Tumor Immune Cell Targeting Chimeras (TICTACs) reprogram tumor-associated macrophages

Abstract

Immune cells in the tumor microenvironment are not only powerful regulators of immunosuppression and tumorigenesis, but also a dominant cell population, with tumor-associated macrophages (TAMs) comprising up to 50% of solid tumor mass. Immunotherapies such as immune checkpoint inhibitors derive efficacy from this cancer-immune interface; however, immune-related adverse events from systemic blockade remain a major challenge. To address this need for potent, tumor-specific immunotherapies, we developed Tumor-Immune Cell TArgeting Chimeras (TICTACs) that selectively deplete immune checkpoint receptors such as SIRP from TAM surfaces. These chimeras consist of a synthetic ligand targeting CD206, a TAM marker, conjugated to a non-blocking antibody that binds without inhibiting the checkpoint receptor. By engaging CD206, which constitutively recycles between the plasma membrane and early endosomes, TICTACs drive robust checkpoint degradation in CD206high macrophages, with no effect on CD206low cells. This decoupling of antibody selectivity from blocking function presents a new paradigm for tumor-specific immunotherapies.