Our data and prior literature suggest that the tumor microenvironment might play a role, e.g., cytokine signaling (IL-6/STAT3) might be more pronounced in obesity-associated cardia cancers, whereas chronic H. pylori infection and associated epigenetic changes (like GATA2 silencing) could facilitate the GATA6/CDX2 program in distal cancers [14,52]. Here, STAT3 is linked to obesity due to melanocortin 4 receptor deficiency.