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.