Pancreatic cancer,characterized by dense tissue and a significant infiltration of myeloid-derived suppressor cells(MDSCs),leads to an almost complete absence of T cells infiltration and a poor response to immunotherap...Pancreatic cancer,characterized by dense tissue and a significant infiltration of myeloid-derived suppressor cells(MDSCs),leads to an almost complete absence of T cells infiltration and a poor response to immunotherapy.A strategy involving external defense of MDSCs recruitment and internal attack on tumor cells may enhance the effectiveness of chemo-immunotherapy for pancreatic cancer.Herein,a MDSCs-derived nanovesicle encapsulating the CD11b agonist leukadherin-1(LA)and the polyamide-oxaliplatin(PAMAM-OXA)nanoparticles(P),named MLR/LA@P,was constructed for pancreatic cancer treatment.The activation of CD11b by LA enhanced the binding of MLR/LA@P to ICAM-1,thereby improving tumor targeting ability and competitively inhibiting MDSCs recruitment for“external defense”.In response to matrix metalloproteinase-2(MMP2)in the tumor microenvironment,MLR/LA@P degraded and released small-sized P for deep penetration.Subsequently,OXA was released in response to glutathione within tumor cells,triggering immunogenic cell death for“internal attack”.MLR/LA@P not only inhibited the growth of orthotopic pancreatic tumors,but also prevented the formation of pre-metastatic niches(PMNs),which is promising for pancreatic cancer treatment.展开更多
基金supported by the Sichuan Science and Technology program(No.2022NSFSC0045)the Fundamental Research Funds for the Central Universities,and the National Natural Science Foundation of China(No.82404566).
文摘Pancreatic cancer,characterized by dense tissue and a significant infiltration of myeloid-derived suppressor cells(MDSCs),leads to an almost complete absence of T cells infiltration and a poor response to immunotherapy.A strategy involving external defense of MDSCs recruitment and internal attack on tumor cells may enhance the effectiveness of chemo-immunotherapy for pancreatic cancer.Herein,a MDSCs-derived nanovesicle encapsulating the CD11b agonist leukadherin-1(LA)and the polyamide-oxaliplatin(PAMAM-OXA)nanoparticles(P),named MLR/LA@P,was constructed for pancreatic cancer treatment.The activation of CD11b by LA enhanced the binding of MLR/LA@P to ICAM-1,thereby improving tumor targeting ability and competitively inhibiting MDSCs recruitment for“external defense”.In response to matrix metalloproteinase-2(MMP2)in the tumor microenvironment,MLR/LA@P degraded and released small-sized P for deep penetration.Subsequently,OXA was released in response to glutathione within tumor cells,triggering immunogenic cell death for“internal attack”.MLR/LA@P not only inhibited the growth of orthotopic pancreatic tumors,but also prevented the formation of pre-metastatic niches(PMNs),which is promising for pancreatic cancer treatment.
