三阴性乳腺癌的雌激素受体、孕激素受体和HER2三大靶点全部阴性，意味着传统靶向药物几乎无效，过去主要依靠化疗，但是复发率较高。众所周知，人体抗癌免疫力主要角色CD8阳性T淋巴细胞可杀死癌细胞，癌细胞又可通过程序性死亡配体PD-L1及其受体PD-1诱发CD8阳性T淋巴细胞进入自杀程序，因此抑制PD-L1或PD-1可恢复人体抗癌免疫力。近年来，PD-1或PD-L1抑制剂已被用于三阴性乳腺癌免疫治疗，但是并非全部患者都能获益。过去通常用PD-L1表达水平指导免疫治疗，但是结果并不理想。那么，我们能否直接用CD8指导三阴性乳腺癌免疫治疗？
2025年10月30日，美国基因与细胞治疗学会官方期刊、美国《细胞》旗下《分子治疗》在线发表复旦大学附属肿瘤医院陈力①、蒋书豪①、柳光宇、余科达、吴炅、狄根红、张文娟、马林晓曦、王中华、邵志敏✉️、李俊杰✉️、恒瑞医药梁倩男和沈煜等学者的FASCINATE-N研究报告，首次对三阴性乳腺癌术前化疗±中国原研PD-1抑制剂卡瑞利珠单抗的有效性和安全性进行随机分组比较。
FASCINATE-N (NCT05582499): Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series Study- Neoadjuvant Therapy
FASCINATE-N虽是二期临床研究，但实际上是一盘很大的棋，计划入组716例早期乳腺癌，对29种药物组成的41个术前治疗方案进行比较。其中，156例为三阴性乳腺癌，经过筛选，于2022年10月至2023年9月将90例局部晚期免疫调节型（CD8阳性T淋巴细胞浸润≥10%）患者按1比1随机分为两组各45例，分别给予术前化疗（白蛋白紫杉醇＋卡铂→表柔比星＋环磷酰胺）±卡瑞利珠单抗（每2周200毫克）。
结果，术前化疗±卡瑞利珠单抗相比：
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病理完全缓解率：62.2%比42.2%（95%置信区间：46.5～76.2%、27.7～57.8%）绝对值提高20.0%（P=0.059）
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≥3级不良事件发生率：88.9%比82.2%
虽然病理完全缓解率P值未低于统计学门槛0.05，但是贝叶斯分析表明免疫化疗优于单用化疗的后验概率达97%。虽然证据链仍需加强，但是数值趋势已经指向临床意义。
对其中11例患者基因组、转录组和病理学标志物关联分析表明，CD8阳性T淋巴细胞浸润率越高，卡瑞利珠单抗治疗后病理完全缓解率越高。CD8≥30%患者病理完全缓解率达85.7%，而且即使PD-L1阴性患者病理完全缓解率也可达50.0%，比单用化疗高14.3%，说明CD8预测能力超过PD-L1。同时，PD-L1表达水平、基质肿瘤浸润淋巴细胞与CD8阳性T淋巴细胞密度显著相关，三者构成免疫生态三角，但CD8是驱动因素，其他是伴随现象。CD8曲线下面积0.689（P=0.035），优于PD-L1联合阳性评分0.608（P=0.260）和基质肿瘤浸润淋巴细胞0.628（P=0.172）。病理完全缓解患者T淋巴细胞受体信号等免疫通路显著富集，而非病理完全缓解患者则偏向代谢通路，这意味着免疫系统被成功唤醒是疗效核心。
因此，该单中心小样本二期临床研究结果表明，根据CD8指导卡瑞利珠单抗术前免疫化疗，可提高肿瘤负荷较高三阴性乳腺癌病理完全缓解率，且毒性反应发生率相似，支持将CD8阳性T淋巴细胞水平作为预测免疫治疗效果的生物学标志物，指导三阴性乳腺癌分型精准治疗，故有必要进一步开展多中心大样本三期临床研究进行验证。
相关链接
Mol Ther. 2025 Oct 30. IF: 12.0
CD8-Guided Immunochemotherapy Improves Pathological Complete Response Rates in High Tumor Burden Triple-Negative Breast Cancer.
Li Chen, Shu-hao Jiang, Guang-Yu Liu, Ke-Da Yu, Jiong Wu, Gen-Hong Di, Wen-Juan Zhang, Lin-xiaoxi Ma, Qian-nan Liang, Yu Shen, Zhong-Hua Wang, Zhi-Ming Shao, Jun-Jie Li.
Fudan University Shanghai Cancer Centre, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China.
In a Phase 2 trial of CD8-enriched, immunomodulatory TNBC, camrelizumab plus neoadjuvant chemotherapy was associated with a numerically higher pathological complete response rates. Multi-omics findings linked benefit to increased CD8+ infiltration and PD-L1/sTIL correlations, suggesting CD8+ levels may help predict response.
Blockade of the programmed cell death 1 ligand 1 (PD-L1) enhances the efficacy of standard chemotherapy in the neoadjuvant treatment of triple-negative early breast cancer (TNBC) but is associated with adverse events. This phase 2 trial evaluated camrelizumab (anti-PD-1) combined with chemotherapy in locally advanced immunomodulatory TNBC (CD8+ T-cell infiltration ≥ 10%). From October 2022 to September 2023, 90 stage II-III TNBC patients were randomized to receive neoadjuvant chemotherapy ± camrelizumab (200 mg biweekly). The camrelizumab-chemotherapy group (n = 45) achieved a pathological complete response (pCR) rate of 62.2% (95% CI:46.5-76.2%) versus 42.2% (27.7-57.8%) in the chemotherapy-alone group (n = 45), with a 20.0% absolute increase (P = 0.059). Grade ≥ 3 adverse events occurred in 88.9% (40/45) and 82.2% (37/45) of patients, respectively. Multi-omics analyses demonstrated significantly elevated CD8+T-cell infiltration in camrelizumab-treated pCR patients, alongside strong correlations between PD-L1 expression, stromal tumor-infiltrating lymphocytes (sTILs), and CD8+ density. These results indicate that CD8-guided immunochemotherapy with camrelizumab improves pCR rates in high tumor burden TNBC with manageable toxicity, supporting CD8+ T-cell levels as a predictive biomarker for immunotherapy response.
DOI: 10.1016/j.ymthe.2025.10.056