Rejuvenation of Tumor‐Specific T Cells via Ultrahigh DAR Antibody‐Polymeric Imidazoquinoline Complexes: Coordinated Targeting of PDL1 and Efficient TLR7/8 Activation in Intratumoral Dendritic Cells

Abstract

AbstractIntratumoral dendritic cells (DCs) are pivotal in tumor treatment due to their immature and pro‐tumoral state induced by the tumor microenvironment. Clinically, these immature DCs correlate with disease progression and recurrence, adversely affecting prognosis. Activation of DCs by the TLR7/8 agonist imidazoquinoline (IMDQ) has yielded promising results, but they are limited by systemic inflammation risks, and high programmed death ligand 1 (PDL1) expression on DCs impedes CD8+ T cell activity. Thus, the study introduces an antibody‐polymeric IMDQ complex (αPDL1‐PLG‐IMDQ) with an ultrahigh drug‐to‐antibody ratio, where αPDL1 is conjugated to Fc‐binding peptides on polymeric IMDQ. This complex targets high PDL1‐expressing intratumoral DCs with high probability, inducing PDL1‐mediated endocytosis to deliver IMDQ to TLR7/8 within endosomes, effectively activating DCs (CD11c+MHC II+: 2.33% versus 1.09%, CD11c+CD86+: 2.49% versus 1.00% on tumors compared to phosphate‐buffered saline treatment) and priming T cells. It also blocks PDL1/PD1 interactions, enhancing tumor‐specific T‐cell activation and memory. Notably, αPDL1‐PLG‐IMDQ achieved a 97% tumor inhibition rate, prevented tumor regrowth in rechallenge experiments, and reduced lung metastases of tumors by 83%. These findings underscore its potential for intratumoral DC‐targeted immunotherapy and novel systemic IMDQ and checkpoint inhibitor combinations.