Spatially Targeted PD‐L1 Blockade for Restoring Exhausted Cytotoxic T Lymphocyte Rejuvenation to Potentiate Multimodal‐Immune Synergistic Therapies for Breast Cancer Treatment

The spatial dynamics and heterogeneity of programmed death-ligand 1 (PD-L1) expression within tumors pose significant challenges to the efficacy of PD-L1/programmed death receptor-1 (PD-1) immune checkpoint therapies. This study addresses these challenges by proposing a dual-mechanism strategy to modulate the spatial distribution and functional activity of PD-L1, thereby rejuvenating exhausted cytotoxic T lymphocytes and enhancing multimodal-immune synergistic cancer therapies. Specifically, a PD-L1 nanomodulator is engineered using a polydopamine nanoplatform, integrating a specific inhibitor D-peptide antagonist of PD-L1 for tumor membrane PD-L1 and metformin that can degrade intracellular PD-L1. This nanomodulator can precise delivery to the tumor site, enabling their sequential release. Upon near-infrared light irradiation, the nanomodulator generates a potent photothermal effect and reactive oxygen species, while simultaneously inhibiting tumor glycolysis. This combination enhances direct cytotoxicity toward tumor cells, activates immune response, and efficiently blocks the interaction between PD-L1 and PD-1 receptors on T cells. Both in vitro and in vivo studies confirm the nanomodulator can significantly amplify antitumor immune responses, and eventually lead to substantial inhibition of tumor growth, metastasis, and recurrence. Collectively, this study introduces a promising paradigm for enhancing breast cancer treatment efficacy through the spatial modulation of PD-L1 distribution with multimodal therapeutic strategies.