Yuan Haitao, Qiu Chong, Wang Xiaoxian, Wang Peili, Yi Letai, Peng Xin, Xu Xiaolong, Huang Wei, Bai Yunmeng, Wei Jinxi, Ma Jingbo, Wong Yin Kwan, Fu Chunjin, Xiao Wei, Chen Chunbo, Long Ying, Li Zhijie, Wang Jigang
Department of Hyperbaric Oxygen Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China.
Center for Drug Research and Development Guangdong Provincial Key Laboratory of Advanced Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, P. R. China.
Adv Mater. 2025 Jan;37(4):e2406662. doi: 10.1002/adma.202406662. Epub 2024 Dec 4.
Triple-negative breast cancer has an immunologically "cold" microenvironment, which leads to resistance to current immunotherapy. The activation of stimulator of interferon genes (STING) pathway has been thought a promising strategy to enhance immunotherapy efficacy. In this study, we adopted a comprehensive strategy that integrates innate immune responses with tumor-targeting photothermal therapy (PTT) to simultaneously tackle multiple immune-suppressive mechanisms in breast cancer. This semiconducting polymeric nanoagonists (DPTT-Mn Lipo NPs) mediated PTT can effectively initiate tumor cell apoptosis and induce ICD, thereby reprogramming the immunosuppressive TME and activating STING. We confirmed the modulation of the TME through the PTT-mediated ICD effect and the transactivation of the cGAS-STING pathway in immune cells of the TME due to the released dsDNA via ICD, such as macrophages and DCs. Indeed, DPTT-Mn Lipo NPs-mediated PTT promoted M1 polarization of tumor-associated macrophages, augmented T-cell infiltration, facilitated dendritic cell (DC) maturation, and regulated type I interferon factor secretion, leading to efficient tumor suppression. Most importantly, the combination of DPTT-Mn Lipo NPs-based PTT with a checkpoint blockade therapy (anti-PD-1) can elicit long-term immune memory besides tumor eradication. Collectively, this nano-system can systemically activate antitumor immunity through STING activation and potentially establish long-term memory against tumor recurrence.
三阴性乳腺癌具有免疫“冷”微环境，这导致对当前免疫疗法产生抗性。干扰素基因刺激物（STING）通路的激活被认为是提高免疫治疗疗效的一种有前景的策略。在本研究中，我们采用了一种综合策略，将先天免疫反应与肿瘤靶向光热疗法（PTT）相结合，以同时应对乳腺癌中的多种免疫抑制机制。这种半导体聚合物纳米激动剂（DPTT-Mn脂质体纳米粒）介导的PTT可有效引发肿瘤细胞凋亡并诱导免疫原性细胞死亡（ICD），从而重新编程免疫抑制性肿瘤微环境（TME）并激活STING。我们通过PTT介导的ICD效应以及由于ICD释放的双链DNA（dsDNA）导致TME免疫细胞中cGAS-STING通路的反式激活，证实了对TME的调节，例如巨噬细胞和树突状细胞（DC）。实际上，DPTT-Mn脂质体纳米粒介导的PTT促进了肿瘤相关巨噬细胞的M1极化，增强了T细胞浸润，促进了树突状细胞（DC）成熟，并调节了I型干扰素因子分泌，从而导致有效的肿瘤抑制。最重要的是，基于DPTT-Mn脂质体纳米粒的PTT与检查点阻断疗法（抗PD-1）的联合应用除了根除肿瘤外，还能引发长期免疫记忆。总的来说，这种纳米系统可以通过激活STING全身激活抗肿瘤免疫，并有可能建立针对肿瘤复发的长期记忆。
