Enhancing Cancer Therapy with Hyperthermia: Synergistic Effects with Natural Compounds and Conventional Treatments.

Hyperthermia (HT) is a promising adjunct to conventional cancer therapies such as chemotherapy and radiotherapy (RT). It offers several advantages, including low toxicity to normal tissues, limited tumor resistance, and synergistic therapeutic effects. HT enhances treatment efficacy by inhibiting DNA repair mechanisms, increasing tumor membrane permeability for improved drug uptake, and improving oxygenation to reduce hypoxia-induced resistance. HT also promotes cancer cell death by inducing oxidative stress, leading to mitochondrial dysfunction, caspase activation, and PARP cleavage. It causes G2/M cell cycle arrest and damages tumor vasculature. Additionally, HT downregulates proangiogenic and invasive factors such as TGF-β1, VEGF, and MMP-2/9, contributing to reduced tumor progression. Combining HT with natural compounds like propolis and flavonoids further improves therapeutic outcomes. These natural agents are accessible, cost-effective, and exhibit multi-targeted anticancer activity. In synergy with HT, they enhance reactive oxygen species (ROS) generation, suppress heat shock proteins, modulate the tumor microenvironment (TME), and activate immune responses. They may also reduce the side effects of conventional therapies and support tissue regeneration. Overall, HT, especially in combination with natural compounds, offers a multifaceted and effective approach to cancer therapy.