查看“免疫荒漠型”的源代码

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            <strong>免疫荒漠型</strong> (Immune Desert) 是肿瘤免疫微环境 (TME) 的一种特定表型，属于典型的<strong>[[冷肿瘤]]</strong> (Cold Tumor)。其核心病理特征是：无论是在肿瘤实质内部还是在肿瘤周边的基质中，几乎完全检测不到功能性的<strong>[[CD8+ T细胞]]</strong>浸润。这与 T 细胞聚集在肿瘤边缘无法进入的<strong>[[免疫豁免型]]</strong> (Immune Excluded) 形成鲜明对比。免疫荒漠型的形成通常源于<strong>[[癌症-免疫循环]]</strong>早期的启动失败，如肿瘤缺乏新抗原（低 <strong>[[TMB]]</strong>）、<strong>[[树突状细胞]]</strong> (DC) 缺失，或存在特定的基因突变（如 <strong>[[STK11]]</strong>/<strong>[[KEAP1]]</strong> 突变、<strong>[[WNT/β-catenin]]</strong> 通路激活）。临床上，<strong>[[胰腺导管腺癌]]</strong> (PDAC)、<strong>[[前列腺癌]]</strong>、<strong>[[微卫星稳定型结直肠癌]]</strong> (MSS CRC) 以及<strong>[[小细胞肺癌]]</strong> (SCLC) 是此类表型的典型代表。此类患者对单纯的<strong>[[免疫检查点抑制剂]]</strong> (ICI) 表现为极度顽固的<strong>[[原发性耐药]]</strong>。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">免疫荒漠型</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Immune Desert Phenotype (点击展开)</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">特征：T细胞完全缺失</div>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">归属分类</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">非炎症性肿瘤 (Non-inflamed)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">关键特征</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>无 T 细胞浸润</strong></td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">驱动基因</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;"><strong>STK11, KEAP1, β-catenin</strong></td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">典型癌种</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">胰腺癌, 前列腺癌, SCLC</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">PD-L1 表达</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">通常为阴性 (TPS < 1%)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">治疗反应</th>
                    <td style="padding: 6px 12px; color: #b91c1c;"><strong>原发性耐药</strong></td>
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        免疫荒漠的形成意味着免疫系统从未识别出肿瘤的存在，或者在识别的最初阶段就被阻断，导致没有效应细胞被招募到肿瘤部位。这通常涉及“癌症-免疫循环”的第一步和第二步障碍。
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        <li style="margin-bottom: 12px;"><strong>免疫启动失败 (Lack of Priming)：</strong>
            <br>这是最根本的原因。可能由于肿瘤<strong>[[TMB]]</strong>过低，缺乏新抗原；或者负责抗原呈递的 <strong>[[树突状细胞]]</strong> (DC) 功能缺陷（如 Batf3+ DC 缺失），导致 T 细胞从未在淋巴结被激活。</li>
        <li style="margin-bottom: 12px;"><strong>WNT/β-catenin 通路激活：</strong>
            <br>在黑色素瘤和 MSS 肠癌中，肿瘤细胞固有的 <strong>[[WNT/β-catenin]]</strong> 信号通路激活会导致 ATF3 表达，抑制趋化因子（如 CCL4）的分泌，从而阻断 DC 细胞的招募。</li>
        <li style="margin-bottom: 12px;"><strong>STK11/KEAP1 突变：</strong>
            <br>在 [[KRAS突变]] 肺腺癌中，<strong>[[STK11]] (LKB1)</strong> 的共突变会抑制干扰素刺激基因 (STING) 通路，导致极度贫瘠的免疫微环境。</li>
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        <h3 style="margin: 0; color: #0f172a; font-size: 1.1em; font-weight: 700;">🛡️ 典型谱系：临床四大“免疫荒漠”</h3>
        <span style="font-size: 0.75em; color: #94a3b8; text-transform: uppercase; letter-spacing: 1px;">Clinical Landscape</span>
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                <th style="padding: 0 15px 5px; font-size: 0.75em; color: #94a3b8; font-weight: 500; width: 25%;">TUMOR TYPE</th>
                <th style="padding: 0 15px 5px; font-size: 0.75em; color: #94a3b8; font-weight: 500; width: 40%;">MECHANISM (COLD)</th>
                <th style="padding: 0 15px 5px; font-size: 0.75em; color: #94a3b8; font-weight: 500; width: 35%;">STRATEGY</th>
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                    <div style="font-weight: 700; color: #0f172a; font-size: 0.95em;">[[胰腺癌]]</div>
                    <div style="font-size: 0.75em; color: #cbd5e1;">PDAC</div>
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                    <span style="background: #fff1f2; color: #be123c; padding: 2px 6px; border-radius: 4px; font-size: 0.75em; font-weight: 700;">物理屏障</span>
                    <div style="font-size: 0.8em; color: #64748b; margin-top: 4px;">纤维化基质阻隔 T 细胞</div>
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                    <div style="color: #0f172a; font-size: 0.85em; font-weight: 600;">🔨 基质耗竭</div>
                    <div style="font-size: 0.75em; color: #64748b;">AG化疗 / CD40激动剂</div>
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                    <div style="font-weight: 700; color: #0f172a; font-size: 0.95em;">[[前列腺癌]]</div>
                    <div style="font-size: 0.75em; color: #cbd5e1;">PCa</div>
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                    <span style="background: #eff6ff; color: #1d4ed8; padding: 2px 6px; border-radius: 4px; font-size: 0.75em; font-weight: 700;">抗原缺失</span>
                    <div style="font-size: 0.8em; color: #64748b; margin-top: 4px;">PTEN 缺失抑制呈递</div>
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                    <div style="color: #0f172a; font-size: 0.85em; font-weight: 600;">💊 合成致死</div>
                    <div style="font-size: 0.75em; color: #64748b;">[[PARP抑制剂]]</div>
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                    <div style="font-weight: 700; color: #0f172a; font-size: 0.95em;">[[MSS结直肠癌]]</div>
                    <div style="font-size: 0.75em; color: #cbd5e1;">CRC</div>
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                    <span style="background: #fff7ed; color: #c2410c; padding: 2px 6px; border-radius: 4px; font-size: 0.75em; font-weight: 700;">WNT通路</span>
                    <div style="font-size: 0.8em; color: #64748b; margin-top: 4px;">抑制 DC 细胞招募</div>
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                <td style="padding: 16px 15px; border-radius: 0 8px 8px 0; vertical-align: middle;">
                    <div style="color: #0f172a; font-size: 0.85em; font-weight: 600;">🕸️ 微环境调节</div>
                    <div style="font-size: 0.75em; color: #64748b;">[[抗血管生成]] (瑞戈非尼)</div>
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                    <div style="font-weight: 700; color: #0f172a; font-size: 0.95em;">[[小细胞肺癌]]</div>
                    <div style="font-size: 0.75em; color: #cbd5e1;">SCLC</div>
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                    <span style="background: #faf5ff; color: #7e22ce; padding: 2px 6px; border-radius: 4px; font-size: 0.75em; font-weight: 700;">呈递缺陷</span>
                    <div style="font-size: 0.8em; color: #64748b; margin-top: 4px;">MHC-I 分子下调</div>
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                <td style="padding: 16px 15px; border-radius: 0 8px 8px 0; vertical-align: middle;">
                    <div style="color: #0f172a; font-size: 0.85em; font-weight: 600;">⚓️ 不依赖MHC</div>
                    <div style="font-size: 0.75em; color: #64748b;">[[DLL3双抗]]</div>
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        <h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">治疗核心原则</h3>
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            对于免疫荒漠型肿瘤，单纯阻断 PD-1/PD-L1（“松刹车”）是无效的，因为缺乏 T 细胞这一“效应器”。治疗必须着眼于<strong>“从头启动免疫循环”</strong>（如诱导抗原释放）或<strong>“绕过 MHC 限制”</strong>（如双抗）。
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        <li style="margin-bottom: 12px;"><strong>诱导免疫原性细胞死亡 (ICD)：</strong> 
            <br>使用<strong>[[化疗]]</strong>（如蒽环类）或<strong>[[SBRT放疗]]</strong>，强行杀伤肿瘤细胞，使其释放危险信号 (DAMPs) 和新抗原，吸引 DC 细胞到来。</li>
        <li style="margin-bottom: 12px;"><strong>双特异性抗体 (Bispecifics)：</strong>
            <br>如针对 SCLC 的 <strong>[[DLL3/CD3双抗]]</strong> (Tarlatamab)，它不需要 MHC 分子呈递抗原，直接物理拉动 T 细胞杀伤肿瘤，完美避开呈递缺陷。</li>
        <li style="margin-bottom: 12px;"><strong>肿瘤疫苗与溶瘤病毒：</strong>
            <br>直接向肿瘤内注射<strong>[[溶瘤病毒]]</strong> 或使用<strong>[[mRNA疫苗]]</strong>，人工引入强免疫原性物质，点燃“冷肿瘤”中的免疫火种。</li>
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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</span>
        
        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [1] <strong>Chen DS, Mellman I. (2013).</strong> <em>Oncology meets immunology: the cancer-immunity cycle.</em> <strong>[[Immunity]]</strong>. 2013;39(1):1-10.<br>
            <span style="color: #475569;">[理论奠基]：提出了著名的“癌症-免疫循环”理论，并首次根据 T 细胞浸润模式将肿瘤分为炎症型、豁免型和荒漠型。</span>
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            [2] <strong>Spranger S, et al. (2015).</strong> <em>Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.</em> <strong>[[Nature]]</strong>. 2015;523(7559):231-235.<br>
            <span style="color: #475569;">[机制突破]：揭示了肿瘤内在的 WNT/β-catenin 通路激活是导致 DC 细胞缺乏和形成“免疫荒漠”的关键分子机制。</span>
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            [3] <strong>Galon J, Bruni D. (2019).</strong> <em>Approaches to treat immune hot, altered and cold tumors with combination immunotherapies.</em> <strong>[[Nature Reviews Drug Discovery]]</strong>. 2019;18(3):197-218.<br>
            <span style="color: #475569;">[治疗综述]：详细分类了三种免疫表型，并针对免疫荒漠型提出了将“冷肿瘤”转变为“热肿瘤”的系统性治疗策略。</span>
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            免疫荒漠型 (Immune Desert) · 知识图谱
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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;">相关表型</td>
                <td style="padding: 10px 15px; color: #334155;">[[免疫豁免型]] (Excluded) • [[免疫炎症型]] (Inflamed) • [[冷肿瘤]]</td>
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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;">关键机制</td>
                <td style="padding: 10px 15px; color: #334155;">[[WNT/β-catenin]] • [[STK11]] (LKB1) • [[MHC-I下调]] • [[DC缺失]]</td>
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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;">治疗对策</td>
                <td style="padding: 10px 15px; color: #334155;">[[联合化疗]] • [[溶瘤病毒]] • [[双特异性抗体]] (Tarlatamab)</td>
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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;">典型肿瘤</td>
                <td style="padding: 10px 15px; color: #334155;">[[胰腺癌]] • [[前列腺癌]] • [[MSS结直肠癌]] • [[小细胞肺癌]]</td>
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