免疫疗法在胃癌（GC）中尚未产生令人满意的治疗效果。然而，靶向骨髓检查点有望扩大免疫疗法的潜力。本研究旨在评估 Siglec-10 肿瘤相关巨噬细胞 (TAM) 在调节抗肿瘤免疫中的关键作用，并探索骨髓检查点 Siglec-10 作为干预靶点的潜力。基于免疫组织化学方法评估 Siglec-10 TAM肿瘤微阵列和RNA测序数据。采用流式细胞术、RNA 测序和单细胞 RNA 测序分析来表征 Siglec-10 TAM 的表型和转录特征及其对 CD8 T 细胞介导的抗肿瘤免疫的影响。使用基于新鲜肿瘤组织的离体 GC 肿瘤片段平台评估了 Siglec-10 阻断的有效性，无论是单独使用还是与抗程序性细胞死亡 1 (PD-1) 联合使用。Siglec-10 主要在 TAM 上表达GC 中，并与肿瘤进展相关。在中山医院队列中，Siglec-10 TAM 预测不良预后（n=446，p<0.001）和辅助化疗耐药（n=331，p<0.001），并在外源队列中得到进一步验证。在三星医疗中心队列中，Siglec-10 TAM 在 GC 中表现出对派姆单抗的较差反应（n=45，p=0.008）。此外，Siglec-10 TAM 表现出免疫抑制表型并阻碍 T 细胞介导的抗肿瘤免疫反应。最后，阻断 Siglec-10 重振了抗肿瘤免疫反应，并协同增强了离体 GC 肿瘤片段平台中的抗 PD-1 免疫治疗。在 GC 中，骨髓检查点 Siglec-10 有助于调节 TAM 的免疫抑制特性，并促进 TAM 的免疫抑制。 CD8 T 细胞耗竭，最终促进免疫逃避。靶向 Siglec-10 代表了 GC 免疫治疗的潜在策略。© 作者（或其雇主）2023。根据 CC BY-NC 允许重复使用。不得商业再利用。请参阅权利和权限。由英国医学杂志出版。

Immunotherapy has not yielded satisfactory therapeutic responses in gastric cancer (GC). However, targeting myeloid checkpoints holds promise for expanding the potential of immunotherapy. This study aims to evaluate the critical role of Siglec-10+ tumor-associated macrophages (TAMs) in regulating antitumor immunity and to explore the potential of the myeloid checkpoint Siglec-10 as an interventional target.Siglec-10+ TAMs were assessed based on immunohistochemistry on tumor microarrays and RNA-sequencing data. Flow cytometry, RNA sequencing, and single-cell RNA-sequencing analysis were employed to characterize the phenotypic and transcriptional features of Siglec-10+ TAMs and their impact on CD8+ T cell-mediated antitumor immunity. The effectiveness of Siglec-10 blockade, either alone or in combination with anti-programmed cell death 1 (PD-1), was evaluated using an ex vivo GC tumor fragment platform based on fresh tumor tissues.Siglec-10 was predominantly expressed on TAMs in GC, and associated with tumor progression. In Zhongshan Hospital cohort, Siglec-10+ TAMs predicted unfavorable prognosis (n=446, p<0.001) and resistance to adjuvant chemotherapy (n=331, p<0.001), which were further validated in exogenous cohorts. In the Samsung Medical Center cohort, Siglec-10+ TAMs demonstrated inferior response to pembrolizumab in GC (n=45, p=0.008). Furthermore, Siglec-10+ TAMs exhibited an immunosuppressive phenotype and hindered T cell-mediated antitumor immune response. Finally, blocking Siglec-10 reinvigorated the antitumor immune response and synergistically enhances anti-PD-1 immunotherapy in an ex vivo GC tumor fragment platform.In GC, the myeloid checkpoint Siglec-10 contributes to the regulation of immunosuppressive property of TAMs and promotes the depletion of CD8+ T cells, ultimately facilitating immune evasion. Targeting Siglec-10 represents a potential strategy for immunotherapy in GC.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.