Background/Aims Genomic instability is characterized by multiple features and is regarded as an important predictor of chemotherapy and immunotherapy responses in cancer treatment. However, most studies on gastric cancers have only focused on a single aspect of genomic instability. Genomic instability-associated lncRNAs have been reported to exert a profound impact on multiple cancers, but research on their effects on gastric cancers is insufficient. The role of UBQLN4, as a newly emerging protein representing the genomic stability state, in GC is still obscure. The aim of our study was to identify a genomic instability-associated lncRNA signature to help predict the survival and chemotherapy response of GCs and assess whether UBQLN4 expression variation can be used for a similar function. Further in-depth study based on multiplexed immunohistochemical staining also helped reveal the immune landscape change based on the variations reflected by both the lncRNA signature and UBQLN4 expression. Methods RNA sequencing and somatic mutation variation (SNV) data from patients with gastric cancer obtained from TCGA datasets were used to explore genomic instability-associated lncRNAs. First, SNV data from all the patients was rearranged in order of decreasing number of cumulative somatic mutations. The top one-quarter of patients were defined as the genomically stable group, while the bottom one-quarter were defined as the genomically unstable group. Differentially expressed lncRNAs with a threshold of |log2 FC | > 1 and P-value < 0.05 between the two groups were defined as genomic instability-associated lncRNAs. Lasso and Cox regression analysis of the selected lncRNAs was performed to establish a genomic instability-associated lncRNA signature. Analysis of immune-associated and chemotherapy responses was further conducted to determine the predictive value of the lncRNA signature. A tissue microarray composed of tissues from 147 patients with gastric from Zhongshan Hospital was used to conduct IHC for UBQLN4. Clinical characteristics were also analysed based the level of UBQLN4 expression levels. Twenty patients were selected based on the UBQLN4 expression level, including 10 patients with low expression and 10 patients with high expression, and then multiplexed immunohistochemical staining was conducted to explore the immune landscape variations. Results The genomic instability-associated lncRNAs included 53 upregulated and 144 downregulated lncRNAs. Hierarchical cluster analyses of the 197 differentially expressed lncRNAs were performed to separate GC patients into two groups, namely, the genomically unstable (GU)-like group (N=318) and the genomically stable (GS)-like group (N=57). The TCGA GC patients were randomly divided into a training cohort (N=169) and a testing cohort (N=168). Univariate Cox proportional hazard regression analysis of the 197 genomic instability-related lncRNAs was conducted to identify lncRNAs with prognostic value in the training cohort. Of all 197 genomic instability-related lncRNAs, 7 lncRNAs were discovered to be prognosis-related (P < 0.05). Multivariate Cox proportional hazards regression analysis of the 7 candidate lncRNAs was further performed, and 6 lncRNAs with independent prognostic value, namely, LINC02678, HOXA10-AS, RHOXF1-AS1, AC010789.1, LINC01150 and TGFB2-AS1, were identified. Based on the established signatures, further comparisons between different risk score groups were performed to assess drug sensitivity and immune landscape variations. IHC staining of a TMA comprising tissues from 147 GC patients also confirmed that UBQLN4 is a protective factor for GCs, especially for patients receiving adjuvant chemotherapy. A distinct immune spectrum was also revealed by multiplexed immunohistochemical staining. Conclusions In the present study, a genomic instability-associated lncRNA signature that can help predict the survival and chemotherapy response of G