Immunotherapy for diffuse gastric cancer: challenges and new avenues

In recent years, several large clinical trials have demonstrated the survival benefits of immunotherapies, mainly immune checkpoint inhibitors (ICIs), in patients with gastric cancer (GC). However, not every GC patient responds equally to immunotherapy. Compared with patients with intestinal GC (IGC), patients with diffuse GC (DGC) are less likely to obtain a survival benefit from the currently approved ICIs. This histological determinant of immunotherapy efficacy in GC has attracted less attention, exposing some patients with DGC to unnecessary risks. Limited data suggest that the cold tumor immune microenvironment, which is shaped by histological and molecular characteristics, challenges the success of immunotherapy in patients with GC. Here, we review the possible mechanisms of resistance and propose new avenues to overcome resistance to immunotherapy in DGC.