Adenosine-modulating synthetic high-density lipoprotein for chemoimmunotherapy of triple-negative breast cancer

Adenosine (ADO) is a common chemotherapy-associated immune checkpoint that hinders anti-tumor immunity-mediated efficacy of chemotherapy. Herein, we created a synthetic high-density lipoprotein (sHDL) by co-assembly of a doxorubicin (DOX)-apolipoprotein A1 mimetic peptide conjugate, PSB-603 (an A2BR inhibitor), phospholipid, and cholesterol oleate with a microfluidic-based method. The obtained DP-sHDL showed a self-promoted drug delivery to cancer cells via remodeling tumor microenvironment. DP-sHDL could trigger the release of ATP from cancer cells and inhibit its conversion into ADO. Consequently, DP-sHDL, while increasing immunogenic cell death, reduced intratumoral ADO levels by 58%. This treatment improved both the density and activity of CD8⁺ T cells as well as NK cells and relieved the immunosuppressive microenvironment, and led to a substantial inhibition of 4T1 tumor growth, thereby extending the survival of mice. The efficacy of DP-sHDL could be further improved when used in combination with immune checkpoint blockade therapy. We envision that this platform provides a simple yet promising strategy to enhance anti-tumor response of chemotherapy by relieving treatment-associated immunosuppression.