众所周知，光热治疗（PTT）的益处受到癌细胞的耐热性限制，这是由于过度表达热休克蛋白（HSP）所致。然后HSP进一步触发应激颗粒（SG）的形成，它们在各种应激条件下调节蛋白表达和细胞存活能力。抑制SG的形成可以增强肿瘤细胞对PTT的敏感性。在此，我们开发了聚乙二醇修饰的pH（低）插入肽（PEG-pHLIP）修饰的中空硫化铜纳米颗粒（HCuS NPs），其中包含SG抑制剂ISRIB，并以相变材料月桂酸（LA）作为门控，构建了一个pH驱动和近红外光响应控制的智能药物传递系统（IL@H-PP）。该纳米医药制剂可以特异性地靶向于微酸性肿瘤部位。在照射下，IL@H-PP实现了PTT，并通过光控释放ISRIB来有效抑制PTT诱导的SG的形成，增强肿瘤细胞对PTT的敏感性，从而提高抗肿瘤效果并诱导强效免疫原性细胞死亡（ICD）。此外，IL@H-PP可以促进肿瘤相关巨噬细胞（TAMs）产生活性氧自由基（ROS），将其极化为M1表型，并重塑免疫抑制的微环境。体外/体内结果揭示了PTT与SG抑制剂相结合的潜力，为抗肿瘤和抗转移提供了新的范式。©2023中国药学会和中国医学科学院药物研究所。Elsevier B.V.生产和托管。

As known, the benefits of photothermal therapy (PTT) are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins (HSPs). Then HSPs further trigger the formation of stress granules (SGs) that regulate protein expression and cell viability under various stress conditions. Inhibition of SG formation can sensitize tumor cells to PTT. Herein, we developed PEGylated pH (low) insertion peptide (PEG-pHLIP)-modified hollow copper sulfide nanoparticles (HCuS NPs) encapsulating the SG inhibitor ISRIB, with the phase-change material lauric acid (LA) as a gate-keeper, to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system (IL@H-PP). The nanomedicine could specifically target slightly acidic tumor sites. Upon irradiation, IL@H-PP realized PTT, and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT, thereby increasing the antitumor effect and inducing potent immunogenic cell death (ICD). Moreover, IL@H-PP could promote the production of reactive oxygen species (ROS) by tumor-associated macrophages (TAMs), repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment. In vitro/vivo results revealed the potential of PTT combined with SG inhibitors, which provides a new paradigm for antitumor and anti-metastases.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.