Liu Xiaolong, Ding Qingzhu, Zhang Han, Zhang Xiang, Chen Qiangda, Weng Shangeng
Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, China; Fujian Abdominal Surgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350001, China; National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350212, China.
Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, China; Fujian Abdominal Surgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350001, China; National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350212, China.
Biochim Biophys Acta Rev Cancer. 2025 Oct;1880(5):189443. doi: 10.1016/j.bbcan.2025.189443. Epub 2025 Sep 8.
Pancreatic ductal adenocarcinoma (PDAC) exhibits persistent resistance to immunotherapy, with a 5-year survival rate around 10 %. The CD39-CD73-adenosine axis emerges as a critical mediator of immune evasion in PDAC, generating pathologically elevated adenosine concentrations that systematically suppress anti-tumor immunity. This purinergic pathway operates through sequential ATP hydrolysis by CD39 and CD73 ectonucleotidases, producing adenosine that engages four G-protein-coupled receptors (A1, A2A, A2B, A3) to orchestrate comprehensive immunosuppression. A2A and A2B receptors mediate the predominant immunosuppressive effects through cAMP-PKA signaling, inhibiting CD8+ T cell and NK cell cytotoxicity while enhancing regulatory T cells, myeloid-derived suppressor cells, and M2-like tumor-associated macrophages. Cancer-associated fibroblasts and tumor cells contribute to adenosine production and respond to its signaling, establishing self-reinforcing immunosuppressive networks. Current therapeutic strategies demonstrate promising early clinical results, with multiple CD73 inhibitors, CD39 antagonists, and adenosine receptor antagonists under evaluation in PDAC trials. However, critical challenges remain: CD73's non-enzymatic functions promote chemoresistance independently of adenosine production, explaining why enzymatic inhibitors fail to enhance chemotherapy sensitivity. The spatial adenosine gradient within tumors, receptor-specific paradoxical effects, and compensatory resistance mechanisms through AMP accumulation further complicate therapeutic targeting. Multi-targeted approaches combining adenosine pathway inhibition with checkpoint blockade, chemotherapy, and stromal modulation show enhanced efficacy. Future directions include developing predictive biomarker panels, optimizing combination sequences, and designing inhibitors targeting both enzymatic and structural functions of purinergic enzymes. Understanding these complex interactions provides the foundation for transforming the adenosine pathway from an immunosuppressive barrier into a therapeutic opportunity in PDAC.
胰腺导管腺癌（PDAC）对免疫疗法表现出持续抗性，5年生存率约为10%。CD39-CD73-腺苷轴成为PDAC免疫逃逸的关键介质，产生病理性升高的腺苷浓度，系统性地抑制抗肿瘤免疫。这条嘌呤能途径通过CD39和CD73外切核苷酸酶依次水解ATP来运作，产生腺苷，腺苷与四种G蛋白偶联受体（A1、A2A、A2B、A3）结合，协调全面的免疫抑制。A2A和A2B受体通过cAMP-PKA信号传导介导主要的免疫抑制作用，抑制CD8+T细胞和NK细胞的细胞毒性，同时增强调节性T细胞、髓源性抑制细胞和M2样肿瘤相关巨噬细胞。癌症相关成纤维细胞和肿瘤细胞促进腺苷生成并对其信号作出反应，建立自我强化的免疫抑制网络。目前的治疗策略显示出有希望的早期临床结果，多种CD73抑制剂、CD39拮抗剂和腺苷受体拮抗剂正在PDAC试验中进行评估。然而，关键挑战仍然存在：CD73的非酶功能独立于腺苷生成促进化疗抗性，这解释了酶抑制剂为何未能增强化疗敏感性。肿瘤内的空间腺苷梯度、受体特异性矛盾效应以及通过AMP积累的补偿抗性机制进一步使治疗靶向复杂化。将腺苷途径抑制与检查点阻断、化疗和基质调节相结合的多靶点方法显示出增强的疗效。未来的方向包括开发预测性生物标志物面板、优化联合用药顺序以及设计针对嘌呤能酶的酶促和结构功能的抑制剂。了解这些复杂的相互作用为将腺苷途径从免疫抑制屏障转变为PDAC的治疗机会奠定了基础。
