胰腺导管腺癌（PDAC）是最致命的癌症之一。尽管免疫检查点阻断在一系列人类癌症中成功应用，但 PDAC 的免疫治疗仍然不成功。 PDAC 的特点是促纤维增生、缺氧和高度免疫抑制的肿瘤微环境 (TME)，其中通常缺乏 T 细胞浸润（免疫荒漠），或者 T 细胞远离肿瘤岛（免疫排除）。将 TME 转化为免疫炎症状态，允许 T 细胞浸润，可以提高 PDAC 免疫治疗的成功率。在这项研究中，我们使用 KPC3 皮下 PDAC 小鼠模型来研究肿瘤源性唾液酸在塑造 PDAC 中的作用。肿瘤免疫景观。唾液酸缺陷型 KPC3 系是通过基因敲除 CMAS（胞苷单磷酸 N-乙酰神经氨酸合成酶）酶而产生的，CMAS 酶是合成含唾液酸聚糖的关键酶。通过使用抗程序性细胞死亡蛋白 1 (PD-1) 和激动性 CD40 治疗来评估唾液酸缺乏对免疫治疗疗效的影响。KPC3 肿瘤中唾液酸的缺乏导致 CD4 和 CD8 T 细胞数量增加TME，并降低 T 细胞群中 CD4 调节性 T 细胞 (Treg) 的频率。重要的是，CD8 T 细胞能够浸润唾液酸缺陷肿瘤中的肿瘤岛。免疫环境的这些有利改变使唾液酸缺乏的肿瘤对免疫疗法敏感，而免疫疗法对表达唾液酸的 KPC3 肿瘤无效。此外，人类胰腺癌中唾液酸化相关基因的高表达与 CD8 T 细胞浸润减少、Treg 细胞增加以及较差的生存概率相关。我们的结果表明，肿瘤来源的唾液酸介导 PDAC 内的 T 细胞排斥TME，从而损害免疫疗法的功效。靶向唾液酸是增强 T 细胞浸润并改善 PDAC 免疫治疗结果的潜在策略。© 作者（或其雇主）2023。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。

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite the successful application of immune checkpoint blockade in a range of human cancers, immunotherapy in PDAC remains unsuccessful. PDAC is characterized by a desmoplastic, hypoxic and highly immunosuppressive tumor microenvironment (TME), where T-cell infiltration is often lacking (immune desert), or where T cells are located distant from the tumor islands (immune excluded). Converting the TME to an immune-inflamed state, allowing T-cell infiltration, could increase the success of immunotherapy in PDAC.In this study, we use the KPC3 subcutaneous PDAC mouse model to investigate the role of tumor-derived sialic acids in shaping the tumor immune landscape. A sialic acid deficient KPC3 line was generated by genetic knock-out of the CMAS (cytidine monophosphate N-acetylneuraminic acid synthetase) enzyme, a critical enzyme in the synthesis of sialic acid-containing glycans. The effect of sialic acid-deficiency on immunotherapy efficacy was assessed by treatment with anti-programmed cell death protein 1 (PD-1) and agonistic CD40.The absence of sialic acids in KPC3 tumors resulted in increased numbers of CD4+ and CD8+ T cells in the TME, and reduced frequencies of CD4+ regulatory T cells (Tregs) within the T-cell population. Importantly, CD8+ T cells were able to infiltrate the tumor islands in sialic acid-deficient tumors. These favorable alterations in the immune landscape sensitized sialic acid-deficient tumors to immunotherapy, which was ineffective in sialic acid-expressing KPC3 tumors. In addition, high expression of sialylation-related genes in human pancreatic cancer correlated with decreased CD8+ T-cell infiltration, increased presence of Tregs, and poorer survival probability.Our results demonstrate that tumor-derived sialic acids mediate T-cell exclusion within the PDAC TME, thereby impairing immunotherapy efficacy. Targeting sialic acids represents a potential strategy to enhance T-cell infiltration and improve immunotherapy outcomes in PDAC.© 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.