In situ programming of CAR-macrophages via a polyplex nanomaterial and STING activation for triple-negative breast...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its aggressive nature and limited treatment options.
• Current therapies offer minimal benefit, leading to frequent relapses and poor patient prognosis.
• Chimeric antigen receptor (CAR) T-cell therapy shows promise in hematological cancers but faces limitations in solid tumors like TNBC.

Purpose of the Study:

• To develop a scalable and cost-effective method for programming macrophages to target solid tumors.
• To engineer macrophages expressing CAR specific to programmed death ligand-1 (PD-L1) for *in situ* treatment of TNBC.
• To evaluate the therapeutic efficacy of *in situ* CAR-macrophage reprogramming combined with STING agonist therapy in TNBC models.

Main Methods:

• A polyplex-based system was designed for *in situ* reprogramming of macrophages into CAR-macrophages (CAR-M).
• Macrophages were engineered to express CAR targeting PD-L1, a marker on TNBC cells.
• The study involved intraperitoneal polyplex injection and intratumoral STING agonist administration in pre-clinical TNBC models.

Main Results:

• Intraperitoneal polyplex injection successfully reprogrammed macrophages into CAR-M, facilitating tumor infiltration and phagocytosis of PD-L1+ cells.
• Intratumoral STING agonist injection promoted CD8+ T-cell infiltration into the tumor microenvironment.
• The combination therapy significantly reduced tumor burden in pre-clinical models.

Conclusions:

• The developed polyplex system provides a scalable and cost-effective strategy for *in situ* macrophage reprogramming.
• This approach overcomes challenges associated with *ex vivo* cell modification for solid tumor immunotherapy.
• The engineered CAR-M, combined with STING agonist therapy, elicits a robust anti-tumor response against TNBC.