2025年12月23日,北京大学第三医院超声医学科梁晓龙研究员团队在Cell Biomaterials(《细胞·生物材料》)上发表了题为“Camptothecin amplified self-luminous nanosystem for highly efficient activation of pyroptosis to stimul...2025年12月23日,北京大学第三医院超声医学科梁晓龙研究员团队在Cell Biomaterials(《细胞·生物材料》)上发表了题为“Camptothecin amplified self-luminous nanosystem for highly efficient activation of pyroptosis to stimulate antitumor immunity”(喜树碱增强型自发光纳米系统高效激活细胞焦亡以激发抗肿瘤免疫)研究成果,研发新型自发光纳米诊疗系统,可实现光动力疗法与化疗的协同增效,高效激活肿瘤细胞焦亡,显著增强抗肿瘤免疫应答。展开更多
Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune check...Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.展开更多
Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CR...Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC50 values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.展开更多
Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differ...Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differentiation 1d(CD1d),rapidly produce cytokines,express natural killer(NK)cell markers,and are mainly found in mucosal and barrier tissues.Acting as a bridge between innate and adaptive immunity,they show great promise for cancer immunotherapy.DevelopingγδT and iNKT cells for treatment involves shared features like thymic origin,MHC-independent recognition,rapid cytotoxicity,low graft-vs.-host disease(GvHD)risk,ex vivo expansion,and genetic modification,making them suitable for adoptive cell therapies.While their mechanisms are similar,iNKT cells rely on CD1d-mediated antigen presentation,provided by CD1d-expressing antigen-presenting cells(APCs)or engineered cell lines,to activate their invariant TCR and expand effectively.Chimeric antigen receptors(CAR)-induced functional activations make these cell types viable alternatives to conventional cell-based or CAR-T therapies with additional safety benefits.Early clinical trials have shown encouraging results,and their completion will confirm their potential for future treatments.This review explores the biology and mechanisms ofγδT and iNKT cells,focusing on how APCs,cytokines,feeder cells,and CARs contribute to boosting their cytotoxic function,cytokine production,and expansion,enhancing their promise as cancer immunotherapies.It also explores the advancements and challenges in developingγδT and iNKT cell-based immunotherapies,with preclinical and early clinical outcomes offering promising insights.展开更多
Objectives:B-cell maturation antigen(BCMA)-targeted antibody–drug conjugates(ADCs)have emerged as promising therapies for relapsed/refractory multiple myeloma(RRMM),but the overall efficacy and safety profile is uncl...Objectives:B-cell maturation antigen(BCMA)-targeted antibody–drug conjugates(ADCs)have emerged as promising therapies for relapsed/refractory multiple myeloma(RRMM),but the overall efficacy and safety profile is unclear.This study aimed to synthesize the available evidence on the safety and efficacy of BCMA-ADCs in development for RRMM.Methods:A systematic search was conducted using six bibliographic databases and ClinicalTrials.gov up to November 2024.Studies were eligible if they were human clinical trials or animal studies evaluating BCMA-ADCs and reported efficacy and safety outcomes.Data extraction and quality assessments were conducted using validated tools,including ROBINS-I and SYRCLE’s risk of bias tool.Results:A total of 21 studies were included:16 clinical trials and five animal studies.Key findings included that belantamab mafodotin demonstrated variable but generally durable response rates(32%–85%)and a broad range of progression-free survival(PFS)(2.8–36.6 months),albeit with ocular toxicities in 51%–96%.Among newer candidates,MEDI2228 showed median PFS 5.1–6.6 months with 14%discontinuation for ocular symptoms,while AMG 224 had an overall response rate(ORR)of 23%(9/40)with anemia 21%,thrombocytopenia 24%,and ocular adverse events(AEs)21%.Animal studies supported the tumor-eradicating potential of all BCMA-ADC candidates,although safety signals such as hepatic and renal toxicity were noted with HDP-101.The risk of bias assessment revealed generally moderate to serious concerns in human trials,while the overall quality of the animal studies was acceptable.Conclusions:BCMA-targeted ADC candidates show encouraging efficacy in RRMM,particularly belantamab mafodotin.However,frequent AEs,especially ocular and hematologic toxicities,underscore the need for optimization in ADC design.Further research should prioritize enhancing safety while maintaining clinical benefit.展开更多
Emerging ferroptosis-immunotherapy strategies,integrating functionalized nanoplatforms with ferroptosis-inducing agents and immunomodulatory therapeutics,demonstrate significant potential in managing primary,recurrent...Emerging ferroptosis-immunotherapy strategies,integrating functionalized nanoplatforms with ferroptosis-inducing agents and immunomodulatory therapeutics,demonstrate significant potential in managing primary,recurrent,and metastatic malignancies.Mechanistically,ferroptosis induction not only directly eliminates tumor cells but also promotes immunogenic cell death(ICD),eliciting damage-associated molecular patterns(DAMPs)release to activate partial antitumor immunity.However,standalone ferroptosis therapy fails to initiate robust systemic antitumor immune responses due to inherent limitations:low tumor immunogenicity,immunosuppressive microenvironment constraints,and tumor microenvironment(TME)-associated physiological barriers(e.g.,hypoxia,dense extracellular matrix).To address these challenges,synergistic approaches have been developed to enhance immune cell infiltration and reestablish immunosurveillance,encompassing(1)direct amplification of antitumor immunity,(2)disruption of immunosuppressive tumor niches,and(3)biophysical hallmark remodeling in TME.Rational nanocarrier design has emerged as a critical enabler for overcoming biological delivery barriers and optimizing therapeutic efficacy.Unlike prior studies solely addressing ferroptosis or nanotechnology in tumor therapy,this work first systematically outlines the synergistic potential of nanoparticles in combined ferroptosis-immunotherapy strategies.It advances multidimensional nanoplatform design principles for material selection,structural configuration,physicochemical modulation,multifunctional integration,and artificial intelligence-enabled design,providing a scientific basis for efficacy optimization.Moreover,it examines translational challenges of ferroptosis-immunotherapy nanoplatforms across preclinical and clinical stages,proposing actionable solutions while envisioning future onco-immunotherapy directions.Collectively,it provides systematic insights into advanced nanomaterial design principles and therapeutic optimization strategies,offering a roadmap for accelerating clinical translation in onco-immunotherapy research.展开更多
文摘2025年12月23日,北京大学第三医院超声医学科梁晓龙研究员团队在Cell Biomaterials(《细胞·生物材料》)上发表了题为“Camptothecin amplified self-luminous nanosystem for highly efficient activation of pyroptosis to stimulate antitumor immunity”(喜树碱增强型自发光纳米系统高效激活细胞焦亡以激发抗肿瘤免疫)研究成果,研发新型自发光纳米诊疗系统,可实现光动力疗法与化疗的协同增效,高效激活肿瘤细胞焦亡,显著增强抗肿瘤免疫应答。
基金supported by the National Natural Science Foundation of China(82472842 and 82473350)and Wuxi Double-Hundred Talent Fund Project(BJ2023075).
文摘Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.
基金supported by the National Natural Science Foundation of China(82441036)Ganzhou Municipal Science and Technology Project(2022-RC1342)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515130004)Key-Area Research and Development Program of Guangdong Province(2019B020234003)Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer(2020B121201004)Open Project Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202210).
文摘Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC50 values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.
文摘Gamma delta(γδ)T cells and invariant natural killer T(iNKT)cells are unconventional T cells with limited T cell receptor(TCR)diversity.Both can recognize lipid or non-peptide antigens,often through cluster of differentiation 1d(CD1d),rapidly produce cytokines,express natural killer(NK)cell markers,and are mainly found in mucosal and barrier tissues.Acting as a bridge between innate and adaptive immunity,they show great promise for cancer immunotherapy.DevelopingγδT and iNKT cells for treatment involves shared features like thymic origin,MHC-independent recognition,rapid cytotoxicity,low graft-vs.-host disease(GvHD)risk,ex vivo expansion,and genetic modification,making them suitable for adoptive cell therapies.While their mechanisms are similar,iNKT cells rely on CD1d-mediated antigen presentation,provided by CD1d-expressing antigen-presenting cells(APCs)or engineered cell lines,to activate their invariant TCR and expand effectively.Chimeric antigen receptors(CAR)-induced functional activations make these cell types viable alternatives to conventional cell-based or CAR-T therapies with additional safety benefits.Early clinical trials have shown encouraging results,and their completion will confirm their potential for future treatments.This review explores the biology and mechanisms ofγδT and iNKT cells,focusing on how APCs,cytokines,feeder cells,and CARs contribute to boosting their cytotoxic function,cytokine production,and expansion,enhancing their promise as cancer immunotherapies.It also explores the advancements and challenges in developingγδT and iNKT cell-based immunotherapies,with preclinical and early clinical outcomes offering promising insights.
文摘Objectives:B-cell maturation antigen(BCMA)-targeted antibody–drug conjugates(ADCs)have emerged as promising therapies for relapsed/refractory multiple myeloma(RRMM),but the overall efficacy and safety profile is unclear.This study aimed to synthesize the available evidence on the safety and efficacy of BCMA-ADCs in development for RRMM.Methods:A systematic search was conducted using six bibliographic databases and ClinicalTrials.gov up to November 2024.Studies were eligible if they were human clinical trials or animal studies evaluating BCMA-ADCs and reported efficacy and safety outcomes.Data extraction and quality assessments were conducted using validated tools,including ROBINS-I and SYRCLE’s risk of bias tool.Results:A total of 21 studies were included:16 clinical trials and five animal studies.Key findings included that belantamab mafodotin demonstrated variable but generally durable response rates(32%–85%)and a broad range of progression-free survival(PFS)(2.8–36.6 months),albeit with ocular toxicities in 51%–96%.Among newer candidates,MEDI2228 showed median PFS 5.1–6.6 months with 14%discontinuation for ocular symptoms,while AMG 224 had an overall response rate(ORR)of 23%(9/40)with anemia 21%,thrombocytopenia 24%,and ocular adverse events(AEs)21%.Animal studies supported the tumor-eradicating potential of all BCMA-ADC candidates,although safety signals such as hepatic and renal toxicity were noted with HDP-101.The risk of bias assessment revealed generally moderate to serious concerns in human trials,while the overall quality of the animal studies was acceptable.Conclusions:BCMA-targeted ADC candidates show encouraging efficacy in RRMM,particularly belantamab mafodotin.However,frequent AEs,especially ocular and hematologic toxicities,underscore the need for optimization in ADC design.Further research should prioritize enhancing safety while maintaining clinical benefit.
基金supported by the National Natural Science Foundation of China(Nos.82302373,81903846)Natural Science Foundation of Sichuan Province(No.2022NSFSC1925)+1 种基金Chengdu Technology Innovation Research and Development Project(No.2022-YF05-01546-SN)the Introduction of Talents Research Project of Chengdu University(No.2081921049)。
文摘Emerging ferroptosis-immunotherapy strategies,integrating functionalized nanoplatforms with ferroptosis-inducing agents and immunomodulatory therapeutics,demonstrate significant potential in managing primary,recurrent,and metastatic malignancies.Mechanistically,ferroptosis induction not only directly eliminates tumor cells but also promotes immunogenic cell death(ICD),eliciting damage-associated molecular patterns(DAMPs)release to activate partial antitumor immunity.However,standalone ferroptosis therapy fails to initiate robust systemic antitumor immune responses due to inherent limitations:low tumor immunogenicity,immunosuppressive microenvironment constraints,and tumor microenvironment(TME)-associated physiological barriers(e.g.,hypoxia,dense extracellular matrix).To address these challenges,synergistic approaches have been developed to enhance immune cell infiltration and reestablish immunosurveillance,encompassing(1)direct amplification of antitumor immunity,(2)disruption of immunosuppressive tumor niches,and(3)biophysical hallmark remodeling in TME.Rational nanocarrier design has emerged as a critical enabler for overcoming biological delivery barriers and optimizing therapeutic efficacy.Unlike prior studies solely addressing ferroptosis or nanotechnology in tumor therapy,this work first systematically outlines the synergistic potential of nanoparticles in combined ferroptosis-immunotherapy strategies.It advances multidimensional nanoplatform design principles for material selection,structural configuration,physicochemical modulation,multifunctional integration,and artificial intelligence-enabled design,providing a scientific basis for efficacy optimization.Moreover,it examines translational challenges of ferroptosis-immunotherapy nanoplatforms across preclinical and clinical stages,proposing actionable solutions while envisioning future onco-immunotherapy directions.Collectively,it provides systematic insights into advanced nanomaterial design principles and therapeutic optimization strategies,offering a roadmap for accelerating clinical translation in onco-immunotherapy research.
