Hippo pathway in cancer cells induces immunosuppressive NCAM1+aSMA+ fibroblasts

Tumor cells adeptly manipulate the tumor microenvironment (TME) to evade host anti-tumor immunity, but the role of tumor cell-intrinsic signaling in shaping the immunosuppressive aspects of the TME remains underexplored. Here, we reveal that the Hippo pathway within tumor cells orchestrates an immunosuppressive TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) prove pivotal in promoting the formation of immunosuppressive NCAM1+aSMA+ CAF expressing TGFb, contributing to T cell dysfunction. Depletion of LATS1/2 in tumor cells results in a less immunosuppressive TME, characterized by a reduced proportion of NCAM1+aSMA+ CAFs and fewer dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1+aSMA+ CAFs are identified in human breast cancer, offering insights with potential implications for cancer immunotherapies aiming to manipulate TME patterns associated with reduced immunosuppression.