肿瘤细胞治疗研究
英文原题：Claudin18.2 and the PD-1/PD-L1 axis in gastric cancer: mechanistic insights and implications for combination immunotherapy.
Claudin18.2 and the PD-1/PD-L1 axis in gastric cancer: mechanistic insights and implications for combination immunotherapy.
本综述提示，Claudin18.2在胃癌中可能作为免疫功能障碍的关键调节因子，而非免疫排斥因子，为将Claudin18.2靶向治疗与免疫检查点抑制相联合的组合策略提供了潜在的生物学依据。
引言：Claudin18.2是在胃癌细胞中选择性表达的高特异性治疗靶点。新兴证据提示，Claudin18.2阳性可能与免疫抑制性肿瘤微环境及对PD-1/PD-L1阻断应答不佳相关，但其潜在机制和治疗意义尚未充分阐明。 方法：本文为采用结构化检索的叙述性综述。通过检索PubMed、Embase、Web of Science、Cochrane Library和Scopus，确定截至2025年9月30日发表的相关研究。按照预设纳入和排除标准筛选探讨Claudin18.2表达、肿瘤免疫微环境特征、免疫检查点调控及胃癌免疫治疗结局之间关系的研究。 结果：Claudin18.2阳性胃癌具有独特的免疫抑制性微环境，表现为NK细胞浸润减少、巨噬细胞和中性粒细胞组成改变、细胞因子信号失调，以及CD8+和CD4+ T细胞浸润增加，但这些T细胞在肿瘤核心区存在功能受损或耗竭证据。从机制上看，Claudin18.2可通过PKC/ERK-MAPK通路上调PD-1，从而调节免疫检查点通路。靶向Claudin18.2的治疗也可能通过免疫活化和JAK/STAT信号通路间接调节PD-L1表达。值得注意的是，靶向Claudin18.2的抗体、CAR-T细胞、双特异性抗体和抗体药物偶联物（ADC）诱导的免疫活化，可能部分逆转免疫抑制并提高对PD-1/PD-L1抑制的敏感性，但直接证据仍有限。 结论：本综述提示，Claudin18.2可能是胃癌免疫功能障碍而非免疫排斥的关键调节因子，为将Claudin18.2靶向治疗与免疫检查点抑制联合提供了潜在生物学依据。鉴于现有研究存在异质性且部分证据为间接证据，应将这些认识视为探索性发现；尽管如此，它们仍可能有助于患者分层，并为Claudin18.2阳性胃癌未来联合免疫治疗试验的合理设计提供参考。
INTRODUCTION: Claudin18.2 is a highly specific therapeutic target selectively expressed in gastric cancer cells. Emerging evidence suggests that Claudin18.2 positivity may be associated with an immunosuppressive tumor microenvironment and suboptimal responses to PD-1/PD-L1 blockade. However, the underlying mechanisms and therapeutic implications remain incompletely understood. METHODS: This article is a narrative review with a structured search. Relevant studies published up to 30 September 2025 were identified through searches of PubMed, Embase, Web of Science, Cochrane Library, and Scopus. Predefined inclusion and exclusion criteria were applied to select studies that addressed the relationship among Claudin18.2 expression, tumor immune microenvironment characteristics, immune checkpoint regulation, and immunotherapy outcomes in gastric cancer. RESULTS: Claudin18.2-positive gastric cancer presents a distinct immunosuppressive microenvironment, characterized by reduced NK cell infiltration, altered macrophage and neutrophil composition, dysregulated cytokine signaling, and increased infiltration of CD8 + and CD4 + T cells with evidence of functional impairment or exhaustion within the tumor core. Mechanistically, Claudin18.2 modulates immune checkpoint pathways by upregulating PD-1 through the PKC/ERK-MAPK pathway. Claudin18.2-targeted therapy may also indirectly regulate PD-L1 expression through immune activation and the JAK/STAT signaling pathway. Importantly, immune activation induced by Claudin18.2-targeted antibodies, CAR-T cells, bispecific antibodies, and ADCs (Antibody-Drug Conjugates) may partially reverse immune suppression and enhance sensitivity to PD-1/PD-L1 inhibition, although direct evidence remains limited. CONCLUSION: This review suggests that Claudin18.2 may serve as a key regulator of immune dysfunction rather than immune exclusion in gastric cancer, providing a potential biological rationale for combinatorial strategies integrating Claudin18.2-targeted therapies with immune checkpoint inhibition. Given the heterogeneity of available studies and the indirect nature of some evidence, these insights should be interpreted as exploratory; they may nonetheless help guide patient stratification and inform the rational design of future combination immunotherapy trials in Claudin18.2-positive gastric cancer.
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