p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Metastatic breast cancer is challenging to treat with immunotherapy.
• The tumor microenvironment significantly influences treatment response.

Purpose of the Study:

• To identify novel therapeutic targets for metastatic breast cancer.
• To enhance the efficacy of immunotherapy by targeting the tumor stroma.

Main Methods:

• p38MAPKα inhibition (p38i) was investigated for its effects on the tumor microenvironment.
• Single-cell RNA sequencing and stromal labeling were used to identify therapeutic targets.
• Combinatorial therapy involving p38i, OX40 agonists, and T-cell engagement was tested in mouse models.

Main Results:

• p38i reprogrammed the metastatic tumor microenvironment, dependent on CD4+ T cells, IFNγ, and macrophages.
• Combination therapy of p38i and an OX40 agonist synergistically reduced tumor growth and improved survival.
• The combination of p38i, anti-OX40, and cytotoxic T-cell engagement led to complete tumor eradication and long-term immune memory in mice.

Conclusions:

• Targeting the p38MAPK pathway in the tumor stroma can unleash an effective anti-tumor immune response.
• Understanding the stromal compartment is crucial for designing effective antimetastatic therapies.
• Combinatorial approaches targeting the stroma and immune system show promise for treating metastatic breast cancer.