Compressed blood and intratumoral lymphatic vessels induced by proliferated tumor cells and elevated interstitial fluid pressure produce regional hypoxic and necrotic region within tumors,which severely reduced the ac...Compressed blood and intratumoral lymphatic vessels induced by proliferated tumor cells and elevated interstitial fluid pressure produce regional hypoxic and necrotic region within tumors,which severely reduced the accessibility of immunogenic cell death(ICD)related drugs and immune-related cells.Herein,the strategy of self-oriented deep tumor delivery by circulating monocyte/macrophage was proposed.Briefly,CS-AI including an indoleamine 2,3-dioxygenase(IDO)inhibitor indoximod(IND)and hydrophilic chitosan(CSO)linked with alanine-alanine-asparagine(AAN)was prepared,which could be selectively cleaved by legumain overexpressed in macrophages and promote the collapse in structure.Then,CS-AI was modified with mannose on the surface and further encapsulated the ICD inducer doxorubicin(DOX)to obtain M-CS-AI/DOX.Upon intravenous injection,MCS-AI/DOX was specially recognized and internalized by circulating monocyte in vivo.The formed drugs/monocyte tend to distribute in hypoxia/necrosis region guided by the homing signals released by tumor.Accumulated monocytes then further differentiated into macrophages,up-regulating the expression of legumain and promoting the sensitive-release of chemo-drug DOX,IND,and the mannose-modified CSO(M-CSO).The released IND would specifically regulate immunosuppressive tumor microenvironment,and synergistically inhibit tumor growth with immune activation elements,ICD-induced DOX,and the favorable adjuvant M-CSO.In summary,the self-oriented deep tumor delivery of legumain-cleavable nanovesicles through circulating monocyte makes it possible for reaching tumor regions inaccessible for nanoparticles and provides a novel insight for precise tumor enrichment and immune activation.展开更多
Tumor-associated macrophages(TAMs),derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2(CCL2)and colony-stimulating factor-1(CSF-1),are pivotal components of t...Tumor-associated macrophages(TAMs),derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2(CCL2)and colony-stimulating factor-1(CSF-1),are pivotal components of the tumor microenvironment(TME).Functionally polarized into distinct subtypes,TAMs play dual roles:proinflammatory M1-type TAMs enhance antitumor immunity through the secretion of cytokines such as interleukin-12(IL-12)and tumor necrosis factor alpha(TNF-α)and direct tumor cell cytotoxicity,whereas M2-type TAMs promote tumor progression by facilitating angiogenesis,metastasis,and immunosuppression.This polarization is dynamically regulated by different cytokines,various signaling pathways,and metabolic cues within the TME.Spatial distribution analyses revealed that M2-like TAMs predominantly infiltrate hypoxic and stromal regions,where they secrete factors such as vascular endothelial growth factor(VEGF),transforming growth factor beta(TGF-β),and matrix metalloproteinases(MMPs)to remodel the extracellular matrix and suppress immune responses via programmed death-ligand 1(PD-L1)and arginase-1 upregulation.Crucially,TAMs interact extensively with immune cells;M2-TAMs secrete interleukin-10(IL-10)and TGF-βto inhibit cytotoxic T lymphocytes while expanding regulatory T(Treg)cells and impairing natural killer(NK)cell function via altered antigen presentation.Conversely,M1-TAMs synergize with dendritic cells to enhance T-cell priming.Therapeutically,targeting TAMs offers promising strategies,including colony-stimulating factor-1 receptor(CSF-1R)inhibitors,CCL2 antagonists,and nanoparticle-mediated repolarization of M2-TAMs toward the M1 phenotype.Emerging genetic approaches,such as clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9(CRISPR-Cas9)editing,aim to disrupt protumorigenic pathways in TAMs.Additionally,TAM-related biomarkers(e.g.,CD206 and CD163)are being evaluated for their prognostic and predictive utility in immunotherapies.Despite progress,challenges persist owing to TAM plasticity and TME heterogeneity across cancers.This review synthesizes TAM biology,immune crosstalk,and therapeutic advancements,providing a foundation for novel oncology strategies aimed at reprogramming TAMs to overcome treatment resistance and improve clinical outcomes.展开更多
基金supported by Zhejiang Provincial Natural Science Foundation of China(No.D19H300001).
文摘Compressed blood and intratumoral lymphatic vessels induced by proliferated tumor cells and elevated interstitial fluid pressure produce regional hypoxic and necrotic region within tumors,which severely reduced the accessibility of immunogenic cell death(ICD)related drugs and immune-related cells.Herein,the strategy of self-oriented deep tumor delivery by circulating monocyte/macrophage was proposed.Briefly,CS-AI including an indoleamine 2,3-dioxygenase(IDO)inhibitor indoximod(IND)and hydrophilic chitosan(CSO)linked with alanine-alanine-asparagine(AAN)was prepared,which could be selectively cleaved by legumain overexpressed in macrophages and promote the collapse in structure.Then,CS-AI was modified with mannose on the surface and further encapsulated the ICD inducer doxorubicin(DOX)to obtain M-CS-AI/DOX.Upon intravenous injection,MCS-AI/DOX was specially recognized and internalized by circulating monocyte in vivo.The formed drugs/monocyte tend to distribute in hypoxia/necrosis region guided by the homing signals released by tumor.Accumulated monocytes then further differentiated into macrophages,up-regulating the expression of legumain and promoting the sensitive-release of chemo-drug DOX,IND,and the mannose-modified CSO(M-CSO).The released IND would specifically regulate immunosuppressive tumor microenvironment,and synergistically inhibit tumor growth with immune activation elements,ICD-induced DOX,and the favorable adjuvant M-CSO.In summary,the self-oriented deep tumor delivery of legumain-cleavable nanovesicles through circulating monocyte makes it possible for reaching tumor regions inaccessible for nanoparticles and provides a novel insight for precise tumor enrichment and immune activation.
基金supported by the National Natural Science Foundation of China(11932017 to X.X.K.,82072624 to K.F.D.)China Postdoctoral Science Foundation General Program under No.2024M762922 to J.S.X.+7 种基金Zhejiang Provincial Health Department General Project under No.2025KY872 to J.S.X.2024 Zhejiang Provincial Postdoctoral Research Project Special Funding under No.2024-00004 to J.S.X.Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2024ZD0520100 to K.F.D.,No.2023ZD0512500 to J.S.X.)Research Program of Zhejiang University Binjiang Institute Research Center for Life Science and Human Health under No.ZY202501SMKY002-4 to J.S.X.Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No.LHDMY22C060002 to X.X.K.the Fundamental Research Funds for the Central Universities(No.226-2022-00009,No.226-2024-00062,No.226-2024-00176)to K.F.D.the Program for Zhejiang Provincial Clinical Research Center for CANCER under No.2022E50008 to K.F.D.Key R&D Program of Zhejiang under 2024C03170 to K.F.D.
文摘Tumor-associated macrophages(TAMs),derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2(CCL2)and colony-stimulating factor-1(CSF-1),are pivotal components of the tumor microenvironment(TME).Functionally polarized into distinct subtypes,TAMs play dual roles:proinflammatory M1-type TAMs enhance antitumor immunity through the secretion of cytokines such as interleukin-12(IL-12)and tumor necrosis factor alpha(TNF-α)and direct tumor cell cytotoxicity,whereas M2-type TAMs promote tumor progression by facilitating angiogenesis,metastasis,and immunosuppression.This polarization is dynamically regulated by different cytokines,various signaling pathways,and metabolic cues within the TME.Spatial distribution analyses revealed that M2-like TAMs predominantly infiltrate hypoxic and stromal regions,where they secrete factors such as vascular endothelial growth factor(VEGF),transforming growth factor beta(TGF-β),and matrix metalloproteinases(MMPs)to remodel the extracellular matrix and suppress immune responses via programmed death-ligand 1(PD-L1)and arginase-1 upregulation.Crucially,TAMs interact extensively with immune cells;M2-TAMs secrete interleukin-10(IL-10)and TGF-βto inhibit cytotoxic T lymphocytes while expanding regulatory T(Treg)cells and impairing natural killer(NK)cell function via altered antigen presentation.Conversely,M1-TAMs synergize with dendritic cells to enhance T-cell priming.Therapeutically,targeting TAMs offers promising strategies,including colony-stimulating factor-1 receptor(CSF-1R)inhibitors,CCL2 antagonists,and nanoparticle-mediated repolarization of M2-TAMs toward the M1 phenotype.Emerging genetic approaches,such as clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9(CRISPR-Cas9)editing,aim to disrupt protumorigenic pathways in TAMs.Additionally,TAM-related biomarkers(e.g.,CD206 and CD163)are being evaluated for their prognostic and predictive utility in immunotherapies.Despite progress,challenges persist owing to TAM plasticity and TME heterogeneity across cancers.This review synthesizes TAM biology,immune crosstalk,and therapeutic advancements,providing a foundation for novel oncology strategies aimed at reprogramming TAMs to overcome treatment resistance and improve clinical outcomes.
