Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune modulation of the tumor microenvironment affect not only cancer progression but also pain signaling. For example, Schwann cells promote cancer cell proliferation, migration, and secretion of nociceptive mediators, whereas neutrophils are implicated in sex differences in pain in animal models of HNC. Emerging evidence supports the existence of a functional loop of cross-activation between the tumor microenvironment and peripheral nerves, mediated by a molecular exchange of bioactive contents (pronociceptive and protumorigenic) via paracrine and autocrine signaling. Brain-derived neurotrophic factor, tumor necrosis factor α, legumain, cathepsin S, and A disintegrin and metalloprotease 17 expressed in the HNC microenvironment have recently been shown to promote HNC pain, further highlighting the importance of proinflammatory cytokines, neurotrophic factors, and proteases in mediating HNC-associated pain. Pronociceptive mediators, together with nerve injury, cause nociceptor hypersensitivity. Oncogenic, pronociceptive mediators packaged in cancer cell–derived exosomes also induce nociception in mice. In addition to increased production of pronociceptive mediators, HNC is accompanied by a dampened endogenous antinociception system (e.g., downregulation of resolvins and µ-opioid receptor expression). Resolvin treatment or gene delivery of µ-opioid receptors provides pain relief in preclinical HNC models. Collectively, recent studies suggest that pain and HNC progression share converging mechanisms that can be targeted for cancer treatment and pain management.

头颈癌 (HNC) 每年影响全球超过 890,000 人，死亡率为 50%。除了生存率低外，HNC 疼痛还会影响患者的饮食和说话，严重降低生活质量。患者不同的疼痛表型（异常性疼痛、痛觉过敏和自发性疼痛）是由癌症之间的解剖学、组织病理学和分子差异共同造成的。较差的病理特征（例如神经周围侵犯、淋巴结转移）与疼痛加剧相关。使用同基因/免疫活性动物模型以及新的神经周围浸润小鼠模型，为 HNC 疼痛的病理生物学提供了新的见解。肿瘤微环境的神经胶质和免疫调节不仅影响癌症进展，还影响疼痛信号传导。例如，雪旺细胞促进癌细胞增殖、迁移和伤害性介质的分泌，而中性粒细胞则与 HNC 动物模型中疼痛的性别差异有关。新出现的证据支持肿瘤微环境和周围神经之间存在交叉激活的功能环，该环路是通过旁分泌和自分泌信号传导的生物活性内容物（促痛性和促肿瘤性）的分子交换介导的。HNC 微环境中表达的脑源性神经营养因子、肿瘤坏死因子 α、legumain、组织蛋白酶 S 和 A 解整合素和金属蛋白酶 17 最近被证明可促进 HNC 疼痛，进一步强调了促炎细胞因子、神经营养因子和蛋白酶在 HNC 中的重要性。介导 HNC 相关疼痛。伤害感受介质与神经损伤一起引起伤害感受器过敏。癌细胞衍生的外泌体中包装的致癌性伤害感受介质也会诱导小鼠伤害感受。除了促伤害感受介质的产生增加之外，HNC 还伴随着内源性抗伤害系统的减弱（例如消退素和μ-阿片受体表达的下调）。Resolvin 治疗或 µ-阿片受体基因传递可缓解临床前 HNC 模型的疼痛。总的来说，最近的研究表明疼痛和 HNC 进展具有共同的机制，可以作为癌症治疗和疼痛管理的目标。