Self-assembled carrier-free nanoparticles enhance O2-economized phototherapy-ferroptosis to boost αPD-L1 immunotherapy of triple-negative breast cancer

Carrier-free IHA NPs achieve multi-drug delivery with nearly 100% loading efficiency. • O 2 supply and consumption restriction alleviate hypoxia to sensitize phototherapy. • Phototherapy-ferroptosis remodels immune microenvironment to boost TNBC αPD-L1 therapy. • Combined therapy inhibits primary/distant tumor growth and lung metastasis in TNBC. Triple-negative breast cancer (TNBC) is featured by high malignancy, poor prognosis, and the absence of effective clinical targeted therapies. Although αPD-L1 immunotherapy blocks tumor immune escape and activates systemic antitumor immunity, its efficacy is limited by low tumor immunogenicity and a hypoxic microenvironment. Phototherapy effectively elevates tumor immunogenicity, whereas it further deteriorates the hypoxic tumor microenvironment. Herein, an O₂-economized phototherapy-ferroptosis synergistic nanoplatform was engineered to strengthen αPD-L1 immunotherapy against TNBC. Specifically, indocyanine green (ICG), hemin and atovaquone (ATO) are self-assembled into carrier-free nanoparticles (IHA NPs) to enhance intratumoral drug accumulation. ICG acts as a photosensitizer, which achieves tumor ablation through synergistic photothermal and photodynamic therapy, induces immunogenic cell death, and enhances tumor immunogenicity. Furthermore, hemin achieves in situ oxygen generation and simultaneously triggers ferroptosis, while ATO inhibits mitochondrial oxidative phosphorylation and reduces oxygen consumption. The two agents construct a synergistic strategy of oxygen supplementation coupled with oxygen consumption restriction, thereby remodeling the hypoxic tumor microenvironment and collaboratively enhancing phototherapeutic efficacy. Combination of IHA NPs with αPD-L1 efficiently suppresses the growth of primary TNBC tumors, distant tumor lesions and pulmonary metastases, and enhances the infiltration of cytotoxic T lymphocytes as well as the formation of effector memory T cells. This study provides novel insights into immunotherapy for TNBC. Download: Download high-res image (101KB) Download: Download full-size image