Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment(TME).Hot tumors,characterized by heightened immune activity and...Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment(TME).Hot tumors,characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors(ICIs),stand in stark contrast to cold tumors,which lack immune infiltration and remain resistant to therapy.To overcome immune evasion mechanisms employed by tumor cells,novel immunologic modulators have emerged,particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4(CTLA-4)and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1).These agents disrupt inhibitory signals and reactivate the immune system,transforming cold tumors into hot ones and promoting effective antitumor responses.However,challenges persist,including primary resistance to immunotherapy,autoimmune side effects,and tumor response heterogeneity.Addressing these challenges requires innovative strategies,deeper mechanistic insights,and a combination of immune interventions to enhance the effectiveness of immunotherapies.In the landscape of cancer medicine,where immune cold tumors represent a formidable hurdle,understanding the TME and harnessing its potential to reprogram the immune response is paramount.This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies,offering hope for patients with immune-resistant tumors.展开更多
Although current anticancer immunotherapies using immune checkpoint inhibitors(ICIs)have been reported with a high clinical success rate,numerous patients still bear‘cold’tumors with insufficient T cell infiltration...Although current anticancer immunotherapies using immune checkpoint inhibitors(ICIs)have been reported with a high clinical success rate,numerous patients still bear‘cold’tumors with insufficient T cell infiltration and low immunogenicity,responding poorly to ICI therapy.Considering the advancements in precision medicine,in-depth mechanism studies on the tumor immune microenvironment(TIME)among cold tumors are required to improve the treatment for these patients.Nanomedicine has emerged as a promising drug delivery system in anticancer immunotherapy,activates immune function,modulates the TIME,and has been applied in combination with other anticancer therapeutic strategies.This review initially summarizes the mechanisms underlying immunosuppressive TIME in cold tumors and addresses the recent advancements in nanotechnology for cold TIME reversal-based therapies,as well as a brief talk about the feasibility of clinical translation.展开更多
Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cel...Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.展开更多
The microenvironment of hypoxia and immune-cold limits the therapeutic outcomes of immune checkpoint blockade(ICB)therapy in solid tumors.It is important and imperative to search new strategies to relieve tumor hypoxi...The microenvironment of hypoxia and immune-cold limits the therapeutic outcomes of immune checkpoint blockade(ICB)therapy in solid tumors.It is important and imperative to search new strategies to relieve tumor hypoxia and reverse immunosuppression of cold tumors.In this study,the oxygen(O_(2))self-replenishing nano-enabled coordination platform can be used to induce potent antitumor immune response in cold tumors.The nanoplatform can produce O_(2)by catalyzing hydrogen peroxide(H_(2)O_(2))in tumor site effectively,showing excellent photodynamic therapy(PDT)performance.Meanwhile,it can further trigger immunogenic cell death(ICD),enhance T cell infiltration,reverse immunosuppression,and reprogram the immune-cold tumor microenvironment.In vitro and in vivo results demonstrate that the nanoplatform has potential for eradicating tumors and long-term immunological memory effect.The nanoplatform opens up a strategy for reprograming the immunosuppressive microenvironment in cold tumors.展开更多
In recent years,immune checkpoint inhibitors(ICIs)have made significant breakthroughs in the treatment of various tumors,greatly improving clinical efficacy.As the fifth most common antitumor treatment strategy for pa...In recent years,immune checkpoint inhibitors(ICIs)have made significant breakthroughs in the treatment of various tumors,greatly improving clinical efficacy.As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery,chemotherapy,radiotherapy and targeted therapy,the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells,features that are also important when distinguishing malignant tumors from“cold tumors”or“hot tumors”.At present,only a small proportion of colorectal cancer(CRC)patients with deficient mismatch repair(dMMR)or who are microsatellite instability-high(MSI-H)can benefit from ICI treatments because these patients have the characteristics of a“hot tumor”,with a high tumor mutational burden(TMB)and massive immune cell infiltration,making the tumor more easily recognized by the immune system.In contrast,a majority of CRC patients with proficient MMR(pMMR)or who are microsatellite stable(MSS)have a low TMB,lack immune cell infiltration,and have almost no response to immune monotherapy;thus,these tumors are“cold”.The greatest challenge today is how to improve the immunotherapy response of“cold tumor”patients.With the development of clinical research,immunotherapies combined with other treatment strategies(such as targeted therapy,chemotherapy,and radiotherapy)have now become potentially effective clinical strategies and research hotspots.Therefore,the question of how to promote the transformation of“cold tumors”to“hot tumors”and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration.Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.展开更多
文摘Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment(TME).Hot tumors,characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors(ICIs),stand in stark contrast to cold tumors,which lack immune infiltration and remain resistant to therapy.To overcome immune evasion mechanisms employed by tumor cells,novel immunologic modulators have emerged,particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4(CTLA-4)and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1).These agents disrupt inhibitory signals and reactivate the immune system,transforming cold tumors into hot ones and promoting effective antitumor responses.However,challenges persist,including primary resistance to immunotherapy,autoimmune side effects,and tumor response heterogeneity.Addressing these challenges requires innovative strategies,deeper mechanistic insights,and a combination of immune interventions to enhance the effectiveness of immunotherapies.In the landscape of cancer medicine,where immune cold tumors represent a formidable hurdle,understanding the TME and harnessing its potential to reprogram the immune response is paramount.This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies,offering hope for patients with immune-resistant tumors.
基金the grants from National Natural Science Foundation of China(21602030 and 81872808)Program of Shanghai Academic Research Leader(18XD1400500)+2 种基金Project Supported by Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJLab,Fudan-SIMM Joint Research Fund(FU-SIMM20182006)Scientific Research Program of Shanghai Health and Family Planning Commission(20184Y0149).
文摘Although current anticancer immunotherapies using immune checkpoint inhibitors(ICIs)have been reported with a high clinical success rate,numerous patients still bear‘cold’tumors with insufficient T cell infiltration and low immunogenicity,responding poorly to ICI therapy.Considering the advancements in precision medicine,in-depth mechanism studies on the tumor immune microenvironment(TIME)among cold tumors are required to improve the treatment for these patients.Nanomedicine has emerged as a promising drug delivery system in anticancer immunotherapy,activates immune function,modulates the TIME,and has been applied in combination with other anticancer therapeutic strategies.This review initially summarizes the mechanisms underlying immunosuppressive TIME in cold tumors and addresses the recent advancements in nanotechnology for cold TIME reversal-based therapies,as well as a brief talk about the feasibility of clinical translation.
基金supported by National Natural Science Foundation of China(81974498 and 82173757)Translational Medicine Core Facility of Shandong UniversityPharmaceutical biology sharing platform of Shandong University for supporting the work。
文摘Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.
基金This work is supported by the National Natural Science Foundation of China(Nos.52103164,and 52173142)Guangdong Basic and Applied Basic Research Foundation(Nos.2021A1515220033 and 2020A1515111059)the Fundamental Research Funds for the Central Universities(No.JUSRP123079).
文摘The microenvironment of hypoxia and immune-cold limits the therapeutic outcomes of immune checkpoint blockade(ICB)therapy in solid tumors.It is important and imperative to search new strategies to relieve tumor hypoxia and reverse immunosuppression of cold tumors.In this study,the oxygen(O_(2))self-replenishing nano-enabled coordination platform can be used to induce potent antitumor immune response in cold tumors.The nanoplatform can produce O_(2)by catalyzing hydrogen peroxide(H_(2)O_(2))in tumor site effectively,showing excellent photodynamic therapy(PDT)performance.Meanwhile,it can further trigger immunogenic cell death(ICD),enhance T cell infiltration,reverse immunosuppression,and reprogram the immune-cold tumor microenvironment.In vitro and in vivo results demonstrate that the nanoplatform has potential for eradicating tumors and long-term immunological memory effect.The nanoplatform opens up a strategy for reprograming the immunosuppressive microenvironment in cold tumors.
基金Supported by National Natural Science Foundation of China,No.82073338Sichuan Science and Technology Support Project,No.2021YFSY0039 and No.22ZDYF0499+1 种基金The 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project West China Hospital,Sichuan University,No.2020HXFH002The 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,No.ZYJC21059.
文摘In recent years,immune checkpoint inhibitors(ICIs)have made significant breakthroughs in the treatment of various tumors,greatly improving clinical efficacy.As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery,chemotherapy,radiotherapy and targeted therapy,the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells,features that are also important when distinguishing malignant tumors from“cold tumors”or“hot tumors”.At present,only a small proportion of colorectal cancer(CRC)patients with deficient mismatch repair(dMMR)or who are microsatellite instability-high(MSI-H)can benefit from ICI treatments because these patients have the characteristics of a“hot tumor”,with a high tumor mutational burden(TMB)and massive immune cell infiltration,making the tumor more easily recognized by the immune system.In contrast,a majority of CRC patients with proficient MMR(pMMR)or who are microsatellite stable(MSS)have a low TMB,lack immune cell infiltration,and have almost no response to immune monotherapy;thus,these tumors are“cold”.The greatest challenge today is how to improve the immunotherapy response of“cold tumor”patients.With the development of clinical research,immunotherapies combined with other treatment strategies(such as targeted therapy,chemotherapy,and radiotherapy)have now become potentially effective clinical strategies and research hotspots.Therefore,the question of how to promote the transformation of“cold tumors”to“hot tumors”and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration.Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.
