Combining STING Agonists with PARP Inhibitors Mounts an NK-Dependent Defense against Therapy-Resistant Breast Cancer

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Breast cancers with BRCA1/2 mutations exhibit homologous recombination deficiency, leading to genomic instability.
• Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit this defect for synthetic lethality but often face acquired resistance.
• PARPi treatment can activate the stimulator of interferon genes (STING) pathway, enhancing anti-tumor immunity.

Purpose of the Study:

• To investigate novel therapeutic strategies to overcome PARPi resistance in BRCA-mutated cancers.
• To evaluate the efficacy of combining a PARPi with a next-generation STING agonist.
• To elucidate the role of natural killer (NK) cell function in mediating response to combination therapy.

Main Methods:

• Utilized PARPi-sensitive and -resistant patient-derived xenografts and mouse-derived allografts.
• Administered olaparib (a PARPi) in combination with diABZI (a STING agonist).
• Assessed tumor response and analyzed the tumor microenvironment, focusing on NK cell infiltration and function.

Main Results:

• The combination of olaparib and diABZI effectively overcame PARPi resistance in preclinical models.
• Therapeutic efficacy was dependent on the function of NK cells within the tumor microenvironment.
• This combination strategy demonstrated a novel mechanism involving STING-dependent innate immune responses.

Conclusions:

• Combining PARPi with next-generation STING agonists represents a promising strategy to combat PARPi-resistant cancers.
• NK cell-mediated immunity plays a crucial role in the anti-tumor activity of this combination therapy.
• Further clinical investigation of STING agonists in combination therapies is warranted for therapy-resistant malignancies.