Nanoprogrammed TCR macrophages for sustained antitumor immunoresponse

Macrophage-based therapies remain a challenge in human papillomavirus positive (HPV + ) cancer, due to the lack of specific surface targets and sustained antitumor activity. Herein, a gene-editing T cell receptor (TCR) macrophage (TCR-M) with iron oxide nanoparticle programming was reported to suppress HPV + head and neck cancer (HNC). After TCR transfection, TCR-M presents a remarkable promotion of targeted killing capacity against HPV + HNC tumor cells. The internalization of superparamagnetic iron oxide nanoparticles (ION) conferred TCR-M a sustained activated antitumor (M1) phenotype. After sequential magnetic manipulation and TCR targeting, the ION@TCR-M enhanced 85% of macrophage accumulation at tumor site. And ION@TCR-M secreted 4-fold more tumor necrosis factor-α (TNF-α) and 9-fold more reactive oxygen species (ROS) to suppress tumor, as compared to macrophage group (Mac). Furthermore, the reprogrammed TCR-M re-educated bystander M2 macrophages to M1 phenotype in a paracrine-like manner, and down-regulated collagen and laminin expression in the tumor to maintain macrophage activation as feedback. Overall, the nanoprogrammed TCR macrophages could be a novel strategy for durable antitumor immunotherapy via microenvironment reconstruction and immune activation.