Paclitaxel prodrug loaded high-density lipoprotein nanoparticles for chemoimmunotherapy of triple-negative breast cancer.

Insufficient tumor-specific immunogenicity and cytotoxic T lymphocytes infiltration limit the therapeutic efficacy of combined chemotherapy and immune checkpoint blockade for triple-negative breast cancer (TNBC). To address this limitation, we developed a paclitaxel prodrug-loaded synthetic high-density lipoprotein nanoparticle (P-sHDL) that both targets tumors and induces immunogenic cell death (ICD) to potentiate immune checkpoint blockade. Leveraging scavenger receptor class B type 1-mediated uptake, P-sHDL efficiently accumulated at tumor sites and triggered ICD in tumor cells, thereby enhancing antitumor immunogenicity. Building on this immunogenicity enhancement, P-sHDL was combined with an anti-programmed death-ligand 1 antibody (αPD-L1) to enhance intratumoral CD8+ T cell activity and alleviate immunosuppression. As a result, this regimen achieved marked therapeutic efficacy in tumor-bearing mice. Collectively, this study highlights that P-sHDL-based immunogenicity enhancement combined with immune checkpoint blockade represents a promising strategy for TNBC chemoimmunotherapy.