肾上腺肿瘤微环境：激素免疫串扰、分子异质性和免疫治疗机会

摘要(中文译文)

肾上腺肿瘤涵盖从功能性腺瘤到具有转移潜能的侵袭性肾上腺皮质癌（ACC）及嗜铬细胞瘤/副神经节瘤（PHEO/PPGL）的异质性谱系。尽管传统上通过激素过多和致癌改变来解读这些肿瘤，现有证据表明它们是内分泌塑造的免疫生态系统，其中激素分泌、分子亚型、基质结构、代谢应激和免疫浸润相互作用，共同决定肿瘤行为和治疗易感性。在不同亚型中呈现出不同的免疫-基质状态：醛固酮 producing 腺瘤（APA）含有M2极化巨噬细胞、特化内皮亚群和代谢异质性；皮质醇 producing 腺瘤（CPA）以局部糖皮质激素驱动的免疫抑制及巨噬细胞和T细胞状态改变为特征；ACC相对免疫耗竭，受糖皮质激素信号、缺氧、衰老和髓系抑制塑造；PHEO/PPGL则表现出与儿茶酚胺生物学和假性缺氧相关的亚型依赖性血管生成和免疫特征。最强的人类证据支持CPA中皮质醇相关的免疫重塑、APA中富含巨噬细胞的微环境以及ACC中的免疫生态型，而CAF介导的免疫排斥、离子通道驱动的免疫调节及若干基于代谢物的机制在很大程度上仍属推断性。临床上，免疫检查点阻断显示出有限且异质性的活性，尤其在ACC中，PD-L1和肿瘤突变负荷未能一致预测应答，而部分PPGL亚群可能在生物学上更具容许性。这些发现支持一种模型，即肾上腺肿瘤不仅应按组织学和激素过多分类，还应按内分泌-免疫微环境状态分类，这对生物标志物开发和合理的联合治疗具有重要意义。

Abstract

Adrenal tumors comprise a heterogeneous spectrum ranging from functional adenomas to aggressive adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PHEO/PPGL) with metastatic potential. Although traditionally interpreted through hormone excess and oncogenic alterations, current evidence indicates that these tumors are endocrine-shaped immune ecosystems in which hormone secretion, molecular subtype, stromal architecture, metabolic stress, and immune infiltration interact to determine tumor behavior and therapeutic vulnerability. Across subtypes, distinct immune-stromal states emerge: aldosterone-producing adenoma (APA) contains M2-polarized macrophages, specialized endothelial subsets, and metabolic heterogeneity; cortisol-producing adenoma (CPA) is characterized by local glucocorticoid-driven immunosuppression and altered macrophage and T-cell states; ACC is relatively immune-depleted and shaped by glucocorticoid signaling, hypoxia, senescence, and myeloid suppression; and PHEO/PPGL exhibits subtype-dependent angiogenic and immune features linked to catecholamine biology and pseudohypoxia. The strongest human evidence supports cortisol-associated immune remodeling in CPA, macrophage-rich niches in APA, and immune ecotypes in ACC, whereas CAF-mediated immune exclusion, ion-channel-driven immune regulation, and several metabolite-based mechanisms remain largely extrapolative. Clinically, immune checkpoint blockade has shown modest and heterogeneous activity, especially in ACC, where PD-L1 and tumor mutational burden have not consistently predicted response, while selected PPGL subsets may be biologically more permissive. These findings support a model in which adrenal tumors should be classified not only by histology and hormone excess, but also by endocrine-immune microenvironmental states, with implications for biomarker development and rational combination therapies.

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