Abstract
The clinical successes in immunotherapy have been staggering but remain partially unsatisfactory. Small molecules may play an important role individually or in combination with antibiotics in this field. Therefore, the aim of this work is to identify small molecules that potentiate antitumor immunity. A natural product library was screened by using a macrophage M2-like polarization model. A series of bisindoles (CX-1-5) exhibited inhibitory effects on macrophage M2-like polarization. CX-1 inhibits histone acetylation by targeting the histone acetyltransferase domain of the P300/CBP proteins. In vivo studies demonstrated that CX-1 effectively induces a phenotypic switch in tumor-associated macrophages (TAMs) from an anti-inflammatory to an inflammatory type, thereby enhancing cytotoxic CD8(+) T cell recruitment and functionality within the tumor microenvironment. Furthermore, CX-1 displays a synergistic effect when combined with anti-PD1 therapy by prolonging the survival of tumor-bearing mice. Collectively, our work introduces P300/CBP inhibition by CX-1 or similar pharmacological agents as a new potential strategy to reactivate TAMs.