Hippo pathway in cancer immunity: tumor microenvironment remodeling, immune evasion, and therapeutic targeting

Abstract The Hippo pathway is an evolutionarily conserved signaling network that controls organ size, tissue homeostasis, regeneration, and tumorigenesis. Dysregulated Hippo signaling, particularly aberrant activation of YAP1 and TAZ, not only promotes tumor cell proliferation, stemness, metastasis, and treatment resistance, but has also emerged as a central regulator of anti-tumor immunity, shaping immune evasion and immunotherapy response across the tumor microenvironment. In cancer cells, the YAP1/TAZ-TEADs axis promotes immune evasion by inducing immune checkpoint expression, suppressing antigen presentation, regulating cytokine and chemokine secretion, and recruiting immunosuppressive populations. In parallel, Hippo pathway components exert distinct effects on controlling the development, survival, differentiation, metabolism, and effector activity of different immune cells. More recently, dysregulated Hippo components in stromal cells, particularly cancer-associated fibroblasts and endothelial cells, has been implicated in immunotherapy resistance, adding a third layer of regulation to the tumor microenvironment. These cancer cell-intrinsic, immune cell-intrinsic and stromal mechanisms jointly influence key steps of the cancer-immunity cycle. Importantly, the immunological effects of Hippo pathway are highly context-dependent and vary according to tumor type, cellular compartment, mechanical cues, inflammatory signals, and therapeutic pressure. Therapeutically, emerging TEAD inhibitors, YAP1/TAZ-targeting approaches, and indirect Hippo modulators provide potential strategies to enhance cancer immunotherapy. However, whether their immune-mediated benefits are independent of direct tumor cell-intrinsic suppression remains to be clarified in future studies. In this review, we summarize how the Hippo pathway regulates tumor immunity across cancer cells, immune cells, and stromal cells, integrate these mechanisms into the cancer-immunity cycle, and discuss strategies for targeting Hippo pathway to improve immunotherapy response.