肿瘤的转移是肿瘤致死的首要因素，尤以骨转移最常见，极大影响了患者的生存期及生活质量。肿瘤细胞改变了骨微环境，且骨微环境促进了肿瘤细胞增殖，二者恶性循环，加剧骨转移。因骨转移位置的不确定性和骨微环境的复杂性，极大限制了其治疗。能否通过激活宿主免疫反应，并同步调节肿瘤微环境的免疫抑制性、改善骨微环境溶蚀性的途径予以解决？对此，本组前期构建了趋骨性载体（JCR,2017；IJP,2017）用于骨转移的治疗，又设计了光动力治疗前药通过对肿瘤微环境的调节以提高疗效（EJMC,2018）。基于此，本课题拟进一步构建光控尺寸可变药物载体，利用近红外光触发产生ROS用于原位肿瘤细胞的杀伤和宿主免疫反应（疫苗）的激活，同时激活IDO前药和易于透过骨环境的抗骨重吸收载体。旨在：1）同步阻断①肿瘤细胞对骨微环境破坏过程和②骨溶蚀刺激肿瘤细胞增殖过程，协同打破二者的恶性循环；2）双重抑制肿瘤原发灶和骨转移的发生。

Metastases are the cause of 90 % of deaths from solid tumors. Bone is the most common organ to be affected, leading to painful and untreatable consequences. As described by the ‘seed and soil’ hypothesis, bone represents a fertile ground for cancer cells to flourish, the ‘vicious cycle’ of reciprocal bone–cancer cellular and osteolytic (bone-resorbing) metastases, promotes the proliferation of tumor cells and exacerbates bone metastasis as well. Due to the uncertainty of the bone metastases location and the particularity of the bone microenvironment, there is still no effective treatment available currently. We suppose if it can be solved by activating the host immune system and regulating the immunosuppression of the tumor microenvironment, accompanied by anti-bone reabsorption therapy simultaneously? Thus, our group constructed the bone-seeking nanoagent (JCR, 2017; IJP, 2017) for the treatment of bone metastasis, and designed photosensitive molecular prodrug to improve the efficacy of photodynamic therapy through the regulation of the tumor microenvironment (EJMC, 2018). Based on the previous research, a light-controlled size variable nano-carrier is going to establish in the current project. This system using near-infrared light to trigger the production of ROS, which play the role for tumor killing, in situ activation of host immune response (vaccine), IDO prodrugs and anti-bone reabsorption drug at the meanwhile. And finally achieve the synergetic inhibition of both the tumor cells and osteoclast, resulting in the interruption of the vicious cycle between the tumor cells and the bone microenvironment. Realizing the dual inhibition treatment model of suppressing both tumor cells and bone microenvironment, and inhibition both metastasis and primary tumor at the same time. We hope this project could put forward a new idea for bone metastasis therapy and prevention.