A CLDN18.2-Targeted Nanoplatform Manipulates Magnetic Hyperthermia Spatiotemporally for Synergistic Immunotherapy in Gastric Cancer

Abstract

Precision treatment of gastric cancer requires specific biomarkers, and CLDN18.2 emerges as a promising target for patients’ stratification and therapeutic guidance. In 563 cases, 54.4% of patients are identified as CLDN18.2-positive, with CLDN18.2 expression negatively correlated with immune-related factors like PD-L1, indicating a “cold” tumor microenvironment. Here, a novel CLDN18.2 monoclonal antibody 1D5 is created with superior high specificity and affinity, and the antibody-dependent fluorescence-magnetic nanoparticle is developed for specific detection and magnetic hyperthermia (MHT). Under the assistance of sensitive fluorescence and deep-penetrating magnetic particle imaging for tracing and timing the optimal nanoparticle dosage, MHT induces robust immunogenic response via DNA mismatch repair and tumor-associated antigen release. It recruits CD11c+ dendritic cells, compensates PD-1 in CD8+ T cells, and enhances CD86+ macrophage polarization. The combination of anti-PD-1 therapy increased TNF-α and IFN-γ secretion and further boosted the cytotoxic efficacy of CD8+ T cells. Excellent therapeutic efficacy is found simultaneously on cell-derived allografts and patient-derived xenografts based on this spatiotemporally manipulated strategy, presenting a therapeutic option for enhancing responsiveness to immunotherapy for CLDN18.2-positive individuals.