Closed‐Loop Brain–Immune–Tumor Modulation via Magnetoelectric Nanocatalysis for Synergistic Cancer Immunotherapy

Abstract Colorectal cancer (CRC) progression is driven by an immunosuppressive tumor microenvironment and systemic neuroimmune dysregulation from sympathetic overactivation. A synergistic approach is developed that combines high‐entropy magnetoelectric nanocatalysis with remote brain neuromodulation to overcome these barriers. A spinel nanocatalyst, (Cu 0 . 2 Mn 0 . 2 Fe 0 . 2 Co 0 . 2 Ni 0 . 2 )Fe 2 O 4 (Fe‐HEO), engineered with multivalent redox centers and lattice distortion, exhibits enhanced magnetoelectric polarization under an alternating magnetic field (AMF) without bulk heating. In the acidic tumor microenvironment, Fe‐HEO generated abundant reactive oxygen species, inducing immunogenic cell death with calreticulin exposure and HMGB1 release, which activates dendritic cells, repolarized macrophages, and stimulated cytotoxic T cells. When targeted to ventral tegmental area dopaminergic neurons, Fe‐HEO act as a magnetoelectric neuromodulator; AMF stimulation triggers dopamine release, suppresses sympathetic noradrenaline signaling, reduces the number of bone marrow–derived suppressor cells, and restores systemic T‐cell immunity. In vivo, the combined therapy inhibits orthotopic colorectal tumor growth, remodels the immune microenvironment, alleviates systemic immune suppression, and improves tumor‐induced anxiety‐ and depression‐like behaviors, establishing a closed‐loop brain–immune–tumor axis for the minimally invasive, controllable treatment of refractory tumors.