肿瘤细胞治疗研究
英文原题：Reprogramming the immune microenvironment in triple-negative breast cancer with mRNA therapeutics.
三阴性乳腺癌（TNBC）是一种侵袭性强且异质性高的亚型，其特征为雌激素受体、孕激素受体和 HER2 表达缺失。
三阴性乳腺癌（TNBC）是一种侵袭性且异质性较高的亚型，其特征为缺乏雌激素受体、孕激素受体和HER2表达。由于缺乏可操作靶点，TNBC患者常较早发生转移、复发率高，且对传统疗法应答有限。尽管免疫检查点抑制剂可使部分患者获益，但总体疗效受到免疫排斥、抗原异质性和高度免疫抑制性肿瘤微环境的限制。基于mRNA的免疫疗法正成为个体化癌症治疗中一种灵活且具有变革潜力的方法，旨在针对肿瘤特异性抗原诱导持久抗肿瘤免疫。其合成、瞬时且不整合入基因组的特性，使治疗开发能够快速、安全并根据患者个体定制。在TNBC中，mRNA平台主要用于三类策略：（1）编码肿瘤相关抗原的个体化疫苗，如MAGE-A3、NY-ESO-1或源自TP53和BRCA突变的新抗原；（2）针对ROR1、Trop-2、Claudin 6和Nectin-4等靶点的mRNA工程化免疫细胞（CAR-T或TCR-T）；（3）编码免疫调节剂的mRNA，递送细胞因子（如IL-12、GM-CSF）或共刺激配体（如OX40L、4-1BBL），以重塑肿瘤微环境。纳米递送系统在这些进展中发挥了核心作用，可保护mRNA载荷、增强细胞摄取，并实现肿瘤或淋巴组织特异性靶向。目前正在优化新一代纳米颗粒，以提高组织特异性、维持mRNA完整性并尽量降低脱靶毒性。本综述聚焦依赖于整合精准抗原靶向、免疫细胞工程化及先进递送技术的TNBC治疗未来进展。总体而言，mRNA免疫疗法有望克服当前治疗障碍，并为TNBC带来更有效、个体化的治疗策略。
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Owing to the absence of actionable targets, TNBC patients frequently develop early metastases, experience high rates of recurrence, and show limited responsiveness to conventional therapies. Although immune checkpoint inhibitors provide clinical benefit in a subset of cases, their overall efficacy is inhibited by immune exclusion, antigenic heterogeneity, and a highly immunosuppressive tumor microenvironment. mRNA-based immunotherapies are emerging as a versatile and transformative approach in personalized cancer treatment, designed to elicit durable antitumor immunity against tumor-specific antigens. Their synthetic, transient, and non-integrating nature enables rapid, safe, and patient-tailored therapeutic developments. In TNBC, mRNA platforms are being deployed across three principal strategies: (1) personalized vaccines encoding tumor-associated antigens such as MAGE-A3, NY-ESO-1, or neoantigens derived from TP53 and BRCA mutations; (2) mRNA-engineered immune cells (CAR-T or TCR-T) directed against targets including ROR1, Trop-2, Claudin 6, and Nectin-4; and (3) mRNA-encoded immunomodulators that deliver cytokines (e.g., IL-12, GM-CSF) or costimulatory ligands (e.g., OX40L, 4-1BBL) to reprogram the tumor microenvironment. Nano delivery systems have been central to these advances, protecting mRNA cargo, enhancing cellular uptake, and enabling tumor- or lymphoid-specific targeting. Next-generation nanoparticles are now being optimized to improve tissue specificity, sustain message integrity, and minimize off-target toxicity. This review focuses on future progress in TNBC therapy that relies on integrating precision antigen targeting, immune cell engineering, and advanced delivery technologies. Together, mRNA-based immunotherapies hold immense promise to overcome current therapeutic barriers and pave the way for more effective, personalized treatment strategies in TNBC.
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