Cantharidin-Loaded Nanomedicine Modified with Amphiphilic Peptides Induce Immunogenic Cell Death to Enhance PD-1 Blockade.

Recent advances in immune checkpoint inhibitors (ICIs), particularly those targeting PD-1/PD-L1, have transformed cancer treatment. However, their efficacy is often hampered by the immunosuppressive tumor microenvironment (TME). Here, we developed a cantharidin-loaded nanomedicine (CA@TPGS-AmP), composed of D-α-tocopheryl polyethylene glycol succinate (TPGS) and naturally derived amphiphilic peptides (AmP), designed to enhance PD-1 blockade via induction of immunogenic cell death (ICD). In vitro, CA@TPGS-AmP markedly improved the solubility of cantharidin and exhibited superior penetration in 3D tumor spheroids. It effectively triggered key ICD events, including calreticulin (CRT) surface exposure, ATP release, and HMGB1 translocation, thereby promoting dendritic cell (DC) maturation. In vivo, CA@TPGS-AmP significantly augmented the antitumor efficacy of PD-1 therapy in 4T1 orthotopic breast cancer and LLC lung cancer models. Mechanistically, the combination therapy remodeled the TME into an immunostimulatory state by increasing CD8+ T cell infiltration and activation, leading to enhanced tumor suppression compared to monotherapies. These findings support CA@TPGS-AmP as a promising adjunct to PD-1 blockade and highlight the potential of natural product-based nanomedicine in advancing cancer immunotherapy.