Epigenetic remodeling in sarcoma promotes T cell infiltration via modulation of the Hippo pathway (human)

Immunotherapy in osteosarcoma remains limited by insufficient T cell infiltration. Considering the importance of epigenetics in sarcomagenesis, the impact of histone modifications in shaping the immune microenvironment was investigated. Using patient-derived ex vivo spheroids and in vivo metastatic osteosarcoma models, we found that pharmacological elevation of H3K27ac by the histone deacetylase 1/3 inhibitor entinostat promotes CD8⁺ T-cell activation, cytotoxicity, and the recruitment of CD8+CD103⁺ tissue-resident memory (TRM) T cells. Mechanistically, these immune-boosting effects are triggered by a Hippo pathway switch, in which Yes-associated protein 1 (YAP1) is suppressed and vestigial-like family member 3 (VGLL3) is induced, thereby rewiring transcription. Furthermore, we identified that VGLL3/CD103 signatures predict a response to anti-PD-1 treatment in sarcoma patients, and that combining H3K27ac induction with anti-PD-1 further augments T cell-mediated killing in ex vivo autologous patient-derived spheroid models. Our findings reveal an epigenetic-Hippo-immunomodulatory axis in osteosarcoma that also extends to other sarcomas, providing a rationale for incorporating epigenetic preconditioning with immunotherapy to improve patient outcomes and pointing towards novel biomarkers for treatment guidance.