ZBP1 pathway promotes tumor immunogenicity in the combination of anti-HER2 therapy and epigenetic therapy

Area of Science:

• Immunology
• Oncology
• Epigenetics

Background:

• Z-form DNA (Z-DNA)-binding protein 1 (ZBP1) mediated RNA sensing is crucial for tumor immunogenicity.
• Augmenting ZBP1 signaling for immunogenic cell death to enhance targeted therapy remains unexplored.

Purpose of the Study:

• To investigate the potential of epigenetic modulation using 5-aza-2 '-deoxycytidine (5AZA) to enhance anti-HER2 targeted therapy through ZBP1 activation.
• To elucidate the role of ZBP1-mediated Z-RNA sensing in bridging tumor stress responses with adaptive immunity.

Main Methods:

• Epigenetic modulation using 5AZA in combination with anti-HER2 therapy.
• Assessment of ZBP1 expression, Z-RNA enrichment, and CD8+ T cell responses.
• Analysis of ZBP1 activation via Z-RNA binding to the Zα2 domain.

Main Results:

• 5AZA combined with anti-HER2 therapy demonstrated significant antitumor effects, dependent on CD8+ T cell responses.
• The combination therapy increased ZBP1 expression and Z-RNA accumulation in tumor cells, activating ZBP1.
• Z-RNA accumulation in senescent tumor cells facilitated prolonged Z-RNA sensing.

Conclusions:

• ZBP1-mediated Z-RNA sensing is a key determinant in combining epigenetic therapy with targeted therapy.
• This pathway bridges tumor stress responses and adaptive immunity, offering a novel immunotherapeutic strategy.
• The findings provide insights into developing innate immune sensing-based cancer immunotherapies.