Sialic acid-binding immunoglobulin-like lectin-9（Siglec-9）对髓系细胞和淋巴细胞具有强大的免疫抑制作用，为其作为治疗靶点提供了坚实的理论基础。然而，高级别浆液性卵巢癌（HGSC）中Siglec-9的表达谱及其关键作用仍未明确。本研究旨在阐明Siglec-9表达的预后意义以及其在HGSC免疫治疗中的预测价值。研究纳入两个队列，包括120例HGSC肿瘤组织芯片（IHC）的标本和40例新鲜肿瘤标本用于流式细胞术（FCM）研究。使用生物信息学分析和FCM分析了免疫细胞中Siglec-9的表达谱。通过IHC和FCM，研究了Siglec-9与免疫抑制性表型相关的Siglec-9+肿瘤相关巨噬细胞（TAMs）之间的关系，并通过体外和体内实验证明Siglec-9的阻断对免疫治疗具有敏感性。Siglec-9主要表达在肿瘤相关巨噬细胞（TAMs）上。高表达Siglec-9+的TAMs与较差的总体生存率相关。肿瘤条件培养基（TCM）和肿瘤腹水导致Siglec-9+TAMs富集，并表现出促肿瘤性表型。Siglec-9+TAMs与免疫抑制性肿瘤微环境（TME）相关，该微环境以CD8+T细胞衰竭和免疫检查点表达增加为特征。Siglec-9的阻断抑制了抑制性磷酸酶SHP-1的磷酸化，并使TAMs转向抗肿瘤表型，恢复了CD8+T细胞的细胞毒活性，体外和体内实验均得到证实。对抗程序性死亡受体-1（anti-PD-1）治疗的反应者与非反应者相比，具有更多Siglec-9+TAMs。此外，阻断Siglec-9与anti-PD-1抗体协同作用，增强了具有更多Siglec-9+TAMs的组织中CD8+T细胞的细胞毒活性。Siglec-9+TAMs可能是HGSC患者预后不良的独立预测因子，但也是抗PD-1/抗程序性死亡配体-1免疫治疗的预测性生物标记。此外，值得进一步探索具有免疫抑制作用的Siglec-9+TAMs作为治疗靶点的潜力。 ©2023作者（或其雇主）原创。根据CC BY-NC许可重新使用。不得进行商业再使用。详见权利和权限。由BMJ出版。

The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for serving as a therapeutic target. However, the expression profile and critical role of Siglec-9 in high-grade serous ovarian cancer (HGSC) remain obscure. This study aimed to elucidate the prognostic significance of Siglec-9 expression and its predictive value for immunotherapy in HGSC.Study enrolled two cohorts, consisting of 120 tumor microarray specimens of HGSC for immunohistochemistry (IHC) and 40 fresh tumor specimens for flow cytometry (FCM). Expression profile of Siglec-9 in immune cells was analyzed by both bioinformatics analysis and FCM. Role of Siglec-9 was studied to identify that Siglec-9+TAMs linked with an immunosuppressive phenotype by IHC and FCM, and block Siglec-9 was sensitive to immunotherapy by ex vivo and in vitro assays.Siglec-9 is predominantly expressed on tumor-associated macrophages (TAMs). High Siglec-9+TAMs were associated with inferior overall survival (OS). Both tumor-conditioned medium (TCM) and tumor ascites induced enrichment of Siglec-9+TAMs with protumorigenic phenotypes. Siglec-9+TAMs were associated with immunosuppressive tumor microenvironment (TME) characterized by exhausted CD8+T cells and increased immune checkpoint expression. Blockade of Siglec-9 suppressed phosphorylation of the inhibitory phosphatase SHP-1 and repolarized TAMs to antitumorigenic phenotype and retrieved cytotoxic activity of CD8+T cells in vitro and ex vivo. Responders toward antiprogrammed death receptor-1 (anti-PD-1) therapy present more Siglec-9+TAMs than non-responders. Furthermore, blockade Siglec-9 synergized with anti-PD-1 antibody to enhance the cytotoxic activity of CD8+T cells in tissues with higher Siglec-9+TAMs.Siglec-9+TAMs may serve as an independent prognostic of poor survival but a predictive biomarker for anti-PD-1/antiprogrammed death ligand-1 immunotherapy in HGSC. In addition, the potential of immunosuppressive Siglec-9+TAMs as a therapeutic target is worth further exploration.© 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.