Magnetic hyperthermia-mediated cancer therapy (MHCT) faces challenges related to heat stress response (HSR), hypoxic tumor microenvironments, and insufficient reactive oxygen species (ROS) generation. To address these, we explored novel approaches to improve therapeutic outcomes.

In the first study, we synthesized magnetic nanoparticles (MNPs) with varied morphologies, including spherical, cubical, rod-shaped, and flower-shaped structures, to evaluate their heating efficiencies and therapeutic efficacy. Among them, cubical MNPs exhibited superior heating performance due to magnetosome-like chain formation and sustained drug release, leading to enhanced magneto-chemotherapy in vitro and in vivo.

To target hypoxic tumor cores, we developed self-propelling "nano-bacteriomagnets" (BacMags) by integrating anisotropic magnetic nanocubes into Escherichia coli. This innovative bacterial delivery system achieved efficient MNP transport, resulting in superior hyperthermic performance, 85% pancreatic cancer cell death in vitro, and complete tumor regression in vivo within 30 days.

Further, we investigated heat stress responses in glioma cells post-MHCT under different tumor microenvironment conditions, including 2D monolayers, 3D monoculture spheroids, and coculture spheroids. We observed HSP90 upregulation during treatment, which limited therapeutic efficacy. A combinatorial approach using the HSP90 inhibitor 17-DMAG alongside MHCT significantly enhanced glioma cell death, achieving 65% and 53% tumor inhibition at primary and secondary sites within eight days and complete tumor regression in vivo within 20 days via immune activation.

We also explored magnetothermodynamic (MTD) therapy by combining ROS generation and heat-induced immunological effects using vitamin K3-loaded copper zinc ferrite nanoparticles (Vk3@Si@CuZnIONPs) under an alternating magnetic field (AMF). This dual mechanism resulted in substantial ROS-mediated oxidative damage and immune activation, achieving a 69% tumor inhibition rate in lung adenocarcinoma within 20 days and complete tumor regression by 30 days.

Additionally, metabolic profiling of cancer-derived exosomes using LC-MS/MS and NMR revealed dysregulated metabolic pathways associated with tumor progression. Identifying common metabolites across pancreatic, lung, and glioma cells highlighted potential biomarkers for early detection and therapeutic monitoring.

These synergistic approaches—optimizing MNP designs, employing bacterial delivery systems, inhibiting HSP90, combining ROS-heat mechanisms, and utilizing exosomal metabolites—demonstrate significant advancements in MHCT, paving the way for more effective cancer therapies and improved clinical outcomes.