肿瘤浸润淋巴细胞（TILs）和程序性死亡配体1（PD-L1）在三阴性乳腺癌（TNBC）的临床预后预测方面仍然存在不足，因为预后不总是与这些生物标志物的表达相关。可能导致这些生物标志物表达的基因组和转录组改变尚未完全揭示。我们评估了TNBC多组学数据集和两个免疫治疗临床试验队列中的PD-L1免疫组织化学（IHC）评分（SP142和28-8）和TILs。然后，我们分析了与TILs、PD-L1表达和患者预后相关的基因组和转录组改变。尽管TILs作为TNBC临床预后的良好预测因子，但仍存在例外情况。我们的研究揭示了几个基因组改变与意外事件的相关性。特别地，PD-L1的表达可能导致TILs和预后之间存在悖论关系。因此，我们根据PD-L1和TILs水平将TNBC分为四组。TIL-PD-L1+和TIL+PD-L1-组均不是典型的“热性”肿瘤；两者与TIL+PD-L1+肿瘤相比，其预后较差，免疫治疗效果较低。PD-L1的拷贝数变异和致癌信号激活与TIL-PD-L1+组中的PD-L1表达相关，而GSK3B诱导的降解可能导致TIL+PD-L1-组中PD-L1无法检测到的表达。这些因素有可能影响PD-L1和TILs的预测功能。在TNBC中，几个基因组和转录组改变可能导致TILs、PD-L1表达和预后之间存在悖论效应。研究和针对这些因素将推动TNBC患者的精准免疫治疗。© 2023作者。由牛津大学出版社出版。保留所有权利。若需获得许可，请发送电子邮件至：journals.permissions@oup.com。

Tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer (TNBC), as outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that might contribute to the expression of these biomarkers remain incompletely uncovered.We evaluated PD-L1 immunohistochemistry (IHC) scores (SP142 and 28-8) and TILs in our TNBC multiomics dataset and two immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression and patient outcomes.Despite TILs serving as a decent predictor for TNBC clinical outcomes, there remained exceptions. Our study revealed that several genomic alterations were correlated with unexpected events. Particularly, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified TNBCs into four groups based on PD-L1 and TIL levels. The TIL-PD-L1+ and TIL+PD-L1- groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL+PD-L1+ tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-PD-L1+ group, whereas GSK3B-induced degradation might cause undetectable PD-L1 expression in the TIL+PD-L1- group. These factors have the potential to affect the predictive function of both PD-L1 and TILs.Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression and prognosis in TNBC. Investigating and targeting these factors will advance precision immunotherapy for TNBC patients.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.