Optimization of Immunogenic Cell Death in Triple-Negative Breast Cancer with Virus-like Particle-Based Photothermal Therapy

Photothermal therapy (PTT) uses near-infrared (NIR) light and a photothermal agent (PTA) to generate heat to kill tumor cells. PTT is an attractive therapy for highly metastatic tumors─such as triple-negative breast cancer (TNBC)─because PTT is a potent activator of immunogenic cell death (ICD). ICD is characterized by the production of damage-associated molecular patterns (DAMPs) that help the immune system recognize cancer cells as "nonself." This generates an immune response against the tumor cells and helps to combat both primary and metastatic tumors. However, an unknown thermal window remains in which ICD is most prevalent. Here, we conjugate an NIR-absorbing dye to the surface of bacteriophage Qβ to generate a viral-based PTA. Additionally, we demonstrate that mild PTT (<45 °C) is not enough to cause significant apoptosis in the murine TNBC model. In comparison, hot PTT (>60 °C) effectively eliminates cancer cells but is less likely to induce ICD. An optimal temperature range is moderate PTT (50-60 °C), where effective cell killing and ICD occur. We show an increased surface expression of DAMPs within this range, along with an increased ratio of pro- to anti-inflammatory cytokines by dendritic cells.