Induction of potent immune responses toward tumors remains challenging in cancer immunotherapy, in which it only showed benefits in a minority of patients with “hot” tumors, which possess pre-existing effector immune cells within the tumor. In this study, we proposed a nanoparticle-based strategy to fire up the “cold” tumor by upregulating the components associated with T and NK cell recruitment and activation and suppressing TGF-β1 secretion by tumor cells. Specifically, LTX-315, a first-in-class oncolytic cationic peptide, and TGF-β1 siRNA were co-entrapped in a polymer-lipid hybrid nanoparticle comprising PLGA, DSPE-mPEG, and DSPE-PEG-conjugated with cRGD peptide (LTX/siR-NPs). The LTX/siR-NPs showed significant inhibition of TGF-β1 expression, induction of type I interferon release, and triggering immunogenic cell death (ICD) in treated tumor cells, indicated via the increased levels of danger molecules, an in vitro setting. The in vivo data showed that the LTX/siR-NPs could effectively protect the LTX-315 peptide from degradation in serum, which highly accumulated in tumor tissue. Consequently, the LTX/siR-NPs robustly suppressed TGF-β1 production by tumor cells and created an immunologically active tumor with high infiltration of antitumor effector immune cells. As a result, the combination of LTX/siR-NP treatment with NKG2A checkpoint inhibitor therapy remarkably increased numbers of CD8⁺NKG2D⁺ and NK1.1⁺NKG2D⁺ within tumor masses, and importantly, inhibited the tumor growth and prolonged survival rate of treated mice. Taken together, this study suggests the potential of the LTX/siR-NPs for inflaming the “cold” tumor for potentiating the efficacy of cancer immunotherapy.

中文翻译：

---

通过纳米颗粒共同递送溶瘤肽和 TGF-β1 siRNA 塑造“热”免疫原性肿瘤微环境，以增强检查点阻断治疗

在癌症免疫治疗中，诱导针对肿瘤的有效免疫反应仍然具有挑战性，其中它仅对少数患有“热”肿瘤的患者显示出益处，这些肿瘤在肿瘤内具有预先存在的效应免疫细胞。在这项研究中，我们提出了一种基于纳米颗粒的策略，通过上调与 T 细胞和 NK 细胞招募和激活相关的成分并抑制肿瘤细胞分泌 TGF-β1 来激发“冷”肿瘤。具体来说，LTX-315（一种一流的溶瘤阳离子肽）和 TGF-β1 siRNA 共同包埋在聚合物-脂质混合纳米颗粒中，该纳米颗粒包含 PLGA、DSPE-mPEG 和与 cRGD 肽缀合的 DSPE-PEG（LTX /siR-NPs）。LTX/siR-NPs 在治疗的肿瘤细胞中显示出对 TGF-β1 表达的显着抑制，诱导 I 型干扰素释放，并触发免疫原性细胞死亡 (ICD)，这通过体外环境中危险分子水平的增加表明。体内数据表明，LTX/siR-NPs可以有效保护LTX-315肽免于血清中的降解，而LTX-315肽在肿瘤组织中高度积累。因此，LTX/siR-NPs 强有力地抑制了肿瘤细胞产生 TGF-β1，并产生了具有高浸润抗肿瘤效应免疫细胞的免疫活性肿瘤。结果，LTX/siR-NP治疗与NKG2A检查点抑制剂治疗的组合显着增加了肿瘤块内CD8 ⁺ NKG2D ⁺和NK1.1 ⁺ NKG2D ⁺的数量，并且重要的是，抑制了肿瘤生长并延长了治疗者的生存率老鼠。总而言之，这项研究表明 LTX/siR-NP 具有使“冷”肿瘤发炎从而增强癌症免疫疗法功效的潜力。