Thinyakul C.Sakamoto Y.Shimoda M.Liu Y.Thongchot S.Reda O.Nita A.Sakamula R.Sampattavanich S.Maeda A.Chunthaboon P.Nduru D.Niimura M.Kanamori Y.Thuwajit P.Nakayama K.I.Guan K.L.Satou Y.Thuwajit C.Moroishi T.Mahidol University2024-10-252024-10-252024-12-01Communications Biology Vol.7 No.1 (2024)https://repository.li.mahidol.ac.th/handle/20.500.14594/101753Cancer cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of cancer cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in cancer cells orchestrates the 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 neural cell adhesion molecule 1 (NCAM1)+alpha-smooth muscle actin (αSMA)+ CAFs expressing the transforming growth factor-β, which is associated with T cell inactivation and dysfunction. Depletion of LATS1/2 in cancer 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, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy. (Figure presented.)Biochemistry, Genetics and Molecular BiologyAgricultural and Biological SciencesMedicineArticleSCOPUS10.1038/s42003-024-07041-42-s2.0-8520662093023993642