Drug Self‐Delivery Nanocubes Enhance O2‐Economized Photodynamic‐Immunotherapy of Triple‐Negative Breast Cancer by Downregulating Wnt/β‐catenin Signaling

Abstract Although the combination of chemotherapy and immune checkpoint inhibitors (ICIs) can treat triple‐negative breast cancer (TNBC), the severe effects of chemotherapy on immune cells significantly reduce the efficacy of the ICIs. Photodynamic therapy (PDT) with high selectivity is an alternative to chemotherapy that can also effectively treat hypoxic TNBC. However, high levels of immunosuppressive cells, and low infiltration of cytotoxic T lymphocytes (CTLs) limit the efficacy of PDT combined with ICIs. This study aims to evaluate the role of drug self‐delivery nanocubes (ATO/PpIX‐SMN) combined with anti‐PD‐L1 in TNBC treatment. Anti‐malarial atovaquone (ATO) enhances protoporphyrin IX (PpIX)‐mediated PDT‐induced immunogenic cell death and downregulates tumor Wnt/β‐catenin signaling. Furthermore, the nanocubes combined with anti‐PD‐L1, which synergistically induce maturation of dendritic cells, promote infiltration of CTLs, reduce regulatory T cells, and significantly activate the host immune system, thus treating primary and distal tumors. This work demonstrates that ATO/PpIX‐SMN can enhance the response rate of anti‐PD‐L1 in TNBC treatment via O2‐economized photodynamic‐downregulating Wnt/β‐catenin signaling.