Polyphenol‐Based Self‐Assembled Nanomedicine for a Three‐Pronged Approach to Reversing Tumor Immunosuppression

Abstract The challenges of multi‐pathway immune resistance and systemic toxicity caused by the direct injection of immune checkpoint inhibitors are critical factors that compromise the effectiveness of clinical immune checkpoint blockade therapy. In this context, natural polyphenols have been employed as the primary component to construct a targeted and acid‐responsive PD‐L1 antibody (αPD‐L1) delivery nanoplatform. This platform incorporates garcinol, an inhibitor of the Nuclear Factor Kappa‐B (NF‐κB) signaling pathway, to regulate pro‐tumor immune escape cytokines and regulatory T cells. Additionally, the nanoplatform has been verified to induce immunogenic cell death (ICD), which promotes the maturation of dendritic cells and enhances the activity of cytotoxic T lymphocytes. In vivo and in vitro experimental results demonstrated that the nanoplatform can boost the immune response through a PD‐L1 and NF‐κB blocking/ICD inducing three‐pronged strategy, thereby effectively combating tumor growth and metastasis.