A unifying feature of many cancers is the well-established causal link with chronic inflammation, which has implicated host immune regulators as candidate genetic factors that can influence disease susceptibility. In this respect, targeting the immune system in cancer thus far has primarily focused on immunotherapies that boost anti-tumor adaptive immunity. However, for numerous cancers, such immunotherapy trials have yielded modest patient outcomes with variable response rates. In contrast, there is a paucity of studies on targeting innate immunity. This is surprising since dysregulated innate immunity is a hallmark of many inflammation-associated cancers, including gastric and pancreatic, and often promotes disease pathogenesis. In this respect, toll-like receptors (TLRs), have recently emerged as key pro-tumorigenic effectors of innate immunity, which can elicit both direct intrinsic effects on cancer cells (e.g. cell proliferation, survival, migration, invasion, metastasis), and indirect effects on stromal cells within the tumor microenvironment (e.g. inflammation, immunosuppression, angiogenesis). Among TLRs, we will present data that TLR2 plays a key driver role in upperGI (i.e. gastric, pancreatic) cancers, and thus serves as a potential new therapeutic target for immune-based therapy in these cancers.