Breast cancer remains the most common cancer worldwide and is the second leading cause of brain metastases after lung cancer. Breast cancer brain metastases (BrM) can emerge up to a decade after the successful treatment of the primary tumor, representing a significant clinical challenge. In addition, BrM patients face poor prognoses due to the difficulty of crossing the blood-brain barrier with current systemic therapies [1]. Cancer vaccines aim to re-educate the patient’s immune system by stimulating T-cell responses to eliminate tumor cells while generating long-term immune memory to prevent metastasis and disease progression [2]. However, most cancer vaccines have not demonstrated clinical benefits as monotherapy for patients with advanced-stage cancers since their anti-tumor efficacy is blocked by compensatory immune escape mechanisms within the tumor microenvironment (TME). Although immune checkpoint blockades are approved for triple-negative breast cancer and other solid tumors, brain malignancies frequently exhibit resistance to anti-PD-1/L1 therapy, making disease management difficult [3]. Here, we hypothesized that the activation of host immunity using a dendritic cell-targeted nanovaccine, while modulating the focal adhesion kinase (FAK) function together with immune checkpoint blockade, can contribute to re-shape the “cold” suppressive BrM-immune-stroma network to a “hot” BrM-permissive landscape, allowing the extensive infiltration of effector T cells to reactivate the anti-tumor immunity.

The synergistic immunotherapeutic potential of our nanovaccine, isolated and in combination with the FAK inhibitor (FAKi) and the immune checkpoint inhibitor αPD-L1 monoclonal antibody, was assessed in both primary and BrM immunocompetent EO771 mouse models.

Mannose nanovaccine combined with FAKi strongly restricted EO771 primary tumor growth, and synergized with PD-L1 blockade, leading to long-term survival when compared with nanovaccine alone. This data was further validated in BrM immunocompetent-bearing mice.

This innovative approach discloses the synergy among the targeted cancer nanovaccine and immune modulatory and checkpoint therapies within the cold and immunosuppressive TME, which overall outcome may constitute a promising nano-immunotherapy for BrM patients. References: [1] Thulin A, et al. Breast. 2020;50:113-24. doi: 10.1016/j.breast.2020.02.007. [2] Hu Z, et al. Nat Med. 2021;27(3):515–525. doi: 10.1038/s41591-020-01206-4. [3] Jenkins RW, et al. Br J Cancer. 2018;118(1):9-16. doi: 10.1038/bjc.2017.434. Acknowledgements: The project that produced these results received funding from the ”la Caixa” Foundation under the grant’s agreements LCF/PR/HR22/52420016 and LCF/HR24/52440018, in addition to funds from FCT-MCTES (UIDB/04138/2020, UIDP/04138/2020, PTDC/BTM-SAL/4350/2021).