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

Z-form DNA (Z-DNA)-binding protein 1 (ZBP1)-mediated RNA sensing plays a critical role in tumor immunogenicity. However, how to augment ZBP1 signaling-mediated immunogenic tumor cell death to boost targeted therapy is yet unknown. Here, we demonstrated that epigenetic modulation by 5-aza-2'-deoxycytidine (5AZA) facilitated antitumor effects of anti-HER2 therapy, which requires antitumor CD8⁺ T cell responses initiated by ZBP1-mediated tumor immunogenicity. Moreover, the combination of anti-HER2 and 5AZA induced increased ZBP1 expression and related Z-RNA enrichment in tumor cells, leading to the activation of ZBP1 via Z-RNA bound to the Zα2 domain. Particularly, the accumulation of Z-RNA is largely sequestered in senescent tumor cells, which presumably allows prolonged Z-RNA sensing. Therefore, our study indicates that ZBP1-mediated Z-RNA sensing acts as a key determinant of targeted therapy combined with epigenetic therapy through bridging tumor stress responses with antitumor adaptive immunity, providing insights into the development of innate immune sensing-based immunotherapeutic strategies for Cancer treatment.