长链非编码RNA（lncRNA）在正常组织和癌症中的基因调控中起着重要作用。通过开发gapmer反义寡核苷酸（ASOs），针对lncRNAs的治疗方法变得可行。转移相关肺腺癌转录物（Malat1）是一种丰富的lncRNA，其在多种癌症中表达上调。虽然Malat1增加了肿瘤细胞的迁移和侵袭能力，但其在肿瘤微环境（TME）中的作用尚不明确。我们使用多个免疫能力的原位移植Tp53-null三阴乳腺癌（TNBC）小鼠模型，模拟人类乳腺癌中的异质性和免疫抑制的TME，探讨了Malat1与肿瘤免疫微环境（TIME）之间的关联。使用Malat1 ASO，我们能够击倒Malat1 RNA表达，导致原发肿瘤生长延迟，增加凋亡并降低增殖。此外，肿瘤浸润淋巴细胞的免疫表型分析显示，Malat1抑制改变了TIME，减少了免疫抑制的肿瘤相关巨噬细胞（TAMs）和髓系抑制性细胞（MDSCs），并增加了细胞毒性CD8+ T细胞的数量。肿瘤细胞，TAMs和MDSCs中的Malat1消耗减少了免疫抑制的细胞因子/趋化因子的分泌，而T细胞中对Malat1的抑制增加了炎症分泌和T细胞增殖。Malat1 ASO与化疗或免疫检查点阻断（ICB）的联合使用改善了预临床模型的治疗反应。这些研究突出了Malat1抑制在TNBC中的免疫刺激效应，Malat1 ASO治疗的好处，以及其与化疗和免疫疗法联合应用的潜力。

Long non-coding RNAs (lncRNA) play an important role in gene regulation in both normal tissues and cancer. Targeting lncRNAs is a promising therapeutic approach that has become feasible through the development of gapmer antisense oligonucleotides (ASOs). Metastasis-associated lung adenocarcinoma transcript (Malat1) is an abundant lncRNA whose expression is upregulated in several cancers. While Malat1 increases the migratory and invasive properties of tumor cells, its role in the tumor microenvironment (TME) is still not well defined. We explored the connection between Malat1 and the tumor immune microenvironment (TIME) using several immune competent preclinical syngeneic Tp53-null triple-negative breast cancer (TNBC) mouse models that mimic the heterogeneity and immunosuppressive TME found in human breast cancer. Using a Malat1 ASO we were able to knockdown Malat1 RNA expression resulting in a delay in primary tumor growth, decreased proliferation and increased apoptosis. Additionally, immunophenotyping of tumor-infiltrating lymphocytes (TILs) revealed that Malat1 inhibition altered the TIME, with a decrease in immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) as well as an increase in cytotoxic CD8+ T cells. Malat1 depletion in tumor cells, TAMs, and MDSCs decreased immunosuppressive cytokine/chemokine secretion while Malat1 inhibition in T cells increased inflammatory secretions and T-cell proliferation. Combination of a Malat1 ASO with chemotherapy or immune checkpoint blockade (ICB) improved the treatment responses in a preclinical model. These studies highlight the immunostimulatory effects of Malat1 inhibition in TNBC, the benefit of a Malat1 ASO therapeutic, and its potential use in combination with chemotherapies and immunotherapies.