Yang Yiyan, Wang Weidong
Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646099, China.
Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, 610041, China.
J Transl Med. 2025 Nov 18;23(1):1314. doi: 10.1186/s12967-025-07370-w.
Significant progress has been made in understanding the complex immune evasion mechanisms of triple-negative breast cancer (TNBC), paving the way for more effective immunotherapies. This review highlights key advances in elucidating the molecular basis of TNBC immune escape, including aberrant immune checkpoint expression, metabolic reprogramming, epigenetic regulation, immune evasion by associated cellular components, and clinical trials of emerging immunotherapies. Specifically, overexpression of immune checkpoint inhibitors such as PD-L1 on TNBC cells and within the tumor microenvironment (TME) plays a critical role in suppressing antitumor immunity. Secondly, TNBC cells evade immune surveillance through metabolic reprogramming. For instance, upregulated glutamine metabolism supports tumor growth and modulates the TME toward immunosuppression by limiting nutrient availability to immune cells. Competitive consumption of amino acids such as tryptophan and arginine further compromises immune cell function, promoting immune escape. Epigenetic modifications, including DNA methylation and histone modifications, are increasingly recognized as key contributors to immune evasion in TNBC. These mechanisms can silence genes involved in antigen presentation and immune activation while promoting the expression of immunosuppressive factors. Long non-coding RNAs (lncRNAs) have been identified as central regulators of immune evasion in TNBC, offering new therapeutic targets for intervention. Moreover, TNBC actively shapes its microenvironment to establish immunosuppression, including recruitment of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2-polarized macrophages, which collectively inhibit effector T cell function. Building on these mechanistic insights, this review also integrates findings from clinical trials evaluating next-generation immunotherapies, including bispecific antibodies targeting PD-1/CTLA-4, LAG-3 inhibitors, and CD47-SIRPα blockers, as well as potential biomarkers. These novel combination strategies aim to overcome resistance to single-agent checkpoint inhibitors, while research explores monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates (ADCs) within biomarker-driven personalized treatment frameworks. The ultimate goal is to improve survival and quality of life for TNBC patients through tailored immunotherapies.
在理解三阴性乳腺癌（TNBC）复杂的免疫逃逸机制方面已取得重大进展，为更有效的免疫疗法铺平了道路。本综述重点介绍了在阐明TNBC免疫逃逸分子基础方面的关键进展，包括异常的免疫检查点表达、代谢重编程、表观遗传调控、相关细胞成分的免疫逃逸以及新兴免疫疗法的临床试验。具体而言，免疫检查点抑制剂如PD-L1在TNBC细胞和肿瘤微环境（TME）中的过表达在抑制抗肿瘤免疫中起关键作用。其次，TNBC细胞通过代谢重编程逃避免疫监视。例如，上调的谷氨酰胺代谢支持肿瘤生长，并通过限制免疫细胞的营养供应将TME调节为免疫抑制状态。色氨酸和精氨酸等氨基酸的竞争性消耗进一步损害免疫细胞功能，促进免疫逃逸。表观遗传修饰，包括DNA甲基化和组蛋白修饰，越来越被认为是TNBC免疫逃逸的关键因素。这些机制可以使参与抗原呈递和免疫激活的基因沉默，同时促进免疫抑制因子的表达。长链非编码RNA（lncRNA）已被确定为TNBC免疫逃逸的核心调节因子，为干预提供了新的治疗靶点。此外，TNBC积极塑造其微环境以建立免疫抑制，包括招募调节性T细胞（Treg）、髓源性抑制细胞（MDSC）和M2极化巨噬细胞，它们共同抑制效应T细胞功能。基于这些机制性见解，本综述还整合了评估下一代免疫疗法的临床试验结果，包括靶向PD-1/CTLA-4的双特异性抗体、LAG-3抑制剂和CD47-SIRPα阻断剂，以及潜在的生物标志物。这些新颖的联合策略旨在克服对单药检查点抑制剂的耐药性，同时研究在生物标志物驱动的个性化治疗框架内探索单克隆抗体、双特异性抗体和抗体药物偶联物（ADC）。最终目标是通过量身定制的免疫疗法提高TNBC患者的生存率和生活质量。
