CD47-SIRPα轴调控及CD47靶向治疗：破解胰腺癌免疫治疗耐药新策略

doi:10.3877/cma.j.issn.2095-3232.2026.03.007

CD47作为肿瘤免疫逃逸的核心因子，通过与受体信号调节蛋白（SIRP）α结合，向巨噬细胞发送“别吃我”信号，使肿瘤细胞得以逃避免疫系统的清除，进而推动肿瘤的发展。CD47-SIRPα轴不仅调控红细胞、Plt、造血干细胞和神经元的稳态过程，还在肿瘤中发挥类似PD-1/PD-L1的适应性免疫调节作用。多种调控因子包括细胞因子、癌基因、microRNA（miR）和酶等参与肿瘤细胞CD47表达的调节，其中IL-1、miR-340和miR-128被证实可特异性调控胰腺癌中CD47的表达。近年来的临床试验结果表明，抗CD47抗体在治疗对PD-1反应率低的胰腺癌有显著的治疗潜力，同时不良反应主要为1~2级血液毒性，可控性良好。当前控制毒性的策略包括剂量调整，构建降低红细胞结合能力的双特异性抗体，阻断CD47-SIRPα轴其他位点以及开发新型靶向递送系统。抗CD47疗法联合其他免疫治疗手段在HER2阳性胃癌中的研究显示了其潜力，这为胰腺癌新辅助治疗和综合治疗提供了新的视角，有望显著改善患者预后。

关键词: 胰腺癌, CD47, CD47-SIRPα轴, 免疫治疗, 免疫检查点, 免疫逃逸

As the core factor of tumor immune escape, CD47 sends a ‘don't eat me’ signal to macrophages by binding with receptor signal regulatory protein (SIRP)α, enabling tumor cells to evade immune clearance and promoting the progression of tumors. CD47-SIRPα axis not only regulates the homeostasis of red blood cells, Plt, hematopoietic stem cells and neurons, but also plays an adaptive immunomodulatory role resembling PD-1/PD-L1 in tumors. Multiple regulatory factors, including cytokines, oncogenes, microRNA(miR) and enzymes, are involved in the regulation of CD47 expression in tumor cells, among which IL-1, miR-340 and miR-128 have been confirmed to specifically regulate the expression level of CD47 in pancreatic cancer. Recent clinical trials show that anti-CD47 antibody has significant therapeutic potential for pancreatic cancer with low response rate to PD-1, and the adverse reactions are mainly grade 1-2 hematotoxicity, which is well controllable. Existing strategies adopted to control toxicities include dose adjustment, construction of bispecific antibodies that reduce the binding capacity of red blood cells, blocking other sites of CD47-SIRPα axis and developing novel targeted delivery systems. Anti-CD47 therapy combined with other immunotherapies shows its therapeutic potential in HER2-positive gastric cancer, which provides a new perspective for neoadjuvant therapy and comprehensive therapy for pancreatic cancer and is expected to significantly improve clinical prognosis of patients.

Key words: Pancreatic cancer, CD47, CD47-SIRPα axis, Immunotherapy, Immune checkpoint, Immune escape

图1 CD47-SIRPα轴适应性免疫调节机制示意图注：CD47-SIRPα信号通路分子机制，可分为以下几个关键部分：（1）核心分子互作：癌细胞表面的CD47与巨噬细胞表面的SIRPα结合，激活SIRPα胞内的ITIM（抑制性免疫受体酪氨酸基序）和ITSM（免疫受体酪氨酸开关基序），进而招募SHP-1/SHP-2磷酸酶，通过酪氨酸残基的磷酸化传递抑制信号，阻止巨噬细胞吞噬癌细胞。（2）其他调控因子：肌球蛋白IIA、血小板反应蛋白-1、CD47 BRIL-B6H12复合物等分子参与该通路的调控，影响CD47与SIRPα的结合或信号传导过程

图2 CD47表达调节机制示意图注：CD47-SIRPα轴介导的免疫逃逸：癌细胞表面的CD47与巨噬细胞表面的SIRPα结合，通过该轴抑制巨噬细胞对癌细胞的吞噬，帮助癌细胞逃避免疫监视。细胞因子与信号通路激活：癌细胞表面的TNF受体结合TNF-α，白介素-6受体结合白介素-6，分别激活核因子-κB和信号转导与转录激活因子3（STAT3）信号通路，进而促进癌基因表达，推动癌细胞增殖、存活。同时，缺氧环境下癌细胞的缺氧诱导因子-1α也参与调控癌基因。微小RNA的调控作用：微小RNA作用于相关分子的3'非翻译区，参与调控其表达，进而影响癌细胞的生物学行为。焦谷氨酸修饰的影响：谷氨酰胺焦磷酸化酶参与的焦谷氨酸修饰也对癌细胞的相关过程产生作用，此外IFN-γ也参与对癌细胞的调控通路中

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Regulation of CD47-SIRPα axis and CD47 targeted therapy: a new strategy to resolve drug resistance of immunotherapy for pancreatic cancer

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Regulation of CD47-SIRPα axis and CD47 targeted therapy: a new strategy to resolve drug resistance of immunotherapy for pancreatic cancer