Stepwise Targeting and Tandem Responsive Peptide Nanoparticles Enhance Immunotherapy through Prolonged Drug Retention

Cancer treatments that combine chemotherapy with immunotherapy are becoming increasingly effective, but chemotherapy is generally considered to have immunosuppressive effects. Moreover, tumor accumulation of chemotherapeutic agents is insufficient and the rate of persistent response to checkpoint blockade therapy is low, leading to tumor treatment failure. Here, we developed a transition-enhanced immunomodulation (TEI) effect to construct a self-assembled peptide TpYCR for drug delivery with stepwise targeting of tumor cells and mitochondria. Doxorubicin (DOX)/TpYCR first targeted tumor cells, and alkaline phosphatase (ALP) in the tumor microenvironment induced their conversion from nanoparticles (NPs) to nanofibers (NFs) with concomitant release of DOX. Subsequently, intracellular overexpression of reduced glutathione (GSH) induced their formation into hydrogels, increasing the intracellular retention of DOX and sustainably inducing immunogenic cell death (ICD). Importantly, DOX/TpYCR inhibited Treg cells, activated DC cells, and stimulated immunogenic factor expression to produce a lasting immune response. Combined PD-1 inhibitor treatment and chemotherapy further improved the response rate to immunosuppressive agents, produced synergistic effects, and ultimately inhibited tumor growth and metastasis. This study sheds new light on the development of self-assembled peptide nanocarriers for immunomodulatory therapy.