Non-small cell lung cancer (NSCLC) treatment is often compromised by acquired resistance and, in the context of photothermal therapy (PTT), by tumor thermotolerance─a protective stress response mediated by the molecular chaperone heat shock protein 90 (HSP90). To address this dual challenge, we developed a multifunctional nanoplatform (Cu9S8@Lum NPs) that synergistically integrates NIR-II PTT with HSP90 inhibition. This nanosystem is based on a Cu9S8 nanocore with high photothermal conversion efficiency, loaded with the HSP90 inhibitor Luminespib and designed for pH-responsive drug release. This spatiotemporally coordinated strategy enables concurrent tumor hyperthermia and molecular interference with the heat-shock defense mechanism. In vitro, the nanoparticles effectively suppressed HSP90 expression, exacerbated cellular oxidative stress, and induced mitochondrial apoptosis, resulting in markedly enhanced cytotoxicity compared to PTT alone. In vivo, the nanoplatform demonstrated effective tumor accumulation and, under mild NIR-II irradiation, achieved significant tumor growth inhibition in a syngeneic model. This work presents a mechanism-informed nanomaterial strategy to overcome thermotolerance in NSCLC, advancing the development of synergistic cancer nanotherapeutics.
Hao et al. (2026) studied this question.