The complex entanglement of Hippo-Yap/Taz signaling in tumor immunity

The Hippo-Yap/Taz pathway, originally identified as a central developmental regulator of organ size, has been found perturbed in many types of human tumors, and linked to tumor growth, survival, evasion, metastasis, stemness, and drug resistance. Beside these tumor-cell-intrinsic functions, Hippo signaling also plays important immune-regulatory roles. In this review, we will summarize and discuss recent breakthroughs in our understanding of how various components of the Hippo-Yap/Taz pathway influence the tumor immune microenvironment, including their effects on the tumor secretome and immune infiltrates, their roles in regulating crosstalk between tumor cells and T cells, and finally their intrinsic functions in various types of innate and adaptive immune cells. While further research is needed to integrate and reconcile existing findings and to discern the overall effects of Hippo signaling on tumor immunity, it is clear that Hippo signaling functions as a key bridge connecting tumor cells with both the adaptive and innate immune systems. Thus, all future therapeutic development against the Hippo-Yap/Taz pathway should take into account their multi-faceted roles in regulating tumor immunity in addition to their growth-regulatory functions. Given that immune therapies have become the mainstay of cancer treatment, it is also important to pursue how to manipulate Hippo signaling to boost response or overcome resistance to existing immune therapies.