肿瘤细胞治疗研究
英文原题：Exosomal lncRNAs as molecular switches driving macrophage-tumor co-evolution in breast cancer.
乳腺癌的进展日益被认为是一个由恶性细胞与肿瘤微环境（TME）之间相互交流所塑造的动态过程。
乳腺癌进展日益被认为是一个由恶性细胞与肿瘤微环境（TME）之间相互通讯所塑造的动态过程。在免疫细胞群体中，肿瘤相关巨噬细胞（TAMs）是免疫抑制、代谢适应、血管生成和治疗耐药的主要调控者。新出现的证据表明，细胞外囊泡（EV）介导的长链非编码RNA（lncRNA）转移构成了乳腺癌中肿瘤-免疫通讯的重要机制。在本综述中，我们总结了经过机制性表征的研究，这些研究探讨了外泌体lncRNA如何调控乳腺癌细胞与巨噬细胞之间的双向信号传导，并促进肿瘤进展、免疫重塑和耐药相关表型。肿瘤来源的外泌体lncRNA通过与信号转导和转录激活因子3（STAT3）、转化生长因子β（TGF-β）、Hippo/Yes相关蛋白（YAP）、缺氧响应信号以及自噬相关重塑相关的通路调节巨噬细胞信号传导，从而促进免疫调节性和肿瘤支持性巨噬细胞表型。相反，巨噬细胞来源的外泌体lncRNA，包括稳定缺氧诱导因子-1α（HIF-1α）的长链非编码RNA（HISLA），在受体肿瘤细胞中增强糖酵解适应、上皮-间质转化、表观遗传重塑、转移可塑性以及治疗耐药。外泌体lncRNA信号还影响γδ T细胞、内皮细胞和基质区室，支持TME内更广泛的多细胞调控。总体而言，当前证据支持外泌体lncRNA作为乳腺癌肿瘤-免疫适应中具有生物学重要性的介质。我们进一步讨论了循环外泌体lncRNA作为微创生物标志物的转化潜力，并评估了靶向EV生物发生、囊泡运输和致癌lncRNA货物分子的治疗策略。最后，我们强调了当前涉及EV异质性、lncRNA化学计量学和体内验证不完整等局限性，这些仍然是临床转化的关键障碍。
Breast cancer progression is increasingly recognized as a dynamic process shaped by reciprocal communication between malignant cells and the tumor microenvironment (TME). Among immune-cell populations, tumor-associated macrophages (TAMs) are major regulators of immune suppression, metabolic adaptation, angiogenesis, and therapeutic resistance. Emerging evidence indicates that extracellular vesicle (EV)-mediated transfer of long non-coding RNAs (lncRNAs) constitutes an important mechanism underlying tumor-immune communication in breast cancer. In this review, we summarize mechanistically characterized studies examining how exosomal lncRNAs regulate bidirectional signaling between breast cancer cells and macrophages and contribute to tumor progression, immune remodeling, and resistance-associated phenotypes. Tumor-derived exosomal lncRNAs modulate macrophage signaling through pathways associated with signal transducer and activator of transcription 3 (STAT3), transforming growth factor beta (TGF-β), Hippo/Yes-associated protein (YAP), hypoxia-responsive signaling, and autophagy-related remodeling, thereby promoting immunoregulatory and tumor-supportive macrophage phenotypes. Conversely, macrophage-derived exosomal lncRNAs, including hypoxia-inducible factor-1 alpha (HIF-1α)-stabilizing long non-coding RNA (HISLA), reinforce glycolytic adaptation, epithelial-mesenchymal transition, epigenetic remodeling, metastatic plasticity, and resistance to therapy in recipient tumor cells. Exosomal lncRNA signaling additionally influences γδ T cells, endothelial cells, and stromal compartments, supporting broader multicellular regulation within the TME. Collectively, current evidence supports exosomal lncRNAs as biologically important mediators of tumor-immune adaptation in breast cancer. We further discuss the translational potential of circulating exosomal lncRNAs as minimally invasive biomarkers and evaluate therapeutic strategies targeting EV biogenesis, vesicle trafficking, and oncogenic lncRNA cargo molecules. Finally, we highlight current limitations involving EV heterogeneity, lncRNA stoichiometry, and incomplete in vivo validation that remain critical barriers to clinical translation.
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