Harnessing Nanotheranostics-Based Dendritic Cells Tracking Mature Tertiary Lymphoid Structures to Boost Anti-Glioma Immunotherapy

Abstract

Anti-glioma immunotherapy is highly challenging, largely due to poor immune infiltration and restricted immune delivery, resulting in poor patient prognosis. Recent studies suggest that mature tertiary lymphoid structures (mTLSs) promote immune cell infiltration into solid tumors, associated with enhanced immune response and better prognosis. However, the formation and visualization of mTLSs becomes extremely difficult resulting from lack of lymphoid tissue formation microenvironment in the brain parenchyma. Herein, theranostic nanoprobes consisting of FITC-HFe₃O₄@Gd (MRI/FI tracer) and internally loaded chemokines CXCL13 and CCL12 are specifically designed to be internalized by dendritic cells (DCs) into biomimetic nanosystem. Subsequently, labeled DCs are integrated into the mTLSs follicular dendritic cell (fDC) network by crossing the high endothelial venules (HEVs), enabling noninvasive visualization of the mTLSs (e.g., maturation, location, and density) by DC tracer technology. Interestingly, CXCL13 and CCL12 released by labeled DCs stimulate the generation of “immune trafficking bridge” that promote the centripetal redistribution of effector lymphocytes (B220⁺ B and CD8⁺ T cells) within the glioma, thereby further enhancing adaptive immune responses and effectively inhibiting glioma progression in vivo. Consequently, this innovative nanostrategy of biomimetic DCs combining mTLSs formation with MRI/FI tracing enables noninvasive assessment and prediction of beneficial immune responses for clinical translation.