Immune, molecular and genetic profiles of gastric signet ring cell carcinoma: Recent progress and future challenges

Gastric signet ring cell carcinoma (GSRCC) is a special type of gastric cancer common in young women. Diffuse gastric cancer (DGC) begins with intramucosal lesions comprising differentiated GSRCC cells. Genetically, GSRCC and DGC are clonally identical, with their morphology influenced by extracellular Wnt signaling. Interestingly, Wnt activation facilitates the transition of indolent GSRCC cells into more invasive DGC cells, indicating the high plasticity of GSRCC cells. With respect to its cellular origin, GSRCC may originate from MUC5AC-/MUC6- pre-pit cells in the proliferative area of the gastric gland. Importantly, the tumor immune microenvironment (TIM) of GSRCC has unique characteristics. Compared with that of non-GSRCC, the TIM of GSRCC seems to be in a relatively "quiescent" state, and CD4⁺ and CD8⁺ T cells are difficult to activate. Moreover, compared with non-GSRCC patients, GSRCC patients have significantly greater Treg infiltration and significantly fewer CD8⁺ T effector cells. This immune "quiescent" state may explain the poor response to immunotherapy in patients with GSRCC. Notably, the depletion of CXCL13 derived from exhausted CD8⁺ T cells (CD8-Tex) and the absence of mature tertiary lymphoid structures are key reasons for the low response to immunotherapy in patients with GSRCC. Therefore, for patients with GSRCC, enhancing the ability of CD8-Tex cells to produce CXCL13 may be the key to improving the immune therapy response. In this review, we explore recent key findings on GSRCC, focusing on molecular mechanisms, immune regulation, and prospective research directions to improve clinical applications.