Rajesh Christabelle, Cummings Richard D, Radhakrishnan Prakash
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Mol Cancer. 2025 Aug 4;24(1):211. doi: 10.1186/s12943-025-02417-4.
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease, and standard of care therapies have failed to yield significant clinical benefit, with invasive surgery being the only curative treatment for patients with early-stage disease. Tumor-associated glycans in pancreatic cancer have direct effects on the survival and propagation of the tumor proper and contribute to an immunosuppressed tumor microenvironment. The existence of a “tumor glycocode” in PDAC and the role of hypersialylation in this cancer have been hugely underscored. Through this initial understanding, significant strides have been made in the field of glycosylation-mediated immune regulation, uncovering glyco-immune checkpoints that facilitate tumor progression in PDAC and other malignancies. Here, we describe the specific roles of glycan-binding proteins, such as C-type lectin receptors, Siglecs, and Galectins, in generating and promoting immunosuppression, exacerbating survival outcomes, and dampening therapeutic efficacy. We illustrate the scale of glycan-mediated regulation of homeostatic immune responses and how cancer glycans facilitate dampened anti-tumor immunity through the major histocompatibility complex (MHC) and the enhanced expression of immune checkpoints, such as PD-L1 and CTLA-4. A wide array of glycan-targeted therapies against PDAC in the clinic, including monoclonal antibodies, enzymes, and vaccines, has been described. With the help of new glycosylation signatures identified and techniques that allow us to reach single-cell resolution, we can target glycans and generate strategies to activate the immune system against PDAC.
胰腺导管腺癌（PDAC）是一种极具侵袭性的疾病，标准治疗方法未能带来显著的临床益处，对于早期疾病患者，侵入性手术是唯一的治愈性治疗方法。胰腺癌中的肿瘤相关聚糖对肿瘤本身的存活和增殖有直接影响，并导致免疫抑制的肿瘤微环境。PDAC中“肿瘤糖代码”的存在以及高唾液酸化在这种癌症中的作用得到了极大的重视。通过这一初步认识，糖基化介导的免疫调节领域取得了重大进展，发现了促进PDAC和其他恶性肿瘤中肿瘤进展的糖免疫检查点。在这里，我们描述了聚糖结合蛋白，如C型凝集素受体、唾液酸结合免疫球蛋白样凝集素和半乳糖凝集素，在产生和促进免疫抑制、恶化生存结果以及削弱治疗效果方面的具体作用。我们阐述了聚糖介导的稳态免疫反应调节的规模，以及癌症聚糖如何通过主要组织相容性复合体（MHC）和免疫检查点（如PD-L1和CTLA-4）的表达增强促进抗肿瘤免疫的抑制。临床上已经描述了一系列针对PDAC的聚糖靶向治疗方法，包括单克隆抗体、酶和疫苗。借助新发现的糖基化特征和能够实现单细胞分辨率的技术，我们可以靶向聚糖并制定激活免疫系统对抗PDAC的策略。
