Pyroptosis, a gasdermin-mediated immunogenic cell death, has been shown to elicit adaptive antitumor immune responses, thereby augmenting the response to cancer immunotherapy when pyroptosis is therapeutically activated. However, despite increased gasdermin E (GSDME) expression, significant pyroptosis remains elusive in certain tumor types, and the underlying regulatory mechanisms are poorly understood. In this study, we observed high signal regulatory protein α1 (SIRPA) expression in head and neck squamous cell carcinoma (HNSCC) cells, a target in cancer immunotherapy. Intriguingly, SIRPA inhibition markedly augmented pyroptosis activity in tumor tissues and modulated tumor growth in a HNSCC mouse model. Subsequent investigations revealed that SIRPA knockout upregulated GSDME expression and potentiated cisplatin-induced pyroptosis in cancer cells. Integrative transcriptomics and metabolomics analysis suggested that the SIRPA knockout profoundly altered protein ubiquitination and augmented argininosuccinic acid levels in cancer cells. Specifically, we demonstrated that ubiquitin-specific peptidase 18 (USP18), a deubiquitinating enzyme, targets GSDME for deubiquitination and that USP18 knockdown suppressed cisplatin-induced pyroptosis. Notably, we found that succinylation of GSDME, which is mediated by succinyl-CoA, promotes GSDME cleavage without affecting caspase-3 activation. Further experiments indicated that SIRPA expression in tumor cells can decrease the antitumor efficacy of chemotherapy and immunotherapy in HNSCC mouse models. In summary, our findings reveal a novel mechanism of pyroptosis evasion in HNSCC, whereby tumor-intrinsic SIRPA enhances GSDME ubiquitylation and inhibits its succinylation. These insights suggest that inhibiting SIRPA expression may improve the efficacy of immunotherapy for HNSCC by inducing pyroptosis.