Cancer treatment has evolved significantly in recent years, with immunotherapy (IT) and targeted therapy (TT) leading the way in innovative approaches. However, despite advancements, many patients still do not respond effectively to these treatments. A recent review highlights the potential of hyperthermia (HT) as an adjuvant therapy, which could enhance the effectiveness of IT and TT by modulating the immune system, sensitizing tumors to treatment, and improving drug delivery.

Hyperthermia involves controlled heating of tumors to 40–44°C using external energy sources such as microwave, radiofrequency, ultrasound, or infrared devices. The treatment is classified into:

Local hyperthermia, targeting specific tumor sites.
Regional hyperthermia, applied to larger areas like organs or limbs.
Whole-body hyperthermia, used for metastatic cancer.

Heat affects cancer cells in multiple ways:

• DNA Damage and Repair Inhibition – HT disrupts DNA repair pathways, making cancer cells more vulnerable to treatments like chemotherapy and radiotherapy.
• Immune System Activation – HT enhances tumor visibility to the immune system by increasing tumor-infiltrating lymphocytes (TILs) and promoting immunogenic cell death (ICD) through the release of damage-associated molecular patterns (DAMPs).
• Improved Drug Delivery – HT increases blood flow and vessel permeability, helping immune cells and therapeutic agents penetrate tumors more effectively.
• Counteracting Hypoxia – Tumors often develop hypoxic environments, which suppress immune responses. HT reduces hypoxia, making tumors more susceptible to immune attack.

There are three major therapy classes that could benefit from combination with HT:

• Immune Checkpoint Inhibitors (ICIs) – ICIs, such as anti-PD-1 and anti-PD-L1 therapies, work best in “hot” tumors with active immune responses. HT can convert “cold” tumors into “hot” ones, improving the efficacy of checkpoint blockade therapies.
• Bispecific T-Cell Engagers (BiTEs) – These drugs guide T-cells to attack tumors but often struggle in solid tumors due to poor immune infiltration. HT increases T-cell trafficking, improving BiTEs’ effectiveness.
• Anti-VEGF Therapies – VEGF inhibitors target blood vessel formation to cut off tumors’ nutrient supply, but some tumors develop resistance. HT can enhance vascular normalization, reducing tumor resistance to these drugs.

While HT has been clinically used for decades, its combination with modern therapies remains underexplored. Early studies suggest promising results, but further clinical trials are needed to optimize parameters like temperature, duration, and treatment combinations. If successfully integrated, hyperthermia could become a crucial tool in improving response rates for immunotherapy and targeted therapies, offering better outcomes for cancer patients worldwide.

Source.