Optimizing Adoptive Cell Therapy for Solid Tumors via Epigenetic Regulation of T-cell Destiny

Abstract

Adoptive cell therapy (ACT) emerged as a promising approach for cancer treatment, yet its application in solid tumors faced challenges such as inadequate tumor infiltration and cellular dysfunction. Histone acetylation is reported to play a crucial role in restoring T-cell function within tumor tissues. Building upon previous research, a novel strategy involving the co-loading of two drugs, G3C12 and vorinostat (SAHA), into PLGA microspheres to form G3C12+SAHA@PLGA is developed for intratumoral injection. The G3C12 peptide enhances adoptive T-cell recruitment to the tumor site by modulating the binding state of IFN-γ. While SAHA, a histone deacetylase inhibitor, promotes memory phenotypes of infiltrating T-cells and prevents their transition to an exhausted state. This synergistic approach effectively augmentes the efficacy of ACT in the “cold” tumor model (4T1) or the “hot” tumor model (CT26). These findings highlight the potential of combining epigenetic regulation with recruitment signaling as a means to enhance the therapeutic impact of ACT in treating solid tumors.