Hippo pathway in cancer cells modulates tumor microenvironment by inducing immunosuppressive NCAM1+αSMA+ fibroblasts

Abstract Tumor cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of tumor cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in tumor cells orchestrated the immunosuppressive TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases, large tumor suppressor 1 and 2 (LATS1/2), promoted the formation of immunosuppressive neural cell adhesion molecule 1 (NCAM1)+alpha-smooth muscle actin (αSMA)+ CAFs expressing the transforming growth factor-β, thereby contributing to T cell dysfunction. Depletion of LATS1/2 in tumor cells resulted in a less immunosuppressive TME, indicated by the reduced proportions of NCAM1+αSMA+ CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1+αSMA+ CAFs were observed in human breast cancer cells, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy.