Photothermal Therapy Generates a Thermal Window of Immunogenic Cell Death in Neuroblastoma

A thermal “window” of immunogenic cell death (ICD) elicited by nanoparticle‐based photothermal therapy (PTT) in an animal model of neuroblastoma is described. In studies using Prussian blue nanoparticles to administer photothermal therapy (PBNP‐PTT) to established localized tumors in the neuroblastoma model, it is observed that PBNP‐PTT conforms to the “more is better” paradigm, wherein higher doses of PBNP‐PTT generates higher cell/local heating and thereby more cell death, and consequently improved animal survival. However, in vitro analysis of the biochemical correlates of ICD (ATP, high‐motility group box 1, and calreticulin) elicited by PBNP‐PTT demonstrates that PBNP‐PTT triggers a thermal window of ICD. ICD markers are highly expressed within an optimal temperature (thermal dose) window of PBNP‐PTT (63.3–66.4 °C) as compared with higher (83.0–83.5 °C) and lower PBNP‐PTT (50.7–52.7 °C) temperatures, which both yield lower expression. Subsequent vaccination studies in the neuroblastoma model confirm the in vitro findings, wherein PBNP‐PTT administered within the optimal temperature window results in long‐term survival (33.3% at 100 d) compared with PBNP‐PTT administered within the higher (0%) and lower (20%) temperature ranges, and controls (0%). The findings demonstrate a tunable immune response to heat generated by PBNP‐PTT, which should be critically engaged in the administration of PTT for maximizing its therapeutic benefits. When an optimal thermal dose of Prussian blue nanoparticle‐based photothermal therapy is administered to tumors, tumor cells undergo immunogenic cell death marked by the release of ATP, HMGB1, and increased calreticulin expression. These effects elicit a potent antitumor immune response associated with improved therapeutic outcomes that are absent if the thermal dose is too low or high.