The human gastrointestinal tract harbors trillions of microorganisms,including bacteria,fungi,and viruses,to form the gut microbiota.Cumulative evidence has demonstrated the critical impact of gut microbes on cancer i...The human gastrointestinal tract harbors trillions of microorganisms,including bacteria,fungi,and viruses,to form the gut microbiota.Cumulative evidence has demonstrated the critical impact of gut microbes on cancer immunity.In cancer,an altered gut microbiota enriched with pathogenic bacteria can actively promote immune evasion and disrupt antitumor immunity,thereby supporting tumor growth and survival.Conversely,beneficial commensal bacteria(e.g.,Lactobacillus and Bifidobacterium)have emerged as therapeutic probiotics for cancer prevention and as adjuvants for cancer therapy.The gut microbiota is also closely linked to the efficacy of immunotherapy.This review summarizes the effects of pathogenic bacteria and beneficial commensals,including T cells,B cells,natural killer cells,innate lymphoid cells,and myeloid-derived suppress cells,on various innate and adaptive immune cell populations in cancer.It also explores the mechanisms by which the gut microbiota influences immunotherapy efficacy,such as the modulation of innate immune cells and CD8^(+)T cells.Given its importance,an increasing number of studies have developed approaches to target the gut microbiota to improve immunotherapy outcomes and reduce immune-related adverse events.These strategies include antimicrobial intervention,probiotics,prebiotics/dietary modifications,microbial metabolites,phage therapy,and fecal microbiota transplantation.This review also evaluates clinical applications that use the gut microbiota to predict immunotherapy outcomes.Overall,the current understanding of host‒microbe interactions within the tumor microenvironment has laid a critical foundation for the translation of microbiota research into clinical practice,ultimately benefiting patients.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
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
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
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
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
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
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
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
Immune imbalance is a critical factor in the occurrence and progression of cancers because it disrupts the immune system's ability to detect and eliminate abnormal cells.Restoring immune balance and reactivating i...Immune imbalance is a critical factor in the occurrence and progression of cancers because it disrupts the immune system's ability to detect and eliminate abnormal cells.Restoring immune balance and reactivating immune cells remain major challenges in cancer immunotherapy.Current immunoregulatory strategies,such as immune checkpoint blockade,adoptive cell therapy,and therapeutic vaccines,aim to influence key immune cells,such as T cells,dendritic cells,and macrophages,to boost anticancer responses.However,conventional material design in immunotherapy usually emphasizes chemical composition and physical morphology,while neglecting the critical role of stereochemistry in immune cell recognition and activation.展开更多
Allogeneic“off-the-shelf”chimeric antigen receptor(CAR)T-cell therapy offers numerous advantages over autologous approaches.However,two critical challenges are encountered:graft-versus-host disease(GVHD)and poor per...Allogeneic“off-the-shelf”chimeric antigen receptor(CAR)T-cell therapy offers numerous advantages over autologous approaches.However,two critical challenges are encountered:graft-versus-host disease(GVHD)and poor persistence due to both extrinsic(host immune rejection)and intrinsic(TCR deletion-mediated)mechanisms.To prevent GVHD and prevent host-mediated graft rejection,allogeneic CAR-T-cell strategies typically employ selective editing of surface receptors or ligands,including(1)reducing the risk of GVHD by gene editing with TCR deletion[1,2];(2)diminishing allogeneic immunogenicity by knocking out HLA andβ2 m,which can alleviate T-cell-mediated immune rejection but inadvertently activates NK cells[3];and(3)preventing NK-cell-dependent lysis by overexpressing NK-inhibitory ligands,such as the nonclassical HLA molecules HLA-E and HLA-G[4].Recently,Wu et al.introduced a novel strategy that targets signal peptide peptidase-like 3(SPPL3)in allogeneic CAR-T cells.This approach confers dual resistance to both allogeneic rejection(mediated by T/NK cells)and Fas-dependent activation-induced cell death(AICD).Importantly,endogenous TCR expression was preserved,thereby enhancing CAR-T-cell persistence without increasing the risk of GVHD.In a phase 1 clinical trial,SPPL3-null CAR-T cells exhibited both safety and promising efficacy in patients with B-cell hematologic malignancies[5].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
Chimeric antigen receptor T cell therapy has revolutionized cancer treatment,but its efficacy remains constrained by the immunosuppressive tumor microenvironment.Emerging evidence identifies the neuro-immune-cancer ax...Chimeric antigen receptor T cell therapy has revolutionized cancer treatment,but its efficacy remains constrained by the immunosuppressive tumor microenvironment.Emerging evidence identifies the neuro-immune-cancer axis as a critical modulator of tumor microenvironment dynamics,offering novel opportunities to reshape immune responses.Neural signaling influences chimeric antigen receptor T cell function,yet therapeutic strategies targeting this axis remain largely unexplored.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
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0500200)Research Talent Hub-Innovation and Technology Fund Hong Kong(ITS/177/21FP)+1 种基金RGC Research Impact Fund Hong Kong(R4032-21F)RGC-CRF(C4008-23 W).
文摘The human gastrointestinal tract harbors trillions of microorganisms,including bacteria,fungi,and viruses,to form the gut microbiota.Cumulative evidence has demonstrated the critical impact of gut microbes on cancer immunity.In cancer,an altered gut microbiota enriched with pathogenic bacteria can actively promote immune evasion and disrupt antitumor immunity,thereby supporting tumor growth and survival.Conversely,beneficial commensal bacteria(e.g.,Lactobacillus and Bifidobacterium)have emerged as therapeutic probiotics for cancer prevention and as adjuvants for cancer therapy.The gut microbiota is also closely linked to the efficacy of immunotherapy.This review summarizes the effects of pathogenic bacteria and beneficial commensals,including T cells,B cells,natural killer cells,innate lymphoid cells,and myeloid-derived suppress cells,on various innate and adaptive immune cell populations in cancer.It also explores the mechanisms by which the gut microbiota influences immunotherapy efficacy,such as the modulation of innate immune cells and CD8^(+)T cells.Given its importance,an increasing number of studies have developed approaches to target the gut microbiota to improve immunotherapy outcomes and reduce immune-related adverse events.These strategies include antimicrobial intervention,probiotics,prebiotics/dietary modifications,microbial metabolites,phage therapy,and fecal microbiota transplantation.This review also evaluates clinical applications that use the gut microbiota to predict immunotherapy outcomes.Overall,the current understanding of host‒microbe interactions within the tumor microenvironment has laid a critical foundation for the translation of microbiota research into clinical practice,ultimately benefiting patients.
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.
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 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.
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.
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(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.
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financially supported by the National Natural Science Foundation of China(Grant Nos.U23A20591,52273158,52273159,and W2421115)the Science and Technology Department Project of Jilin Province(Grant No.20250204068YY)the Youth Innovation Promotion Association of Chinese Academy of Sciences(Grant No.Y2023066).
文摘Immune imbalance is a critical factor in the occurrence and progression of cancers because it disrupts the immune system's ability to detect and eliminate abnormal cells.Restoring immune balance and reactivating immune cells remain major challenges in cancer immunotherapy.Current immunoregulatory strategies,such as immune checkpoint blockade,adoptive cell therapy,and therapeutic vaccines,aim to influence key immune cells,such as T cells,dendritic cells,and macrophages,to boost anticancer responses.However,conventional material design in immunotherapy usually emphasizes chemical composition and physical morphology,while neglecting the critical role of stereochemistry in immune cell recognition and activation.
文摘Allogeneic“off-the-shelf”chimeric antigen receptor(CAR)T-cell therapy offers numerous advantages over autologous approaches.However,two critical challenges are encountered:graft-versus-host disease(GVHD)and poor persistence due to both extrinsic(host immune rejection)and intrinsic(TCR deletion-mediated)mechanisms.To prevent GVHD and prevent host-mediated graft rejection,allogeneic CAR-T-cell strategies typically employ selective editing of surface receptors or ligands,including(1)reducing the risk of GVHD by gene editing with TCR deletion[1,2];(2)diminishing allogeneic immunogenicity by knocking out HLA andβ2 m,which can alleviate T-cell-mediated immune rejection but inadvertently activates NK cells[3];and(3)preventing NK-cell-dependent lysis by overexpressing NK-inhibitory ligands,such as the nonclassical HLA molecules HLA-E and HLA-G[4].Recently,Wu et al.introduced a novel strategy that targets signal peptide peptidase-like 3(SPPL3)in allogeneic CAR-T cells.This approach confers dual resistance to both allogeneic rejection(mediated by T/NK cells)and Fas-dependent activation-induced cell death(AICD).Importantly,endogenous TCR expression was preserved,thereby enhancing CAR-T-cell persistence without increasing the risk of GVHD.In a phase 1 clinical trial,SPPL3-null CAR-T cells exhibited both safety and promising efficacy in patients with B-cell hematologic malignancies[5].
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.
基金supported by the National Natural Science Foundation of China(82530008)。
文摘Chimeric antigen receptor T cell therapy has revolutionized cancer treatment,but its efficacy remains constrained by the immunosuppressive tumor microenvironment.Emerging evidence identifies the neuro-immune-cancer axis as a critical modulator of tumor microenvironment dynamics,offering novel opportunities to reshape immune responses.Neural signaling influences chimeric antigen receptor T cell function,yet therapeutic strategies targeting this axis remain largely unexplored.
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.
