FAP是一种膜结合的蛋白酶，因其在肿瘤中高水平而在正常组织中表达有限，正在作为全癌症靶点进行研究。FAP-2286是一种放射性药物，由两个功能元素组成，FAP靶向肽和用于连接放射性同位素的螯合剂，用于临床治疗固体肿瘤。在临床前阶段，我们评估了FAP-2287在免疫调节和抗肿瘤效力方面的作用，FAP-2287是FAP-2286的小鼠代用品，与放射性同位素Lutetium-177（177Lu）结合用于单一疗法和与PD-1抗体联合治疗。我们使用携带MCA205小鼠FAP表达肿瘤（MCA205-mFAP）的C57BL/6小鼠分别接受177Lu-FAP-2287、抗PD-1或两种联合治疗。使用SPECT/CT扫描评估177Lu-FAP-2287在肿瘤中的吸收，使用肿瘤体积和生存时间测量治疗效果。通过流式细胞术、RNA表达和免疫组织化学分析，评估肿瘤浸润细胞的免疫分析。177Lu-FAP-2287迅速积聚于MCA205-mFAP肿瘤中，导致显著抑制肿瘤生长和更长的生存时间。抗PD-1和联合治疗也观察到显著的肿瘤生长抑制。在肿瘤的流式细胞术分析中，177Lu-FAP-2287增加了CD8+ T细胞的浸润，该浸润在与抗PD-1合并治疗中得以保持。CD8+ T细胞的增加伴随着STING介导的I型干扰素应答的诱导和共刺激分子（如CD86）水平的增高。在临床前模型中，FAP靶向放射治疗通过调节肿瘤微环境和增加肿瘤浸润的CD8+ T细胞，增强了抗PD-1介导的肿瘤生长抑制。这些发现为在FAP阳性肿瘤中开展联合177Lu-FAP-2286放射治疗和免疫检查点抑制的临床研究提供了合理性。

FAP is a membrane-bound protease under investigation as a pan-cancer target, given its high levels in tumors but limited expression in normal tissues. FAP-2286 is a radiopharmaceutical in clinical development for solid tumors that consists of two functional elements: a FAP-targeting peptide and a chelator used to attach radioisotopes. Preclinically, we evaluated the immune modulation and anti-tumor efficacy of FAP-2287, a murine surrogate for FAP-2286, conjugated to the radionuclide lutetium-177 (177Lu) as a monotherapy and in combination with a PD-1 targeting antibody.C57BL/6 mice bearing MCA205 mouse FAP-expressing tumors (MCA205-mFAP) were treated with 177Lu-FAP-2287, anti-PD-1, or both. Tumor uptake of 177Lu- FAP-2287 was assessed by SPECT/CT scanning, while therapeutic efficacy was measured by tumor volume and survival. Immune profiling of tumor infiltrates was evaluated through flow cytometry, RNA expression, and immunohistochemistry analyses.177Lu-FAP-2287 rapidly accumulated in MCA205-mFAP tumors leading to significant tumor growth inhibition (TGI) and longer survival time. Significant TGI was also observed from anti-PD-1 and the combination. In flow cytometry analysis of tumors, 177Lu-FAP-2287 increased CD8+ T cell infiltration which was maintained in the combination with anti-PD-1. The increase in CD8+ T cells was accompanied by an induction of STING-mediated type I interferon response and higher levels of co-stimulatory molecules such as CD86.In a preclinical model, FAP-targeted radiotherapy enhanced anti-PD-1-mediated TGI by modulating the TME and increasing the recruitment of tumor-infiltrating CD8+ T cells. These findings provide a rationale for clinical studies of combined 177Lu-FAP-2286 radiotherapy and immune checkpoint inhibition in FAP-positive tumors.© 2023. The Author(s).