Nanodrug regulates lactic acid metabolism to reprogram the immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

Tian, LiRong; Lin, Minzhao; Zhong, Huihai; Cai, Yujun; Li, Bo; Xiao, Zecong; Shuai, Xintao

doi:10.1039/d2bm00650b

Cited by 28 publications

(15 citation statements)

References 39 publications

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“…Lactate acidosis has been found to reduce immune evasion in TNBCs [ 25 , 26 ]. Therefore, extracellular lactate reduction has been considered as an anti-cancer approach to enhancing the therapeutic effect of immune therapy[ 27 ]. CAXII has been reported to maintain pH and CO 2 homeostasis, thereby affecting cancer progression, invasion, and resistance to therapy [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Tiliroside suppresses triple-negative breast cancer as a multifunctional CAXII inhibitor

Han

Yang

Lü³

et al. 2022

Cancer Cell Int

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Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. In this preclinical study, we examines Tiliroside (TS, C30H26O13), as one of the major compounds of Tribulus terrestris L. which has been used as an alternative therapy in clinic practice of breast cancer treatment, for its therapeutic use in TNBC. The association between CAXII expression level and survival probability of TNBC patients, and the difference of CAXII expression level between TNBC and normal samples were evaluated by using publicly accessible databases. To determine the anticancer efficacy of TS on TNBC cells, cell proliferation, wound healing, cell invasion, and 3D spheroid formation assays were performed and excellent anticancer activities of TS were displayed. Mouse models further demonstrated that TS significantly reduced the tumor burden and improved survival rate. The properties of TS as a novel CAXII inhibitor have also been evaluated by CAXII activity assay, pHi, pHe and lactate level assay. Further RT-PCR and Caspase-3 activity analyses also revealed the positive regulating effects of TS on E2F1,3/Caspase-3 axis in TNBC cells cultured in 2D or 3D systems. The findings indicate that TS suppresses TNBC progression as a potential novel CAXII inhibitor in preclinical experiments, which warrants further investigation on its therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Tiliroside suppresses triple-negative breast cancer as a multifunctional CAXII inhibitor

Han

Yang

Lü³

et al. 2022

Cancer Cell Int

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show abstract

“…Lactate acidosis has been found to reduce immune evasion in TNBCs [23,24]. Therefore extracellular lactate reduction has been considered as an anti-cancer approach to enhancing the therapeutic effect of immune therapy [25]. CAXII has been reported to maintain pH and CO2 homeostasis, therefore affect cancer progression, invasion, and resistance to therapy [26].…”

Section: Discussionmentioning

confidence: 99%

Tiliroside suppresses Triple-negative breast cancer as a multifunctional CAXII inhibitor

Han¹,

Yang

Lü³

et al. 2022

Preprint

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Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. In this preclinical study, we examines Tiliroside (TS, C30H26O13), as one of the major compounds of Tribulus terrestris L. which has been used as alternative therapy in clinic practice of breast cancer treatment, for its therapeutic use in TNBC. The association between CAXII expression level and survival probability of TNBC patients, and the difference of CAXII expression level between TNBC and normal samples were evaluated by using public databases. To determine the anticancer efficacy of TS on TNBC cells, cell proliferation, wound healing, cell invasion, and 3D spheroid formation assays were performed and excellent anticancer activities of TS were displayed. Mouse models further demonstrate that TS significantly reduces the tumor burden and improves survival rate. The properties of TS as a novel CAXII inhibitor have also been evaluated by CAXII activity assay, pHi, pHe and lactate level assay. Further RT-PCR and Caspase-3 activity analyses also revealed the positive regulating effects of TS on E2F1,3/Caspase-3 axis in TNBC cells cultured in 2D or 3D systems. The findings indicate that TS suppresses TNBC progression as a potential novel CAXII inhibitor in preclinical experiments, which warrants further investigation on its therapeutic implications.

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“…134 Recently, Tian et al proposed the strategy of disturbing lactate metabolism with a lonidamine (here as an HK2 inhibitor to block lactate generation) and syrosingopine (MCT4 inhibitor to block the lactate efflux) co-loaded liposome nanoparticle for tumor immunotherapy. 135 By concurrently suppressing lactate production and efflux, this nanoparticle synergistically normalized the TME pH to reverse the tumor immunosuppression, which was proven by the polarization of TAMs from the tumor-supportive M2 type to the tumor-suppressive M1 type, the increased proportion of NK cells, and the decreased amount of Treg cells, and thereby inhibited tumor growth. Given that the accumulation of adenosine in the TME contributes to tumor immunosuppression, Dai et al developed a sub-6 nm MnFe 2 O 4 nanoparticle conjugated with DCA (PDK1 inhibitor to reduce lactate production) to modulate tumor lactate metabolism and ATP catabolism to synergistically remodel the immunosuppressive TME for immunotherapy.…”

Section: Enhanced Immune Responsementioning

confidence: 99%

Engineering lactate-modulating nanomedicines for cancer therapy

Chen

Zhu

et al. 2023

Chem. Soc. Rev.

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Nanodrug regulates lactic acid metabolism to reprogram the immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

Abstract: A novel strategy of tumor microenvironment reprogramming by Intra/extracellular lactic acid exhausting for antitumor immune therapy.

Cited by 28 publications

References 39 publications

Tiliroside suppresses triple-negative breast cancer as a multifunctional CAXII inhibitor

Tiliroside suppresses triple-negative breast cancer as a multifunctional CAXII inhibitor

Tiliroside suppresses Triple-negative breast cancer as a multifunctional CAXII inhibitor

Engineering lactate-modulating nanomedicines for cancer therapy

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