A Self-Delivering Oxygen Modulator for Breast Cancer Immunotherapy via Pyroptosis Induction and PD-L1 Degradation

Abnormal tumor microenvironments and the immunosuppressive phenotype of tumor cells substantially hinder their therapeutic effect. In this work, a self-delivering oxygen modulator (PPCT) is fabricated to simultaneously suppress mitochondrial respiration and downregulate PD-L1 expression, thereby enhancing photodynamic therapy (PDT) and promoting pyroptosis-mediated immunogenic cell death for synergistic breast Cancer Immunotherapy. Specifically, the PPCT nanoplatform is constructed by conjugating the Photosensitizer protoporphyrin IX and a PD-L1-blocking peptide via a hydrophilic oligo (ethylene glycol) linker and a matrix metallopeptidase 2 (MMP-2)-cleavable peptide sequence (PLGLAG). These amphiphilic conjugates spontaneously self-assemble into micelles capable of encapsulating Tamoxifen (Tam). Through PD-L1 recognition, PPCT can effectively accumulate in tumor tissues, where it not only blocks PD-L1 but also facilitates its degradation, thereby disrupting immune escape mechanisms. Upon exposure to MMP-2 in the tumor microenvironment, PPCT releases Tam to reduce cellular oxygen consumption and accordingly increase the efficacy of PDT. Furthermore, the PDT-induced oxidative stress triggers pyroptotic cell death, promoting the release of tumor-associated antigens and eliciting robust antitumor immune responses. In vivo studies demonstrate that PPCT dramatically inhibits primary tumor growth and markedly reduces lung metastases, highlighting a promising therapeutic strategy for the treatment of metastatic breast Cancer.

cell pyroptosis; hypoxia; immunogenic cell death; photosensitizer-peptide conjugate; programmed death-ligand 1.