HER2 (human epidermal growth factor receptor 2) is a receptor tyrosine kinase which is overexpressed in ~20% of patients with oesophagogastric adenocarcinoma (EGA). HER2 represents a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, which plays a crucial role in cell proliferation, survival, and differentiation. HER2 significantly influences the tumour microenvironment (TME) through various mechanisms, creating a niche that supports tumour progression, immune evasion, and therapeutic resistance. In HER2-positive EGA, aberrant signalling pathways, such as PI3K/AKT and MAPK/ERK, enhance tumour cell survival and proliferation, whilst upregulation of angiogenic factors like VEGF fosters vascularization, meeting a tumour’s metabolic demands and facilitating its proliferation. HER2 also modulates the tumour immune microenvironment (TIME) by downregulating MHC molecules and recruiting immunosuppressive cells, including regulatory T-cells (T-reg) and tumour-associated macrophages (TAMs), which release cytokines that further inhibit anti-tumour immune responses. Together, these factors foster a pro-inflammatory, immunosuppressive microenvironment that underpins resistance to HER2-targeted therapies. As more HER2-directed treatments become available, such as trastuzumab–deruxtecan (T-DXd), gaining a deeper understanding of the multifaceted influence of HER2 on the TME in EGA will be crucial for the development of improved targeted treatments that can overcome these challenges and lead to advancements in targeted treatment for HER2-overexpressing EGA. This review provides a comprehensive overview of the impact of HER2 on the TME in EGA and highlights the challenge it represents as well as the opportunity for novel therapeutic development and the implications for patients in terms of clinicopathological outcomes.
HER2（人表皮生长因子受体2）是一种受体酪氨酸激酶，在约20%的食管胃腺癌（EGA）患者中存在过表达。作为表皮生长因子受体（EGFR）家族中可靶向的跨膜糖蛋白受体，HER2在细胞增殖、存活和分化过程中发挥关键作用。HER2通过多种机制显著影响肿瘤微环境（TME），形成支持肿瘤进展、免疫逃逸和治疗抵抗的生态位。在HER2阳性EGA中，异常的PI3K/AKT和MAPK/ERK等信号通路增强了肿瘤细胞的存活与增殖，同时血管内皮生长因子（VEGF）等促血管生成因子上调促进了血管生成，满足肿瘤代谢需求并加速其增殖。HER2还通过下调MHC分子表达、招募调节性T细胞（T-reg）和肿瘤相关巨噬细胞（TAMs）等免疫抑制细胞来调控肿瘤免疫微环境（TIME），这些细胞释放的细胞因子进一步抑制抗肿瘤免疫应答。这些因素共同促成了促炎性、免疫抑制的微环境，构成了HER2靶向治疗耐药的基础。随着曲妥珠单抗-德鲁替康（T-DXd）等更多HER2靶向疗法的出现，深入理解HER2对EGA肿瘤微环境的多维度影响，对于开发能够克服这些挑战的新型靶向治疗、推动HER2过表达EGA的精准治疗进展至关重要。本综述全面阐述了HER2对EGA肿瘤微环境的影响，既揭示了其带来的治疗挑战，也指出了新疗法开发的机遇，并探讨了其对患者临床病理结局的潜在意义。
肿瘤(癌症)患者之家