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.