In this review, we explore the underlying molecular biology of medullary thyroid carcinoma (MTC) and its interplay with the host immune system. MTC is consistently driven by a small number of specific pathogenic variants, beyond which few additional genetic events are required for tumorigenesis. This explains the exceedingly low tumour mutational burden seen in most MTC, in contrast to other cancers. However, because of the low tumour mutational burden (TMB), there is a correspondingly low level of tumour-associated neoantigens that are presented to the host immune system. This reduces tumour visibility and vigour of the anti-tumour immune response and suggests the efficacy of immunotherapy in MTC is likely to be poor, acknowledging this inference is largely based on the extrapolation of data from other tumour types. The dominance of specificRET(REarranged during Transfection) pathogenic variants in MTC tumorigenesis rationalizes the observed efficacy of the targeted RET-specific tyrosine kinase inhibitors (TKIs) in comparison to multi-kinase inhibitors (MKIs). Therapeutic durability of pathway inhibitors is an ongoing research focus. It may be limited by the selection pressure TKI treatment creates, promoting survival of resistant tumour cell clones that can escape pathway inhibition through binding-site mutations, activation of alternate pathways, and modulation of the cellular and cytokine milieu of the tumour microenvironment (TME).
本文综述探讨了甲状腺髓样癌（MTC）的分子生物学基础及其与宿主免疫系统的相互作用。MTC始终由少数特定致病性变异驱动，除这些变异外，肿瘤发生几乎不需要其他遗传事件。这解释了大多数MTC中肿瘤突变负荷极低的现象，与其他癌症形成鲜明对比。然而，由于肿瘤突变负荷（TMB）较低，呈现给宿主免疫系统的肿瘤相关新抗原水平也相应较低。这降低了肿瘤的可见性和抗肿瘤免疫反应的强度，并提示免疫疗法在MTC中的疗效可能较差——需要指出的是，这一推论主要基于对其他肿瘤类型数据的推断。特定RET（转染重排）致病性变异在MTC肿瘤发生中的主导地位，解释了靶向RET特异性酪氨酸激酶抑制剂（TKIs）相较于多激酶抑制剂（MKIs）的疗效优势。通路抑制剂的治疗持久性是当前研究重点，其疗效可能受TKI治疗产生的选择压力所限：这种压力会促进耐药肿瘤细胞克隆的存活，这些克隆可通过结合位点突变、替代通路激活以及调控肿瘤微环境（TME）的细胞与细胞因子环境来逃逸通路抑制。
肿瘤(癌症)患者之家