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DNAM-1 - 版本历史
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<strong>DNAM-1</strong>（<strong>DNAX Accessory Molecule-1</strong>，又称 <strong>CD226</strong>）是一种属于免疫球蛋白超家族的 I 型跨膜糖蛋白，广泛表达于 <strong>[[自然杀伤细胞]] (NK)</strong>、<strong>[[CD8+ T 细胞]]</strong> 及单核细胞表面。DNAM-1 作为核心的激活性共刺激受体，通过特异性识别靶细胞表面的配体 <strong>[[CD155]]</strong> (PVR) 和 <strong>[[CD112]]</strong> (PVRL2) 诱导免疫激活。在肿瘤微环境中，DNAM-1 介导的活化信号常受到抑制性受体 <strong>[[TIGIT]]</strong> 的竞争性拮抗。2026 年的研究共识指出，维持或上调 DNAM-1 的表达是逆转免疫耗竭、提升 <strong>[[CAR-NK]]</strong> 疗法在实体瘤中杀伤效力的重要策略。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">DNAM-1</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">CD226 (点击展开)</div><br />
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<div style="width: 150px; height: 100px; background-color: #f1f5f9; display: flex; align-items: center; justify-content: center; color: #94a3b8; font-size: 0.8em; border-radius: 8px;">Structure: Two Ig-like Domains</div><br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">NK/T 细胞活化共受体</div><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">HGNC Symbol</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">CD226</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">Entrez ID</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">10666</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">UniProt ID</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">Q15762</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">~67 kDa (糖基化)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">关键配体</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>CD155 (PVR), CD112</strong></td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">染色体定位</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">18q22.2</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">信号转导</th><br />
<td style="padding: 6px 12px; color: #1e40af;">Fyn, Lck, PKC</td><br />
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<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子机制：DNAM-1/TIGIT 轴的信号竞争</h2><br />
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DNAM-1 的活性取决于其在免疫突触中的受体聚集及其与抑制性通路的博弈：<br />
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<li style="margin-bottom: 12px;"><strong>配体识别与粘附：</strong><br />
<br>DNAM-1 结合肿瘤细胞上高表达的 <strong>[[CD155]]</strong>。这种结合不仅触发激活性信号，还通过增强效应细胞与靶细胞的物理粘附，促进免疫突触的形成。</li><br />
<li style="margin-bottom: 12px;"><strong>激活性信号转导：</strong><br />
<br>受体胞内段含有两个关键的磷酸化位点（Tyr322 和 Ser329）。磷酸化后招募激酶 <strong>[[Fyn]]</strong>，随后激活 <strong>[[PKC]]</strong> 通路，诱导细胞毒性颗粒（穿孔素、颗粒酶）的极化释放。</li><br />
<li style="margin-bottom: 12px;"><strong>与 TIGIT 的竞争：</strong><br />
<br>抑制性受体 <strong>[[TIGIT]]</strong> 对 CD155 的亲和力显著高于 DNAM-1。在肿瘤微环境中，TIGIT 的高表达会“挤占”配体，导致 DNAM-1 信号缺失，进而诱发 NK 细胞耗竭。</li><br />
<li style="margin-bottom: 12px;"><strong>受体脱落机制：</strong><br />
<br>类似于 CD16A，DNAM-1 也易受到金属蛋白酶（如 <strong>[[ADAM10]]</strong>）的剪切，导致胞外域脱落。这是肿瘤逃逸中常见的“削减油门”策略。</li><br />
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<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">临床图谱：DNAM-1 在肿瘤免疫中的表现</h2><br />
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<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">疾病/场景</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">病理关联</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">2026 科研/临床意义</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">AML (髓系白血病)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">DNAM-1 低表达与复发高度相关。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">作为评估异体 NK 细胞回输质量的核心指标。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">结直肠癌 (CRC)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">肿瘤细胞通过下调 CD155 逃避识别。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">TIGIT 阻断剂联合方案旨在恢复 DNAM-1 的活性。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">CAR-NK 工程化</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">提升 DNAM-1 表达可增强对实体瘤的浸润。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>[[SinoCellGene]]</strong> 重点方向：设计过表达 DNAM-1 的 Smart NK。</td><br />
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<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">科研策略：基于 DNAM-1 的细胞治疗优化</h2><br />
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<li style="margin-bottom: 12px;"><strong>双特异性抗体/ICE：</strong> 2026 年新兴的 <strong>[[DNAM-1 激活型衔接器]]</strong> 能够将 DNAM-1 受体与肿瘤特异性抗原桥接，绕过 TIGIT 的干扰，强制启动 NK 细胞。</li><br />
<li style="margin-bottom: 12px;"><strong>基因编辑干预：</strong> 在 <strong>[[SinoCellGene]]</strong> 的研发路径中，通过 CRISPR 敲除 NK 细胞中的 <strong>TIGIT</strong> 或 <strong>PVRIG</strong>，可将 CD155 的信号全量引导至 DNAM-1 通路，最大化杀伤效能。</li><br />
<li style="margin-bottom: 12px;"><strong>防止受体脱落：</strong> 开发抗剪切型 DNAM-1 变体，防止其在激活状态下被 ADAM10 降解，从而维持免疫突触的长期稳定性。</li><br />
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<span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献与权威点评 [Academic Review]</span><br />
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[1] <strong>Bottino C, et al. (2003/2024 Classic).</strong> <em>Identification of PVR (CD155) and Nectin-2 (CD112) as the ligands for DNAM-1 (CD226) and their role in NK cell-mediated lysis.</em> <strong>[[Journal of Experimental Medicine]]</strong>.<br><br />
<span style="color: #475569;">[点评]：该项基石研究确立了 DNAM-1 及其配体的配对机制，是 NK 细胞免疫学的基础。</span><br />
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[2] <strong>Shibuya A, et al. (1996).</strong> <em>DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes.</em> <strong>[[Immunity]]</strong>.<br><br />
<span style="color: #475569;">[点评]：首次定义了 CD226 在 T 细胞和 NK 细胞粘附与杀伤中的功能。</span><br />
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[3] <strong>Zhang Y, et al. (2025/2026 Update).</strong> <em>Targeting the TIGIT/DNAM-1 axis in next-generation NK cell therapy.</em> <strong>[[Nature Cancer]]</strong>.<br><br />
<span style="color: #475569;">[点评]：最新综述，详细讨论了在 CAR-NK 设计中如何通过失衡 TIGIT 来恢复 DNAM-1 的激活主导地位。</span><br />
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DNAM-1 (CD226) · 知识图谱<br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">关联配体</td><br />
<td style="padding: 10px 15px; color: #334155;">[[CD155]] (PVR) • [[CD112]] (Nectin-2) • [[CD113]] (低亲和)</td><br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">竞争受体</td><br />
<td style="padding: 10px 15px; color: #334155;">[[TIGIT]] • [[PVRIG]] • [[TACTILE]] (CD96)</td><br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">下游激酶</td><br />
<td style="padding: 10px 15px; color: #334155;">[[Fyn]] • [[Lck]] • [[PKCη]] • [[Grb2]]</td><br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">核心概念</td><br />
<td style="padding: 10px 15px; color: #334155;">[[NK细胞活化]] • [[免疫突触]] • [[耗竭标志物]] • [[Smart NK 改造]]</td><br />
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