食管鳞癌免疫微环境异质性及免疫治疗联合策略

doi:10.3969/j.issn.1006-5725.2026.06.006

摘要/Abstract

摘要：

食管鳞癌（ESCC）是全球范围内发病与死亡率较高的恶性肿瘤，其免疫微环境（tumor immune microenvironment， TIME）具有高度异质性，是导致免疫检查点抑制剂（immune checkpoint inhibitors， ICIs）疗效差异及耐药的核心原因。该文从空间分布、时间动态、细胞组成、功能状态及分子表达等多个层面系统解析了ESCC TIME的多维异质性；针对异质性机制，重点探讨了联合治疗新策略的创新性与实用性，通过免疫联合化疗、放疗、抗血管生成治疗，以及靶向Tregs、巨噬细胞等重塑TIME，逆转免疫抑制，并将“冷肿瘤”转化为“热肿瘤”；此外还强调了基于生物标志物的个体化治疗策略在克服异质性和提升疗效中的关键作用。本文为理解ESCC免疫微环境的复杂性提供了新视角，并为临床实践中制定精准联合免疫治疗方案提供了理论依据与方向。

关键词: 食管癌, 鳞状细胞癌, 免疫微环境异质性, 免疫治疗, 免疫检查点抑制剂, 耐药

Abstract:

Esophageal squamous cell carcinoma （ESCC） is a malignant tumor with high global incidence and mortality. Its tumor immune microenvironment （TIME） is highly heterogeneous， which is a core reason for the varied efficacy and resistance to immune checkpoint inhibitors （ICIs）. This article systematically analyzes the multi-dimensional heterogeneity of the ESCC TIME across several aspects： spatial distribution， temporal dynamics， cellular composition， functional states， and molecular expression. To address the mechanisms of this heterogeneity， we focus on innovative and practical combination strategies. These include combining immunotherapy with chemotherapy， radiotherapy， anti-angiogenic therapy， and novel approaches targeting Tregs， macrophages. These strategies can reshape the TIME， reverse immunosuppression， and convert "cold" tumors into "hot" tumors. Additionally， we emphasize the critical role of biomarker-based individualized treatment strategies in overcoming heterogeneity and improving therapeutic outcomes. This review offers a novel perspective for understanding the complexity of the ESCC immune microenvironment. It also provides a theoretical foundation and direction for developing precise combination immunotherapy regimens in clinical practice.

Key words: esophagus cancer, squamous-cell carcinoma, tumor immune microenvironment heterogeneity, immunotherapy, immune checkpoint inhibitors, resistance

中图分类号:

R735

张瓅方,张晖,李凯,卞华. 食管鳞癌免疫微环境异质性及免疫治疗联合策略[J]. 实用医学杂志, 2026, 42(6): 944-951.

Lifang ZHANG,Hui ZHANG,Kai LI,Hua BIAN. Heterogeneity of the immune microenvironment in esophageal squamous cell carcinoma and combination immunotherapy strategies[J]. The Journal of Practical Medicine, 2026, 42(6): 944-951.

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肿瘤区域	主要免疫细胞类型	特征性分子表达	免疫功能状态
侵袭前沿	CAFs，SPP1?巨噬细胞， Tregs	JAG1，NOTCH1，TGF-β，VEGFA	免疫抑制（“冷”微环境）
肿瘤核心	耗竭CD8? T细胞，TAMs	PD-1，TIM-3，LAG-3，IL-10	T细胞功能障碍
TLS	B细胞，Tfh，DCs	CXCL13，CD21，CD23	免疫激活（“热”微环境）

响应类型	治疗前标志	治疗后变化	机制
应答者	CD8?Tex-CXCL13细胞富集	终末耗竭T细胞分化；M1-TAMs↑、成熟DCs↑；微环境类型：“炎症型”；	免疫激活通路增强（如IFN-γ信号）
非应答者	LRRC15?CAFs、SPP1?巨噬细胞富集^[18]	Tregs↑、MDSCs↑；持续免疫抑制；	LRRC15?CAFs分泌IL-6、 TGF-β；SPP1?巨噬细胞通过VEGFA促血管生成和T细胞排斥