Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A_2A receptor (A_2AR) on trigeminal ganglia. Antagonism of trigeminal A_2AR with a selective A_2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A_2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A_2AR. Therefore, we established trigeminal A_2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.

口腔鳞状细胞癌（OSCC）相关的疼痛通常可以预测患者的不良事件。这一临床特征表明在恶性肿瘤的发展过程中，感觉神经元上存在伤害感受器。然而，目前尚不清楚靶向肿瘤代谢物相关的伤害感受过程是否可以阻碍 OSCC 的进展。在这项研究中，我们报道了渗透到临床样本和小鼠肿瘤异种移植物中的伤害性末梢与较差的临床结果相关，并推动体内肿瘤进展，临床组织微阵列分析和小鼠舌去神经术证明了这一点。我们观察到，由于 CD73 上调，OSCC 微环境具有腺苷过多的特征，这对 TCGA-HNSC 患者队列的临床结果产生负面预测。值得注意的是，这种腺苷集中的 OSCC 生态位与三叉神经节上腺苷 A _2A受体 (A _2A R) 的刺激有关。三叉神经 A _2A R 与选择性 A _2A R 抑制剂 SCH58261 的拮抗作用导致体内 OSCC 生长受阻。我们发现，OSCC 异种移植物中三叉神经 A _2A R 过度刺激不会导致三叉神经节中 CGRP 转录水平发生任何变化，但会显着触发 CGRP 的释放，这一效应被 SCH58261 抵消。我们通过给小鼠喂食临床批准的 CGRP 受体拮抗剂 rimegepant，抑制 ERK 和 YAP 的激活，进一步证明了 CGRP 的促肿瘤作用。最后，我们用伊曲茶碱（一种针对神经元 A _2A R 的临床可用药物）减少了 CGRP 对 OSCC 的影响。 因此，我们将三叉神经 A _2A R 介导的 CGRP 释放确定为 OSCC 治疗中一种有前景的药物回路。