Helicobacter pylori (H. pylori) infection has a complex relationship with immunotherapy for gastrointestinal (GI) cancers. In gastric cancer (GC), H. pylori-positive patients showed improved immune-related progression-free survival (irPFS) and immune-related overall survival (irOS) compared to H. pylori-negative patients, suggesting that H. pylori infection may create a "hot" tumor microenvironment (TME) favorable for immunotherapy. This was associated with higher densities of PD-L1-positive cells and non-exhausted CD8+ T cells in the TME. Transcriptomic analysis revealed that H. pylori-positive GC shared molecular characteristics with immunotherapy-sensitive GC. However, in DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC), H. pylori infection was linked to shorter irPFS and irOS, indicating a negative impact on immunotherapy. The study also found that H. pylori infection had a negative effect on immunotherapy in liver and pancreatic cancers. These findings highlight the importance of H. pylori testing in cancer patients undergoing immunotherapy, as its presence can influence treatment outcomes depending on the cancer type. The study underscores the need for further research to understand the mechanisms by which H. pylori affects immunotherapy responses, particularly in dMMR/MSI-H cancers. Overall, H. pylori infection appears to be a beneficial factor for immunotherapy in GC but may be detrimental in certain GI cancers.Helicobacter pylori (H. pylori) infection has a complex relationship with immunotherapy for gastrointestinal (GI) cancers. In gastric cancer (GC), H. pylori-positive patients showed improved immune-related progression-free survival (irPFS) and immune-related overall survival (irOS) compared to H. pylori-negative patients, suggesting that H. pylori infection may create a "hot" tumor microenvironment (TME) favorable for immunotherapy. This was associated with higher densities of PD-L1-positive cells and non-exhausted CD8+ T cells in the TME. Transcriptomic analysis revealed that H. pylori-positive GC shared molecular characteristics with immunotherapy-sensitive GC. However, in DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC), H. pylori infection was linked to shorter irPFS and irOS, indicating a negative impact on immunotherapy. The study also found that H. pylori infection had a negative effect on immunotherapy in liver and pancreatic cancers. These findings highlight the importance of H. pylori testing in cancer patients undergoing immunotherapy, as its presence can influence treatment outcomes depending on the cancer type. The study underscores the need for further research to understand the mechanisms by which H. pylori affects immunotherapy responses, particularly in dMMR/MSI-H cancers. Overall, H. pylori infection appears to be a beneficial factor for immunotherapy in GC but may be detrimental in certain GI cancers.