Magnetotactic bacterial-reprogrammed TCR-macrophages for durable anti-tumor photoimmune therapy

Abstract

Macrophage have shown great promise in the clinical treatment for head and neck cancer (HNC). However, macrophage therapies confront significant hurdles due to a deficiency of tumor-specific targets and tumor resistance. Herein, we report the development of a magnetotactic bacterial-reprogrammed T-cell receptor macrophage (TCR-M) that integrates human papillomavirus (HPV) associated HNC specific targeting with innate macrophage infiltration capacity, enabling potent immune cytotoxicity against head and neck squamous cell carcinoma (HNSCC). By internalizing magnetotactic bacteria AMB-1, the TCR-M combination achieves tumor-specific targeting and controllable magnetic responsiveness to elicit durable anti-tumor photoimmune response. Notably, AMB-1 incorporation endows macrophages with magnetic navigation capability and laser-responsive polarization into Bac@TCR-M+L, which acquires M1 phenotypes with sustained anti-tumor photoimmune response. Under magnetic actuation, Bac@TCR-M+L demonstrates significantly enhanced tumor site accumulation compared to untreated TCR-M, accompanied by elevated secretion of TNF-α and IFN-γ and augmented reactive oxygen species (ROS) production. Furthermore, Bac@TCR-M+L re-educates tumor-associated macrophages (TAMs) into anti-tumor M1 phenotypes, achieving collaborative tumor destruction. Our findings establish Bac@TCR-M+L as a paradigm-shifting macrophage therapy that integrates microbial engineering, robotic control, and cell therapy, yielding durable anti-tumor effects in HNC treatment and opening new avenues for overcoming cancer resistance.