Dual-Functional Anti-SIRPα-cGAMP Conjugate Reprograms the Tumor Immune Microenvironment and Enhances Antitumor Immunity.

Therapeutic targeting of the CD47-SIRPα axis has emerged as a pivotal strategy for enhancing phagocytic clearance of tumor cells and overcoming immune evasion in solid malignancies, yet clinical outcomes with single-agent checkpoint blockade remain suboptimal due to limited activation of innate immunity and on-target toxicities. Administration of STING agonists is hampered by poor pharmacokinetics and nonspecific toxicity, highlighting the need for cell-selective delivery systems that can orchestrate immune activation and checkpoint inhibition. Herein, we conjugated cGAMP to an anti-SIRPα antibody, aiming to effectively reprogram the tumor immune microenvironment. Systemic administration of anti-SIRPα-cGAMP conjugate significantly inhibited tumor growth in a mouse model of colon adenocarcinoma and improved survival in vivo by simultaneously blocking the CD47-SIRPα "do not eat me" checkpoint and selectively delivering the STING agonist to myeloid cells. These findings suggest that targeted immunostimulatory ADCs may be an effective strategy for overcoming immune resistance in solid tumors.