Duesberg Max, LeVee Alexis, Chang Hannah, Tsai Karen, Crossman Bridget, Tadi Marissa, Xu Sharon, Wheeler Deric, Kang Irene
Department of Internal Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA.
Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Cancer Treat Res. 2025;129:67-82. doi: 10.1007/978-3-031-97242-3_4.
Immunotherapy has reshaped the treatment landscape of several malignancies, including breast cancer. While historically considered less immunogenic, breast cancer-particularly the triple-negative subtype (TNBC)-has demonstrated responsiveness to immune checkpoint inhibitors (ICIs). TNBC is characterized by higher tumor mutational burden, elevated PD-L1 expression, and increased tumor-infiltrating lymphocytes, making it a leading focus of immunotherapy development. In metastatic TNBC with PD-L1 expression, trials such as KEYNOTE-355 have shown improvements in progression-free and overall survival with the addition of the ICI, pembrolizumab to chemotherapy, leading to regulatory approval. In early-stage TNBC, KEYNOTE-522 established a neoadjuvant chemotherapy plus ICI as the standard of care for stage II and III tumors. This was based on improved pathologic complete response and event-free survival in this pivotal clinical trial regardless of PD-L1 expression. ICIs in other subtypes, such as HER2-positive and hormone receptor-positive/HER2-negative disease, remain under active investigation. Ongoing studies are also exploring novel strategies including dual immune checkpoint blockade, cellular therapies (e.g., CAR-T, TILs), cancer vaccines, and rational combinations with targeted agents and antibody-drug conjugates (ADCs). Biomarkers such as PD-L1, tumor mutational burden, immune gene signatures, and the gut microbiome are being evaluated to refine patient selection and predict response. Additionally, effective management of immune-related toxicities is critical, particularly in curative-intent settings. As the role of immunotherapy expands, a multidisciplinary, biomarker-driven approach will be essential to optimize outcomes and broaden its applicability across breast cancer subtypes.
免疫疗法重塑了包括乳腺癌在内的多种恶性肿瘤的治疗格局。虽然乳腺癌在历史上被认为免疫原性较低，但乳腺癌——尤其是三阴性亚型（TNBC）——已显示出对免疫检查点抑制剂（ICI）有反应。TNBC的特征是肿瘤突变负担较高、PD-L1表达升高以及肿瘤浸润淋巴细胞增加，这使其成为免疫疗法开发的主要焦点。在有PD-L1表达的转移性TNBC中，诸如KEYNOTE-355等试验表明，在化疗中添加ICI帕博利珠单抗可改善无进展生存期和总生存期，从而获得监管批准。在早期TNBC中，KEYNOTE-522确立了新辅助化疗加ICI作为II期和III期肿瘤的标准治疗方案。这是基于该关键临床试验中病理完全缓解率和无事件生存期的改善，无论PD-L1表达如何。ICI在其他亚型中，如HER2阳性和激素受体阳性/HER2阴性疾病，仍在积极研究中。正在进行的研究也在探索新策略，包括双重免疫检查点阻断、细胞疗法（如CAR-T、肿瘤浸润淋巴细胞）、癌症疫苗以及与靶向药物和抗体药物偶联物（ADC）的合理联合。诸如PD-L1、肿瘤突变负担、免疫基因特征和肠道微生物群等生物标志物正在进行评估，以优化患者选择并预测反应。此外，有效管理免疫相关毒性至关重要，尤其是在有治愈意图的情况下。随着免疫疗法作用的扩大，多学科、生物标志物驱动的方法对于优化治疗结果和扩大其在乳腺癌各亚型中的适用性至关重要。
