Post-resection recurrence remains a severe problem in melanoma treatment.New therapeutic strategies,such as chemodynamic therapy(CDT),exhibit high specificity and responsiveness,demonstrating potential to elicit antit...Post-resection recurrence remains a severe problem in melanoma treatment.New therapeutic strategies,such as chemodynamic therapy(CDT),exhibit high specificity and responsiveness,demonstrating potential to elicit antitumor immune responses by triggering immunogenic cell death(ICD).However,the efficacy of CDT still faces challenges from the immunosuppressive tumor microenvironment(TME)characterized by elevated lactate levels.Herein,we propose a strategy to construct an immunomodulatory hydrogel to synergistically reprogram tumor-associated macrophages and amplify ICD to inhibit melanoma recurrence after surgery.The hyaluronic acid hydrogel containing borosilicate glasses(BGs)and Fe_(3)O_(4) nanoparticles(HBF hydrogel)are obtained,which can neutralize tumor acidity to reprogram macrophages to M1 phenotype.Furthermore,the HBF hydrogel induces reactive oxygen species production in melanoma cells,which could induce ICD through CDT and stimulate strong antitumor immune responses,thereby promoting tumor immunotherapy.The cooperative ICD induced by CDT and immunosuppressive TME remodeling leads to effective suppression of tumor recurrence.This work provides a promising strategy for immunomodulation-enhanced melanoma therapy through the fabrication of hydrogel to prevent postsurgical tumor recurrence.展开更多
The endoplasmic reticulum(ER)and the plasma membrane(PM)form ER–PM contact sites(EPCSs)that allow the ER and PM to exchange materials and information.Stress-induced disruption of protein folding triggers ER stress,an...The endoplasmic reticulum(ER)and the plasma membrane(PM)form ER–PM contact sites(EPCSs)that allow the ER and PM to exchange materials and information.Stress-induced disruption of protein folding triggers ER stress,and the cell initiates the unfolded protein response(UPR)to resist the stress.However,whether EPCSs play a role in ER stress in plants remains unclear.VESICLE-ASSOCIATED MEMBRANE PROTEIN(VAMP)-ASSOCIATED PROTEIN 27-1(VAP27-1)functions in EPCS tethering and is encoded by a family of 10 genes(VAP27-1–10)in Arabidopsis thaliana.Here,we used CRISPR-Cas9-mediated genome editing to obtain a homozygous vap27-1 vap27-3 vap27-4(vap27-1/3/4)triple mutant lacking three of the key VAP27 family members in Arabidopsis.The vap27-1/3/4 mutant exhibits defects in ER–PM connectivity and EPCS architecture,as well as excessive UPR signaling.We further showed that relocation of VAP27-1 to the PM mediates specific VAP27-1-related EPCS remodeling and expansion under ER stress.Moreover,the spatiotemporal dynamics of VAP27-1 at the PM increase ER–PM connectivity and enhance Arabidopsis resistance to ER stress.In addition,we revealed an important role for intracellular calcium homeostasis in the regulation of UPR signaling.Taken together,these results broaden our understanding of the molecular and cellular mechanisms of ER stress and UPR signaling in plants,providing additional clues for improving plant broad-spectrum resistance to different stresses.展开更多
基金National Key Research and Development Program of China (2021YFC2400500)National Natural Science Foundation of China (52173271, 52361165659, and 52221006)Beijing Outstanding Young Scientist Program(BJJWZYJH01201910010024)。
文摘Post-resection recurrence remains a severe problem in melanoma treatment.New therapeutic strategies,such as chemodynamic therapy(CDT),exhibit high specificity and responsiveness,demonstrating potential to elicit antitumor immune responses by triggering immunogenic cell death(ICD).However,the efficacy of CDT still faces challenges from the immunosuppressive tumor microenvironment(TME)characterized by elevated lactate levels.Herein,we propose a strategy to construct an immunomodulatory hydrogel to synergistically reprogram tumor-associated macrophages and amplify ICD to inhibit melanoma recurrence after surgery.The hyaluronic acid hydrogel containing borosilicate glasses(BGs)and Fe_(3)O_(4) nanoparticles(HBF hydrogel)are obtained,which can neutralize tumor acidity to reprogram macrophages to M1 phenotype.Furthermore,the HBF hydrogel induces reactive oxygen species production in melanoma cells,which could induce ICD through CDT and stimulate strong antitumor immune responses,thereby promoting tumor immunotherapy.The cooperative ICD induced by CDT and immunosuppressive TME remodeling leads to effective suppression of tumor recurrence.This work provides a promising strategy for immunomodulation-enhanced melanoma therapy through the fabrication of hydrogel to prevent postsurgical tumor recurrence.
基金supported by the National Natural Science Foundation of China(32170689,91954202,32030010)National Key Research and Development Program of China(2022YFF0712500)+1 种基金the Program of Introducing Talents of Discipline to Universities(111 Project,B13007)Beijing Forestry University Outstanding Postgraduate Mentoring Team Building(YJSY-DSTD2022005).
文摘The endoplasmic reticulum(ER)and the plasma membrane(PM)form ER–PM contact sites(EPCSs)that allow the ER and PM to exchange materials and information.Stress-induced disruption of protein folding triggers ER stress,and the cell initiates the unfolded protein response(UPR)to resist the stress.However,whether EPCSs play a role in ER stress in plants remains unclear.VESICLE-ASSOCIATED MEMBRANE PROTEIN(VAMP)-ASSOCIATED PROTEIN 27-1(VAP27-1)functions in EPCS tethering and is encoded by a family of 10 genes(VAP27-1–10)in Arabidopsis thaliana.Here,we used CRISPR-Cas9-mediated genome editing to obtain a homozygous vap27-1 vap27-3 vap27-4(vap27-1/3/4)triple mutant lacking three of the key VAP27 family members in Arabidopsis.The vap27-1/3/4 mutant exhibits defects in ER–PM connectivity and EPCS architecture,as well as excessive UPR signaling.We further showed that relocation of VAP27-1 to the PM mediates specific VAP27-1-related EPCS remodeling and expansion under ER stress.Moreover,the spatiotemporal dynamics of VAP27-1 at the PM increase ER–PM connectivity and enhance Arabidopsis resistance to ER stress.In addition,we revealed an important role for intracellular calcium homeostasis in the regulation of UPR signaling.Taken together,these results broaden our understanding of the molecular and cellular mechanisms of ER stress and UPR signaling in plants,providing additional clues for improving plant broad-spectrum resistance to different stresses.
