Self‐Promoting Targeted Delivery of Epigenetic Immunostimulants to Activate Breast Cancer Immunity via HDACs Downregulation and PD‐L1 Upregulation

Abstract The low immunogenicity and immunosuppressive phenotype of breast cancer significantly limit the effectiveness of immunotherapy. This study reveals that histone deacetylases (HDACs) are upregulated in breast cancer, while lower levels of HDACs and higher levels of programmed cell death ligand 1 (PD‐L1) are associated with better patient prognosis. Moreover, Trichostatin A (TSA) is confirmed to suppress HDACs and increase PD‐L1 expression. Building on these insights, a self‐promoting targeted immunostimulant (SPT‐IS) is developed to activate breast cancer immunity by epigenetically upregulating PD‐L1. SPT‐IS can selectively accumulate in PD‐L1‐overexpressing breast cancer cells for co‐delivery of Chlorin e6 (Ce6) and TSA. Notably, SPT‐IS‐induced epigenetic upregulation of PD‐L1 creates a self‐promoting tumor‐targeting loop that enhances drug delivery efficiency. Besides, SPT‐IS generates reactive oxygen species (ROS) to kill tumor cells and release damage‐associated molecular patterns, increasing tumor immunogenicity. Additionally, the epigenetic regulation ability of SPT‐IS upregulates immunomodulatory cytokines and stimulates T cell cytotoxicity for immune activation. Immunological results confirm robust immunomodulatory effects of SPT‐IS, significantly enhancing tumor‐infiltrating lymphocytes recruitment and proliferation, leading to notable anti‐tumor efficacy. These findings highlight the potential of a self‐promoting targeted strategy to enhance drug delivery and provide an epigenetic approach to boost the immune response against breast cancer.