Chen Meixu, Song Linlin, Zhou Yao, Xu Tianyue, Sun Ting, Liu Zhihui, Xu Zihan, Zhao Yujie, Du Peixin, Ma Yingying, Huang Liwen, Chen Xiaoting, Yang Guang, Jing Jing, Shi Hubing
Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China.
Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China; Department of Ultrasound & Laboratory of Ultrasound Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Acta Biomater. 2025 Mar 1;194:305-322. doi: 10.1016/j.actbio.2025.01.015. Epub 2025 Jan 11.
Although immunotherapy has revolutionized clinical cancer treatment, the efficacy is limited due to the lack of tumor-associated antigens (TAAs) and the presence of compensatory immune checkpoints. To overcome the deficiency, a nano-system loaded with ozone and CD47 inhibitor RRx-001 is designed and synthesized. Upon irradiation, reactive oxygen species (ROS) generated from ozone reacts with nitric oxide (NO) metabolized from RRx-001 to form reactive nitrogen species (RNS), which presents a much stronger cell-killing ability than ROS. Molecular mechanism studies further reveal that RNS induce extensive immunogenic cell death (ICD). The released TAAs promote infiltration of cytotoxic T lymphocytes, which provides the basis for immune checkpoint blockade (ICB) therapy. Meanwhile, RRx-001 carried by the nanoparticles and the produced radicals repolarize M2-type tumor-associated macrophages (TAMs) into the anti-tumor M1-type, consequently reversing the immunosuppressive tumor microenvironment (TME). In a xenograft triple-negative breast cancer (TNBC) animal model, O-001@lipo (liposome enwrapping O and RRx-001) plus irradiation shows a significant anti-tumor efficacy by improving cytotoxic lymphocyte infiltration and regulating immunosuppressive TME. In summary, the O-001@lipo nano-system triggered by irradiation potently improves the efficacy of immunotherapy by introducing strong cytotoxic RNS, which not only enriches the toolbox of ICD inducer but also provides a strategy of treatment for immune deficient tumor. STATEMENT OF SIGNIFICANCE: This study introduces a nano-system that leverages ozone and RRx-001 in the presence of X-ray irradiation to generate reactive nitrogen species, enhancing immunogenic cell death and promoting T-lymphocyte infiltration in triple-negative breast cancer, addressing a significant unmet need in the field. The scientific contribution is the development of a clinically translatable nano-system that not only induces ICD but also reshapes the tumor microenvironment, which is expected to have a profound impact on the readership in pharmaceutics, material science, and nano-bio interaction, particularly for those interested in advanced immune therapy approaches.
尽管免疫疗法彻底改变了临床癌症治疗，但由于缺乏肿瘤相关抗原（TAA）以及存在代偿性免疫检查点，其疗效有限。为克服这一缺陷，设计并合成了一种负载臭氧和CD47抑制剂RRx-001的纳米系统。经照射后，臭氧产生的活性氧（ROS）与RRx-001代谢产生的一氧化氮（NO）反应形成活性氮物种（RNS），其细胞杀伤能力比ROS强得多。分子机制研究进一步表明，RNS可诱导广泛的免疫原性细胞死亡（ICD）。释放的TAA促进细胞毒性T淋巴细胞浸润，这为免疫检查点阻断（ICB）治疗提供了基础。同时，纳米颗粒携带的RRx-001和产生的自由基将M2型肿瘤相关巨噬细胞（TAM）重新极化为抗肿瘤的M1型，从而逆转免疫抑制性肿瘤微环境（TME）。在异种移植三阴性乳腺癌（TNBC）动物模型中，O-001@lipo（包裹O和RRx-001的脂质体）加照射通过改善细胞毒性淋巴细胞浸润和调节免疫抑制性TME显示出显著的抗肿瘤疗效。总之，照射触发的O-001@lipo纳米系统通过引入强细胞毒性RNS有力地提高了免疫疗法的疗效，这不仅丰富了ICD诱导剂的工具箱，还为免疫缺陷肿瘤提供了一种治疗策略。重要性声明：本研究引入了一种纳米系统，该系统在X射线照射下利用臭氧和RRx-001生成活性氮物种，增强免疫原性细胞死亡并促进三阴性乳腺癌中的T淋巴细胞浸润，满足了该领域一项重大的未满足需求。科学贡献在于开发了一种临床可转化的纳米系统，该系统不仅诱导ICD，还重塑肿瘤微环境，预计将对pharmaceutics、材料科学和纳米生物相互作用领域的读者产生深远影响，特别是对于那些对先进免疫治疗方法感兴趣的读者。
