Gas-Mediated Tumor Energy Remodeling for Sensitizing Mild Photothermal Therapy.

Abstract

The metabolic reprogramming of tumors requires ATP to maintain therapeutic resistance, posing a major challenge for photothermal therapy (PTT). Although raising the temperature can help in tumor ablation, it frequently leads to severe side effects such as chronic inflammation and hyper-immunogenicity. Therefore, improving therapeutic responsiveness and promoting wound healing are crucial considerations in PTT development. In this context, we proposed a gas-mediated energy remodeling strategy to enhance the efficacy of mild PTT at moderate temperatures while minimizing side effects. In the proof-of-concept study, an FDA-approved drug-based hydrogen sulfide (H2S) donor was developed to provide a sustained supply of H2S to tumor sites, serving as an adjuvant to mild PTT. This approach proved to be highly effective in disrupting the mitochondrial respiratory chain, inhibiting ATP generation, and reducing the overexpression of heat shock protein 90 (HSP90), which ultimately amplified the therapeutic outcome. With the ability to reverse tumor thermotolerance, this strategy delivered a greatly potent antitumor response, achieving complete tumor ablation in a single treatment while minimizing harm to healthy tissues. Thus, it holds great promise to overcome the limitations of PTT and may serve as a valuable paradigm for the future clinical translation of photothermal nanoplatforms.