Abstract

Pituitary corticotroph tumors are the primary cause of Cushing’s disease. Even after transsphenoidal surgery, residual tumor cells frequently persist, leading to a recurrence rate of approximately 20%. However, safe and effective adjuvant treatments for these residual lesions are lacking. In this study, we analyzed single-cell RNA sequencing data to characterize the transcriptional profile of corticotroph tumors. On the basis of the high activity of the POMC promoter and its transcriptional regulators, we designed an adeno-associated virus vector carrying the pro-apoptotic gene Puma, with expression controlled by the Pomc promoter for lineage-specific targeting. We also developed an injectable, self-assembling peptide hydrogel for the sustained local delivery of the Puma gene and tested its therapeutic efficacy in subcutaneous and post-resection mouse models. Results showed the Pomc promoter drove selective Puma expression in corticotroph tumor cells, inducing mitochondrial membrane potential loss and apoptosis in vitro. In vivo, the virus suppressed tumor growth and lessened systemic tumor effects; when delivered via the hydrogel into surgical cavities, it completely eliminated residual tumors without detectable toxicity in major organs. This targeted, localized strategy, thus has translational potential as an adjuvant therapy for reducing the recurrence of Cushing’s disease.