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Napabucasin deactivates STAT3 and promotes mitoxantrone-mediated cGAS-STING activation for hepatocellular carcinoma

Lingzhi Wang1, Shengnan Bi2, Zhuo Li2

  • 1School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China.

Biomaterials
|August 24, 2024
PubMed

Insights

Mitoxantrone activates immune responses in liver cancer by targeting the cGAS-STING pathway. Co-delivery with napabucasin via nanoparticles enhances immunotherapy efficacy against hepatocellular carcinoma (HCC).

Area of Science:

  • Oncology
  • Immunology
  • Nanomedicine

Background:

  • Hepatocellular carcinoma (HCC) exhibits immune resistance, limiting the effectiveness of immune checkpoint blockade therapy.
  • Chemotherapy regimens can potentially reverse tumor microenvironment (TME) immune resistance, enhancing immunotherapy.
  • Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway in tumor cells can evoke adaptive immunity and remodel the immunosuppressive TME.

Purpose of the Study:

  • To investigate mitoxantrone's (MIT) ability to activate the cGAS-STING signaling pathway in HCC cells.
  • To develop a nano-formulation for co-delivery of MIT and a signal transducer and activator of transcription 3 (STAT3) inhibitor, napabucasin (NAP), to enhance HCC chemo-immunotherapy.
  • To evaluate the efficacy of this co-delivery system in reshaping the immunoresistant TME and improving anti-PD-1 therapy response in HCC models.

Main Methods:

  • Mitoxantrone (MIT) was used to activate the cGAS-STING pathway in HCC cells.
  • Napabucasin (NAP), a STAT3 inhibitor, was co-formulated with MIT.
  • An aminoethyl anisamide (AEAA)-targeted, polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA) nanocarrier was developed for co-delivery of MIT and NAP.
  • The nano-formulation's effects on the TME and its synergy with anti-PD-1 antibody were assessed in an orthotopic HCC mouse model.

Main Results:

  • Mitoxantrone was shown to activate the cGAS-STING signaling pathway in HCC cells.
  • The developed co-nanoformulation successfully delivered MIT and NAP, eliciting cGAS-STING-based immune responses.
  • The nano-formulation reshaped the immunosuppressive TME and significantly enhanced the efficacy of anti-PD-1 antibody therapy.
  • Treatment resulted in suppressed HCC development, prolonged survival, and inhibited tumor recurrence in mice.

Conclusions:

  • Mitoxantrone holds potential for activating the cGAS-STING pathway, offering a novel strategy for HCC treatment.
  • Nano co-delivery of MIT and NAP is a feasible and effective approach for chemo-immunotherapy of HCC.
  • This strategy demonstrates promise in overcoming immune resistance and improving therapeutic outcomes in hepatocellular carcinoma.
Keywords:
Combination therapyImmunoresistanceLiver cancerNano drug delivery systemTumor immune microenvironment

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