负性费城染色体（Ph-）的骨髓增生性肿瘤（MPN）包括血小板增多性血管瘤（ET）、红细胞增多性血管瘤（PV）和骨髓纤维化（MF），这些疾病属于持久而广为人知的病症。这些疾病的特点是体内造血干细胞中一个或多个造血细胞系列的异常增长，导致器官肿大和全身症状的表现。大量研究证据表明，这些疾病的发病机制涉及免疫系统失调和慢性炎症存在，这两个因素都非常重要。最近，癌症治疗，包括血液系统恶性肿瘤的治疗，在指向免疫系统、细胞因子环境、免疫疗法剂和靶向免疫治疗剂等方面取得了进展。免疫检查点是调节肿瘤微环境中T细胞功能的分子。第一线的主要免疫检查点是程序性细胞死亡-1（PD-1）/程序性细胞死亡配体-1（PD-L1）和细胞毒性T淋巴细胞抗原-4（CTLA-4）。免疫检查点抑制剂疗法（ICIT）通过阻断T细胞的抑制途径发挥其抗肿瘤作用，对癌症治疗产生了革命性的影响。尽管ICIT取得了令人印象深刻的临床成功，但肿瘤内部抵抗对肿瘤学家提出了挑战，导致固体肿瘤和血液系统恶性肿瘤的低反应率。进行了一项针对具有后期血栓性血小板增多症骨髓纤维化、原发性骨髓纤维化或后期红细胞增多症骨髓纤维化患者的尼伐珠单抗的II期试验（标识符：NCT02421354）。该试验检测了一种名为尼伐珠单抗的PD-1阻断剂的疗效，但由于不良事件和疗效缺乏而提前终止。进行了一项多中心、II期、单臂开放标签研究，包括彭布罗单抗治疗先天性血栓性血小板增多症、后期血栓性血小板增多症或后期红细胞增多症骨髓纤维化患者，这些患者不适合或以前接受了鲁索利替尼治疗。该研究表明，彭布罗单抗治疗不会引起许多不良事件，但没有相关的临床反应，因此在完成第一阶段后被终止。为了利用免疫疗法的益处，免疫检查点的范式已经转向肿瘤微环境中的新免疫检查点，如淋巴细胞激活基因-3（LAG-3）、T细胞免疫球蛋白和黏液结构域3（TIM-3）、T细胞免疫球蛋白和ITIM结构域（TIGIT）、含有V域的免疫球蛋白抑制T细胞激活（VISTA）和人类内源性逆转录病毒-H长末端重复关联蛋白2（HHLA2），这些形成了下一代ICIT的基础。本文的主要目的在于强调并阐明下一代ICIT在MPN背景下的意义。具体而言，我们旨在探索单克隆抗体作为靶向免疫疗法以及开发针对特定MPN表位的疫苗的潜力，以增强与肿瘤相关的免疫反应。预计这些以免疫疗法为基础的治疗方式将不仅扩大还增强MPN患者现有的治疗方案。我们实验室的初步研究显示，在MDSC中存在过度表达的中性粒细胞分化相关蛋白和过度表达的VISTA，在祖细胞和免疫细胞中指明需要进行更多使用下一代ICI治疗MPN的临床试验。

The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body's stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.