Combining Raddeanin A With Caspase Inhibitor Boosts Immunotherapy For OSCC

This study investigates the effects of Raddeanin A (RA) combined with a caspase inhibitor on immunotherapy in oral squamous cell carcinoma (OSCC) and precancerous lesions, exploring mechanisms underlying enhanced therapeutic sensitivity to provide novel strategies. Network pharmacology identified RA targets in OSCC. Cellular assays, subcutaneous tumor models, and 4NQO-induced precancerous models were used to evaluate caspase inhibition’s role in augmenting RA-induced antitumor immunity. RA inhibited Hsp90 to activate caspases in OSCC cells, generating genomic/mitochondrial DNA fragments and triggering apoptosis. Caspase blockade upregulated interferon (IFN)-β secretion via the cGAS-STING pathway. The combination enhanced RA-induced immunogenic cell death (ICD), releasing damage-associated molecular patterns (HMGB1, ATP, Calreticulin) in vitro and exerting antitumor effects in vivo. Remarkable therapeutic efficacy was also observed in oral precancerous lesions. Pharmacological modulation of caspase pathways enhanced RA-driven tumor type I IFN production and immunogenicity via the cGAS-STING axis, promoting dendritic cell-mediated antigen cross-presentation and T-cell activation. This combination also demonstrated potent immunotherapeutic effects in oral precancerous lesions, effectively preventing malignant progression.