TY - JOUR
T1 - Immunogenic cell death effects induced by doxorubicin improved chemo-immunotherapy via restoration of granzyme B activity
AU - Huang, Tao
AU - Sun, Xiaofan
AU - Qi, Yingqiu
AU - Yang, Xi
AU - Fan, Linyao
AU - Chen, Mengdie
AU - Yue, Yale
AU - Ge, Hong
AU - Li, Yiye
AU - Nie, Guangjun
AU - Min, Huan
AU - Sun, Xianfu
N1 - Publisher Copyright:
© 2023, Tsinghua University Press.
PY - 2023/12
Y1 - 2023/12
N2 - Chemotherapy remains one of the irreplaceable treatments for cancer therapy. The use of immunogenic cell death (ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells, simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B (GrB). However, numerous malignant cancers adaptively acquired the capacity of secreting serpinb9 (Sb9), a physiological inhibitor of GrB, which can reversibly inhibit the biological activity of GrB. To circumvent this dilemma, in this study, an integrated tailor-made nanomedicine composed of tumor-targeting peptide (Arg-Gly-Asp, RGD) decorated liposome, doxorubicin (DOX, an effective ICD inducer), and the compound 3034 (an inhibitor of Sb9), is developed (termed as D3RL) for breast cancer chemo-immunotherapy. In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD. Meanwhile, D3RL can competitively relieve the inhibition of Sb9 to GrB. The restored GrB can not only effectively induce tumor immunotherapy, but also degrade matrix components in the tumor microenvironment, consequently improving the infiltration of immune cells and the penetration of nanomedicines, which in return enhance the combined antitumor effect. Taken together, this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemoimmunotherapy for breast cancer. [Figure not available: see fulltext.]
AB - Chemotherapy remains one of the irreplaceable treatments for cancer therapy. The use of immunogenic cell death (ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells, simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B (GrB). However, numerous malignant cancers adaptively acquired the capacity of secreting serpinb9 (Sb9), a physiological inhibitor of GrB, which can reversibly inhibit the biological activity of GrB. To circumvent this dilemma, in this study, an integrated tailor-made nanomedicine composed of tumor-targeting peptide (Arg-Gly-Asp, RGD) decorated liposome, doxorubicin (DOX, an effective ICD inducer), and the compound 3034 (an inhibitor of Sb9), is developed (termed as D3RL) for breast cancer chemo-immunotherapy. In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD. Meanwhile, D3RL can competitively relieve the inhibition of Sb9 to GrB. The restored GrB can not only effectively induce tumor immunotherapy, but also degrade matrix components in the tumor microenvironment, consequently improving the infiltration of immune cells and the penetration of nanomedicines, which in return enhance the combined antitumor effect. Taken together, this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemoimmunotherapy for breast cancer. [Figure not available: see fulltext.]
KW - chemo-immunotherapy
KW - granzyme B
KW - immunogenic cell death
KW - nanomedicine
KW - serpinb9
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U2 - 10.1007/s12274-023-5581-6
DO - 10.1007/s12274-023-5581-6
M3 - Article
AN - SCOPUS:85150199772
SN - 1998-0124
VL - 16
SP - 13250
EP - 13258
JO - Nano Research
JF - Nano Research
IS - 12
ER -