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

Area of Science:

• Immunology
• Oncology
• Drug Delivery

Background:

• CD47-SIRPα axis blockade enhances phagocytosis but has suboptimal clinical outcomes in solid tumors.
• STING agonists show promise but suffer from poor pharmacokinetics and toxicity.
• A need exists for targeted delivery systems to combine immune checkpoint inhibition with innate immune activation.

Purpose of the Study:

• To develop a novel therapeutic strategy by conjugating cGAMP (a STING agonist) to an anti-SIRPα antibody.
• To reprogram the tumor immune microenvironment by simultaneously blocking the CD47-SIRPα checkpoint and delivering STING agonists selectively to myeloid cells.

Main Methods:

• Conjugation of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) to an anti-SIRPα antibody.
• Systemic administration of the anti-SIRPα-cGAMP conjugate in a mouse model of colon adenocarcinoma.
• Evaluation of tumor growth inhibition and survival rates.

Main Results:

• The anti-SIRPα-cGAMP conjugate significantly inhibited tumor growth in vivo.
• Improved survival rates were observed in the treated mouse model.
• The conjugate demonstrated dual action: blocking the CD47-SIRPα "do not eat me" checkpoint and delivering the STING agonist to myeloid cells.

Conclusions:

• Targeted immunostimulatory antibody-drug conjugates (ADCs) represent a promising strategy for overcoming immune resistance in solid tumors.
• This approach effectively reprograms the tumor immune microenvironment by combining checkpoint blockade with targeted innate immune activation.