靶向PD-L1的α核素分子探针内照射治疗与NSCLC免疫治疗的协同效应及机制研究

针对PD-1/PD-L1的免疫检查点阻断疗法是NSCLC治疗的重大突破，然而响应率低是其关键瓶颈和科学难点，联合核素内照射的协同策略是解决途径之一。我们前期制备靶向NSCLC肽受体的α核素分子探针（211At-ATE-奥曲肽），发现内照射致肿瘤细胞凋亡或坏死，并增强其免疫原性；同时获得特异性靶向肺癌PD-L1的小分子多肽WL12。基于此，拟利用211At标记WL12，构建新型分子探针211At-ATE-WL12，联合抗PD-1单抗免疫阻断治疗，通过体内外生物学评价和表征分析以及单细胞测序，验证“靶向PD-L1的α核素致肿瘤细胞DNA断裂，进一步激活抗肿瘤免疫应答，从而增益免疫治疗”的协同效应，阐明α核素对肿瘤微环境中免疫细胞和相关信号通路的调控作用，并解析该过程协同增强免疫治疗效果的机制。该研究有望为新型核素分子探针应用于PD-L1高表达NSCLC的临床转化奠定基础，为肺癌治疗提供新思路。

The immunotherapy targeting immune checkpoint PD-1/PD-L1 has achieved remarkable breakthrough of clinical efficacy for NSCLC. However, it has a low response rate, which is the essential bottleneck in its clinical application. Combining immunotherapy and internal irradiation therapy is one of the solutions. We previously constructed an alpha nuclide molecular probe (211At-ATE-octreotide) that targets the NSCLC peptide receptor, and found that internal irradiation can induce apoptosis or necrosis of tumor cells and enhance the immunogenicity. Additionally, we constructed a small molecule polypeptide WL12 specifically targeting PD-L1. Based on this, a new molecular probe 211At-ATE-WL12, combined with anti-PD-1 monoclonal antibodies immune blocking therapy, is constructed to treat NSCLC. Through in vivo and in vitro biological evaluation, characterization analysis and single-cell sequencing, we try to verify that "Alpha nuclide targeting PD-L1 could break the DNA of tumor cells, further activate the anti-tumor immune effect, and thereby increase the synergistic effect of immunotherapy", and clarify the regulatory role of alpha nuclide on immune cells and related signaling pathways in the tumor microenvironment, and analyze the mechanism of combining immunotherapy and internal irradiation therapy. This study is expected to lay the foundation for the clinical application of new nuclide molecular probes in the treatment of NSCLC which overexpress PD-L1, and to provide new strategy for the diagnosis and treatment of lung cancer.