Magnetic Reprogramming of Macrophages Stimulates Phagocytosis of Breast Cancer Cells via a TRPC1‐STING Inflammatory Axis

The reprogramming of tumor‐associated macrophages (TAMs) from a pro‐tumoral M2 to an anti‐tumoral M1 phenotype is an attractive therapeutic strategy whose clinical translation is undermined by the systemic toxicity of currently available pharmacological approaches. Here, we demonstrate that non‐invasive and localizable pulsed electromagnetic fields (PEMFs) induce macrophage reprogramming downstream of transient receptor potential canonical 1 (TRPC1) channel activation. Brief (10 min) PEMF exposure polarized macrophages toward an M1 phenotype by activating Stimulator of Interferon Genes (STING)‐dependent NF‐κB inflammatory pathways that were abolished by TRPC1 knockdown or inhibition. PEMF exposure directly enhanced the immunogenicity of breast cancer cells and modified macrophage‐cancer crosstalk to promote M1 macrophage polarization and the attraction of STING‐activated macrophages to the cancer cells. In co‐cultures, PEMF exposure stimulated macrophage‐mediated phagocytosis of cancer cells in a STING‐ and TRPC1‐dependent manner. In spheroids, PEMFs induced the reprogramming of TAMs to an M1 status and selectively enhanced infiltration of M1 macrophages, resulting in STING‐mediated phagocytosis of cancer cells. In mice, 2 weeks of twice‐weekly PEMF exposure resorbed engrafted tumors and selectively eliminated cancer cells within tumors while promoting immune cell recruitment. PEMFs offer a non‐invasive manner to locally reprogram TAMs within the tumor microenvironment to preferentially eliminate cancer cells.