years,the influence of lipids on the cancer—immunity cycle has also been gradually discovered.First,regarding antigen presentation,cholesterol prevents tumor antigens from being identified by antigen presenting cells.Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells,impairing antigen presentation to T cells.Prostaglandin E2(PGE2)reduce the accumulation of tumor-infiltrating dendritic cells.Regarding T-cell priming and activation,cholesterol destroys the structure of the T-cell receptor and reduces immunodetection.In contrast,cholesterol also promotes T-cell receptor clustering and relative signal transduction.PGE2 represses T-cell proliferation.Finally,regarding T-cell killing of cancer cells,PGE2 and cholesterol weaken granule-dependent cytotoxicity.Moreover,fatty acids,cholesterol,and PGE2 can improve the activity of immunosuppressive cells,increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines.Given the regulatory role of lipids in the cancer—immunity cycle,drugs that modulate fatty acids,cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy.These strategies have been studied in both preclinical and clinical studies.
基金supported by National Key Research and Development Program of China(2018YFC2000500)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29020000)the National Natural Science Foundation of China(31771481,91857101,81873548)。
文摘Innate lymphoid cells(ILCs)are a group of innate immune cells,which constitute the first line of defense in the immune system,together with skin and mucous membrane.ILCs also play an important role in maintaining the homeostasis of the body,particularly in the complex and diverse environment of the intestine.ILCs respond to different microenvironments,maintaining homeostasis directly or indirectly through cytokines.As a result,ILCs,with complex and pleiotropic characteristics,are associated with many gastrointestinal diseases.Their ability of transition among those subgroups makes them function as both promoting and inhibiting cells,thus affecting homeostasis and disease progressing to either alleviation or deterioration.With these special characteristics,ILCs theoretically can be used in the new generation of immunotherapy as an alternative and supplement to current tumor therapy.Our review summarizes the characteristics of ILCs with respect to category,function,and the relationship with intestinal homeostasis and gastrointestinal diseases.In addition,potential tumor immunotherapies involving ILCs are also discussed to shed light on the perspectives of immunotherapy.
基金supported by“Pioneer”and“Leading Goose”R&D Program of Zhejiang Province(2022C03004 to Jianxiang Chen,China),Research Project of Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022029C to Yiting Qiao,China),National Natural Science Foundation of China(82373888 to Yiting Qiao,82072646,82372664 to Jianxiang Chen),Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT320-02 to Yiting Qiao,China)The joint foundation of National Administration of Traditional Chinese Medicine&Zhejiang Province-major project(GZY-ZJ-KJ-24045 to Jianxiang Chen,China)+1 种基金Research Unit Project of Chinese Academy of Medical Sciences(2019‒I2M‒5‒030 to Shusen Zheng,China)Postgraduate research innovation project of Hangzhou Normal University(2022HSDYJ SKY244 to Yunxin Pei,2022HSDYJ SKY015 to Menglan Wang,China).
文摘Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward the anaerobic and immune-suppressive TME,which makes them ideal natural vehicles for cancer gene therapy.Here,we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2(Il2)expression plasmid onto the surface of VNP20009,an attenuated Salmonella typhimur-ium strain with well-documented anti-cancer activity,and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella.Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Sal-monella maintained the tumor-targeting feature of bacteria,and could be effectively phagocytosed by in-tratumoral macrophages,thus leading to the expression and secretion of IL2 in TME.The detailed analysis of tumor immune microenvironment(TIME)showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME,marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME,thus leading to significant anti-tumor effects in melanoma,orthotopic hepatocellular carcinoma,and pulmonary metastasis models.More importantly,Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems.Taken together,we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effec-tive TME-targeted delivery of therapeutic gene,as well as synergistic re-activation of TIME.
基金Natural Science Foundation of Beijing Municipality(L212013)AI+Health Collaborative Innovation Cultivation Project(Z211100003521002)National Natural Science Foundation of China(82073786,81872809,U20A20412,81821004).
文摘As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient’s own immune system to eradicate the cancer cells.However, the limited population of patients who benefitfrom the current immunotherapies and the immune relatedadverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure,which leads to cancer immune evasion and immunity cycleblockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicityof their therapeutic cargos by spatiotemporally controllingthe biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to makeclinical translation, which are now established platforms fordiverse areas. In this perspective, we discuss the availablelipid-based nanoparticles in research and market here, thendescribe their application in cancer immunotherapy, withspecial emphasis on the T cells-activated and macrophagestargeted delivery system. Through perpetuating each step ofcancer immunity cycle, lipid-based nanoparticles can reduceimmunosuppression and promote drug delivery to triggerrobust antitumor response.
基金financial support from the National Natural Science Foundation of China(91229204)the Major Project of the Chinese National Programs for Fundamental Research and Development(2015CB910304)
文摘Sphingosine-1-phosphate(S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival,cell proliferation, cell migration, angiogenesis and many other cellular processes. S1 P either activates S1 P receptors(S1PR1-5) through "inside-out signaling" or acts directly on intracellular targets to regulate various cellular processes. In the past two decades, much progress has been made in exploring S1 P signaling and its pathogenic roles in diseases as well as in developing modulators of S1 P signaling, including S1 P agonists, S1 P antagonists and sphingosine kinase(SphK) inhibitors.Ceramide and S1 P have been defined as reciprocal regulators of cell fate, and S1 P signaling has been shown to be crucial for the pathogenesis of various diseases, including autoimmune diseases, inflammation and cancer; therefore, targeting S1 P signaling may curtail the process of pathogenesis and serve as a potential therapeutic target for the treatment of these diseases. In this review, we describe recent advances in our understanding of S1 P signaling in cancer development(particularly in inflammationassociated cancer) as well as in innate and adaptive immunity, and we also discuss modulators of S1 P signaling in cancer treatment.
基金supported by the National Natural Science Foundation of China(91129000)
文摘While STING(STimulator of INterferon Genes) has been shown to be essential for cytosolic DNA-triggered innate immune activation, accumulated evidence obtained from various studies suggested that an intrinsic relevance of STING-associated signaling in tumorigenesis can be observed. Also, several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for STING, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. However, cases have also been reported where the involvement of STING shows a protective role in tumor growth. Here we summarize recent findings that have pointed towards the STING pathway as an innate immune sensing mechanism driving type I interferon production in the tumor context. Better understanding of this pathway can guide further development of novel immunotherapeutic strategies in the treatment of cancer.
基金partly supported by National Natural Science Foundation of China for Key Projects(No.81430096,China)National New Drug Innovation(No.2017ZX09301062,China)Tianjin Science and Technology Plan Project(No.19YFSLQY00110,China)。
文摘Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance,preventing autoimmune responses,and minimizing tissue damage by regulating the duration and intensity of the immune response.Furthermore,immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response.Based on substantial physiological analyses as well as preclinical and clinical studies,checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers.In the last few years,extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines(TCMs).The main advantage of TCMs and natural medicine is that they usually contain multiple active components,which can act on multiple targets at the same time,resulting in additive or synergistic effects.The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest.For example,Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals,and these antibodies can overcome the exhaustion of immune cells under tumor immune evasion.Furthermore,many other TCM molecules could also be novel and effective drug candidates for the treatment of cancers.Therefore,it is essential to assess the application of immune checkpoints in the development of new drugs and TCMs.In this review,we focus on research progress in the field of immune checkpoints based on three topics:(1)immune checkpoint targets and pathways,(2)development of novel immune checkpoint-based drugs,and(3)application of immune checkpoints in the development of TCMs.
基金supported by grants from the Jiangsu Provincial Nature Science Foundation(BK20192005,China)National Natural Science Foundation of China(81630092,81903143,81802338,and 82072646)+1 种基金Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(LR21H160001)Start-up Grant of HZNU(4125C5021820470,China)。
文摘Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts.Since flagella are key inducers of the host immune response during bacterial infection,flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy.The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects,even when more bacteria were administered to offset the difference in invasion efficiency.Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5(TLR5)signalling pathway.Indeed,we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma.Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy,thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.
基金supported by the Science and Technology Innovation Team of Shanxi Province (201605D131045-18)Key Laboratory of Effective Substances Research and Utilization in Traditional Chinese Medicine of Shanxi Province (201605D111004).
文摘AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism regulation.Metabolic changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy.
