Abstract
<title>Abstract</title> <p> Antibody-drug conjugate (ADC) is an effective cancer therapy strategy that specifically induces tumor cell death. Combining ADC with immune checkpoint inhibitors (ICIs) has improved the clinical outcomes in some patients with solid tumors. However, the mechanism of this new combination therapy has not yet been fully elucidated. In this study, we found that monomethyl auristatin E (MMAE), a cytotoxic payload attached to RC108 (a novel c-Met-targeting ADC), activated Gasdermin E (GSDME)-induced pyroptosis in pancreatic and lung cancers. Plasma membrane rupture caused by pyroptosis releases damage associated molecular patterns (DAMPs) into the extracellular fluid, which activate immunogenic cell death (ICD) mediated by mature dendritic cell and CD8 <sup>+</sup> T cells. The ICIs amplified the ICD effect together with RC108. Therefore, RC108 combined with ICIs synergistically inhibited tumor growth <italic>in vivo</italic> . With GSDME knocked-down, pyroptosis inhibition weakened the efficacy of the combination therapy by reducing DAMPs release. Clinically, GSDME expression was positively correlated with c-Met in patients with pancreatic cancer, indicating its benefits in RC108 combination therapy. Our findings revealed that GSDME-dependent pyroptosis improved the efficacy of the combination of ADC and ICIs, suggesting a new theoretical basis for further understanding the mechanism of such a combination strategy in solid tumor treatment. </p>