Shen Zhisen, Jiang Hao, Lu Shuaijun, Tian Hailong, Gao Feng, Deng Hongxia, Huang Canhua
Department of Otolaryngology-Head and Neck Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315000, China.
Ningbo Key Laboratory of Digital Medicine Precision Diagnosis and Treatment of Otorhinolaryngology, Head and Neck Diseases, Ningbo, China.
J Nanobiotechnology. 2025 Jul 11;23(1):500. doi: 10.1186/s12951-025-03559-9.
Immunotherapy represents a transformative advance in cancer treatment; however, its efficacy in head and neck cancer (HNC) remains constrained by tumor cell stemness and profound immunosuppression within the tumor microenvironment (TME). Overcoming these barriers necessitates innovative strategies to simultaneously eradicate stem-like populations and reprogram the TME.
We engineered a tumor-targeted polymer prodrug nanoplatform, Biotin@P-Cur/T780 NPs, integrating disulfide-linked polycurcumin (P-Cur) and the photothermal agent T780. DSPE-PEG-Biotin surface functionalization enables active tumor targeting. The nanoplatform exploits high intratumoral glutathione (GSH) to trigger disassembly, releasing curcumin monomers and T780. This elicits dual GSH depletion and reactive oxygen species (ROS) amplification, inducing ROS-mediated apoptosis and ferroptosis. Concurrently, localized near-infrared irradiation activates T780, synergizing photothermal (PTT) and photodynamic (PDT) therapies to intensify immunogenic cell death (ICD).
The Biotin@P-Cur/T780 NPs potently suppressed tumor cell stemness in vitro and in vivo. ROS/ferroptosis-driven ICD, amplified by PTT/PDT, reversed TME immunosuppression, enhancing dendritic cell maturation and cytotoxic T lymphocyte infiltration. This multimodal mechanism significantly inhibited primary tumor growth and metastasis in HNC models, while extending survival.
Our prodrug nanoplatform overcomes key resistance mechanisms in HNC by coordinately targeting stemness, inducing dual apoptosis/ferroptosis, and potentiating ICD through PDT/PTT-enhanced immunomodulation. This strategy provides a potent combinatorial approach to augment immunotherapy efficacy in refractory tumors.
免疫疗法是癌症治疗领域的一项变革性进展；然而，其在头颈部癌（HNC）中的疗效仍受肿瘤细胞干性和肿瘤微环境（TME）中严重免疫抑制的限制。克服这些障碍需要创新策略，以同时根除干细胞样群体并重新编程TME。
我们构建了一种肿瘤靶向聚合物前药纳米平台，即生物素@P-姜黄素/T780纳米颗粒，它整合了二硫键连接的聚姜黄素（P-姜黄素）和光热剂T780。DSPE-PEG-生物素表面功能化实现了肿瘤的主动靶向。该纳米平台利用肿瘤内高浓度的谷胱甘肽（GSH）触发分解，释放姜黄素单体和T780。这引发了双重GSH消耗和活性氧（ROS）扩增，诱导ROS介导的凋亡和铁死亡。同时，局部近红外照射激活T780，协同光热疗法（PTT）和光动力疗法（PDT）增强免疫原性细胞死亡（ICD）。
生物素@P-姜黄素/T780纳米颗粒在体外和体内均有效抑制肿瘤细胞干性。由PTT/PDT放大的ROS/铁死亡驱动的ICD逆转了TME免疫抑制，增强了树突状细胞成熟和细胞毒性T淋巴细胞浸润。这种多模式机制在HNC模型中显著抑制了原发性肿瘤生长和转移，同时延长了生存期。
我们的前药纳米平台通过协同靶向干性、诱导双重凋亡/铁死亡以及通过PDT/PTT增强免疫调节增强ICD，克服了HNC中的关键耐药机制。该策略提供了一种有效的联合方法来提高难治性肿瘤的免疫治疗疗效。
