Human epidermal growth factor receptor 2 (HER-2), a famous therapeutic target for breast cancer, is also associated with an increased risk of recurrence and poor outcomes of other malignancies, including gastric cancer. Yet the mechanism of HER-2 therapy resistance remains controversial due to the heterogeneity of gastric adenocarcinoma. We know, Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 3 (PLOD3), a key gene coding enzymes that catalyze the lysyl hydroxylation of extracellular matrix collagen, plays an important contributor to HER-2 targeting agent Trastuzumab resistance in gastric cancer. Herein, we analyzed clinical samples of gastric cancer patients and gastric cancer cell lines and identified PLOD3, unveiled that depletion of PLOD3 leads to decreased cell proliferation, tumor growth and Trastuzumab sensitivity in these Trastuzumab resistant GC cell lines. Clinically, increased PLOD3 expression correlates with decreased Trastuzumab therapy responsiveness in GC patients. Mechanistically, we show that PLOD3 represses tumor suppressor FoxO3 expression, therefore upregulating Survivin protein expression that contributes to Trastuzumab resistance in GC. Therefore, our study identifies a new signaling axis PLOD3-FoxO3- Survivin pathway that may be therapeutically targeted in HER-2 positive gastric cancer.

Brain metastasis, most commonly originating from lung cancer, increases cancer morbidity and mortality. Although metastatic colonization is the rate‐limiting and most complex step of the metastatic cascade, the underlying mechanisms are poorly understood. Here, in vivo genome‐wide CRISPR‐Cas9 screening revealed that loss of interferon‐induced transmembrane protein 1 (IFITM1) promotes brain colonization of human lung cancer cells. Incipient brain metastatic cancer cells with high expression of IFITM1 secrete microglia‐activating complement component 3 and enhance the cytolytic activity of CD8+ T cells by increasing the expression and membrane localization of major histocompatibility complex class I. After activation, microglia (of the innate immune system) and cytotoxic CD8+ T lymphocytes (of the adaptive immune system) were found to jointly eliminate cancer cells by releasing interferon‐gamma and inducing phagocytosis and T‐cell‐mediated killing. In human cancer clinical trials, immune checkpoint blockade therapy response was significantly correlated with IFITM1 expression, and IFITM1 enhanced the brain metastasis suppression efficacy of PD‐1 blockade in mice. Our results exemplify a novel mechanism through which metastatic cancer cells overcome the innate and adaptive immune responses to colonize the brain, and suggest that a combination therapy increasing IFITM1 expression in metastatic cells with PD‐1 blockade may be a promising strategy to reduce metastasis.