Gastroesophageal cancer (GEC) is a heterogeneous disease that encompasses adenocarcinoma of the stomach, esophagus, and gastroesophageal junction, as well as squamous cell carcinoma of the esophagus (Smyth et al., 2017, 2020). Although many breakthroughs have been made in the prevention, diagnosis, and treatment of cancer in the past few decades, GEC still ranks top 10 cancer types for estimated cases and deaths worldwide in 2020 and has become a significant health burden in the world (Sung et al., 2021). Due to its insufficient signs and symptoms, most GEC patients were diagnosed at an advanced stage where curative treatment is challenging or impossible (Jones and Smyth, 2020). Although the survival time of GEC patients can be improved by surgery and chemotherapy, the prognosis of GEC is still poor, with 5-year overall survival (OS) rates ranging from 30% to 40% (Ma et al., 2022). Globally, there is no standardized approach, and treatment varies with geographic location (Ku, 2017). The question remains of how to select the optimal perioperative treatment that will maximize the benefit for patients while avoiding toxicities from unnecessary therapies. Therefore, new treatment protocols must be developed. With the advance of molecular biology, more and more new targeted therapies are being used for GEC treatments. Among them, human epidermal growth factor receptor-2(HER-2) targeted therapy and immunotherapy were considered as a potential treatment strategy against tumors due to its high repression for tumor cells and fewer side effects for patients.

As a proto-oncogene, amplification or overexpression of HER-2 is frequently observed in a variety of epithelial tumors including breast cancer, gastroesophageal cancer, esophageal cancer, colorectal cancer, and lung cancer et al. (Ahn et al., 2022; Kuo et al., 2022; Mimura et al., 2005; Morrison et al., 2006; Rossi et al., 2009), and is associated with more rapid malignant tumor progression, worse biological behavior, worse prognosis, and more frequent drug resistance (Fanotto et al., 2016; Oh and Bang, 2020). In GEC, the incidence of HER-2 positive occurs in 7–38% of patients, and some critical therapeutic targets in HER-2 positive GEC has been firmly established (Bartley et al., 2016). One of the most successful milestones is the Trastuzumab for Gastric Cancer study (TOGA) study, in which the combination of trastuzumab and conventional chemotherapy regimen improved the median OS of HER2 positive GEC patients by 2.7 months over the initial chemotherapy alone regimen(13.8 months VS 11.1 months), which makes trastuzumab plus chemotherapy the current standard of care for HER-2 positive GEC (Bang et al., 2010) However, this still does not benefit well all patients, so finding new treatment options that furtherly improve the prognosis of these patients becomes the next primary research direction.

Initial studies of immune checkpoint inhibitors in biomarker unselected GEC yielded limited improvement in survival. However, emerging data from recent clinical trials suggest immunotherapies may offer a meaningful clinical benefit within selected populations (Booth and Smyth, 2022; Dubois et al., 2022). Recently, an increasing number of studies have found that HER-2-positive tumors have a particular tumor microenvironment (TME), implying the feasibility of immunotherapy in HER-2-positive malignancies (Kim et al., 2017). Based on that, some clinical research results of HER-2 targeted therapy combined with immune checkpoint inhibitors in HER-2 positive cancer have shown perceptible efficacy and acceptable side effects. In a real-world retrospective cohort study of HER-2 mutant lung adenocarcinoma, immune checkpoint inhibitors combined with targeted therapy.

In this review, we describe the special TME of HER-2 positive GEC relevant to immunotherapy, the role of immunotherapy combined with HER-2 targeted therapy in this disease setting, and discuss the prognostic biomarkers as well as challenges and prospects.