Dong Minh Phuong, Dharmaraj Neeraja, Kaminagakura Estela, Xue Jianfei, Leach David G, Hartgerink Jeffrey D, Zhang Michael, Hanks Hana-Joy, Ye Yi, Aouizerat Bradley E, Vining Kyle, Thomas Carissa M, Dovat Sinisa, Young Simon, Viet Chi T
Department of Oral and Maxillofacial Surgery, School of Dentistry, Loma Linda University, Loma Linda, CA 92350, USA.
Katz Department of Oral Maxillofacial Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
Biomedicines. 2024 Apr 21;12(4):920. doi: 10.3390/biomedicines12040920.
Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism has been investigated as an anti-cancer strategy. We have developed STINGel, an extended-release formulation that prolongs the availability of STING agonists, which has demonstrated an enhanced anti-tumor effect in OSCC compared to STING agonist injection. This study investigates the impact of intra-tumoral STINGel on OSCC-induced pain using two separate OSCC models and nociceptive behavioral assays. Intra-tumoral STINGel significantly reduced mechanical allodynia in the orofacial cancer model and alleviated thermal and mechanical hyperalgesia in the hind paw model. To determine the cellular signaling cascade contributing to the antinociceptive effect, we performed an in-depth analysis of immune cell populations via single-cell RNA-seq. We demonstrated an increase in M1-like macrophages and N1-like neutrophils after STINGel treatment. The identified regulatory pathways controlled immune response activation, myeloid cell differentiation, and cytoplasmic translation. Functional pathway analysis demonstrated the suppression of translation at neuron synapses and the negative regulation of neuron projection development in M2-like macrophages after STINGel treatment. Importantly, STINGel treatment upregulated TGF-β pathway signaling between various cell populations and peripheral nervous system (PNS) macrophages and enhanced TGF-β signaling within the PNS itself. Overall, this study sheds light on the mechanisms underlying STINGel-mediated antinociception and anti-tumorigenic impact.
口腔鳞状细胞癌（OSCC）由于其生存率低以及原发癌部位剧痛而带来了重大的治疗挑战。癌痛使人衰弱，导致生活质量下降，并引起阿片类药物耐受性。干扰素基因刺激物（STING）激动作用已作为一种抗癌策略进行了研究。我们开发了STINGel，一种延长释放制剂，可延长STING激动剂的可用性，与注射STING激动剂相比，它在OSCC中已显示出增强的抗肿瘤作用。本研究使用两种独立的OSCC模型和伤害感受行为测定法，研究肿瘤内注射STINGel对OSCC引起的疼痛的影响。肿瘤内注射STINGel可显著降低口腔面部癌症模型中的机械性异常性疼痛，并减轻后爪模型中的热痛觉过敏和机械性痛觉过敏。为了确定促成抗伤害感受作用的细胞信号级联反应，我们通过单细胞RNA测序对免疫细胞群体进行了深入分析。我们证明了STINGel治疗后M1样巨噬细胞和N1样中性粒细胞增加。所确定的调控途径控制免疫反应激活、髓样细胞分化和细胞质翻译。功能途径分析表明，STINGel治疗后M2样巨噬细胞中神经元突触处的翻译受到抑制以及神经元投射发育的负调控。重要的是，STINGel治疗上调了各种细胞群体与外周神经系统（PNS）巨噬细胞之间的TGF-β途径信号传导，并增强了PNS自身内的TGF-β信号传导。总体而言，本研究揭示了STINGel介导的抗伤害感受和抗肿瘤作用的潜在机制。
