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.