Tackling Esophageal Squamous Cell Carcinoma with ITFn‐Pt(IV): A Novel Fusion of PD‐L1 Blockade, Chemotherapy, and T‐cell Activation

Abstract PD‐1/PD‐L1 blockade immunotherapy has gained approval for the treatment of a diverse range of tumors; however, its efficacy is constrained by the insufficient infiltration of T lymphocytes into the tumor microenvironment, resulting in suboptimal patient responses. Here, a pioneering immunotherapy ferritin nanodrug delivery system denoted as ITFn‐Pt(IV) is introduced. This system orchestrates a synergistic fusion of PD‐L1 blockade, chemotherapy, and T‐cell activation, aiming to augment the efficacy of tumor immunotherapy. Leveraging genetic engineering approach and temperature‐regulated channel‐based drug loading techniques, the architecture of this intelligent responsive system is refined. It is adept at facilitating the precise release of T‐cell activating peptide Tα1 in the tumor milieu, leading to an elevation in T‐cell proliferation and activation. The integration of PD‐L1 nanobody KN035 ensures targeted engagement with tumor cells and mediates the intracellular delivery of the encapsulated Pt(IV) drugs, culminating in immunogenic cell death and the subsequent dendritic cell maturation. Employing esophageal squamous cell carcinoma (ESCC) as tumor model, the potent antitumor efficacy of ITFn‐Pt(IV) is elucidated, underscored by augmented T‐cell infiltration devoid of systemic adverse effects. These findings accentuate the potential of ITFn‐Pt(IV) for ESCC treatment and its applicability to other malignancies resistant to established PD‐1/PD‐L1 blockade therapies.