Background/Objectives: Doxorubicin (DOX) is commonly used as a chemotherapeutic agent for the treatment of breast cancer. Nonetheless, its systemic delivery via intravenous injection and toxicity towards healthy tissues commonly result in a broad range of detrimental side effects. Breast cancer severity was previously shown to be correlated with TRPC1 channel expression that conferred upon it enhanced vulnerability to pulsed electromagnetic field (PEMF) therapy. PEMF therapy was also previously shown to enhance breast cancer cell vulnerability to DOX in vitro and in vivo that correlated with TRPC1 expression and mitochondrial respiratory rates. Methods: DOX uptake was assessed by measuring its innate autofluorescence within murine 4T1 or human MCF7 breast cancer cells following magnetic exposure. Cellular vulnerability to doxorubicin uptake was assessed by monitoring mitochondrial activity and cellular DNA content. Results: Here, we demonstrate that 10 min of PEMF exposure could augment DOX uptake into 4T1 and MCF7 breast cancer cells. DOX uptake could be increased by TRPC1 overexpression, whereas inhibiting the activity of TRPC1 channels with SKF-96356 or genetic knockdown, precluded DOX uptake. PEMF exposure enhances DOX-mediated killing of breast cancer cells, reducing the IC₅₀ value of DOX by half, whereas muscle cells, representative of collateral tissues, were less sensitive to PEMF-enhanced DOX-mediated cytotoxicity. Vesicular loading of DOX correlated with TRPC1 expression. Conclusions: This study presents a novel TRPC1-mediated mechanism through which PEMF therapy may enhance DOX cytotoxicity in breast cancer cells, paving the way for the development of localized non-invasive PEMF platforms to improve cancer outcomes with lower systemic levels of DOX.

Preclinical studies have shown that the blood from female mice exposed weekly to magnetic fields inhibited breast cancer growth. This double-blind randomized controlled trial investigated whether analogous magnetic therapy could produce similar anticancer sera from human subjects. Twenty-six healthy adult females (ages 30–45) were assigned to either a magnetic therapy group, receiving twice weekly 1 mT magnetic exposures (10 min/session) for 4 weeks, or a control group, who underwent identical sham exposure. Blood sera were evaluated for their capacity to modulate breast cancer-related cellular responses and epithelial–mesenchymal transition. The sera from the magnetic therapy group subjects exhibited significant anticancer effects that were strongest one month after the last magnetic exposure, whereas the sera from unexposed females or unexposed or exposed males showed no effect. Female sera from the magnetic therapy group (n = 12) reduced breast cancer cell proliferation (16.1%), migration (11.8%) and invasion (28.2%) and reduced the levels of key EMT markers relative to the control sera (n = 14). Magnetic therapy modulated the serum levels of angiogenic and myogenic biomarkers in a manner consistent with improved cancer management. Muscle-targeted magnetic therapy holds the potential to enhance the anticancer properties of human blood via an adaptive process, akin to exercise training.

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.