Targeting c-Myc-p300-CARM1 complex induces ferroptosis and reduces CD8(+) T cell exhaustion in esophageal squamous cell carcinoma.

Amplification and high expression of the c-Myc gene promote the proliferation and metastasis of cancer, contributing to treatment resistance and poor prognosis. In this study, we analyzed whole genome sequencing data from 663 pairs of esophageal squamous cell carcinoma (ESCC) tumors and matched adjacent noncancerous esophagus tissues. The analysis revealed that c-Myc had an amplification rate of 16.4%, and its high expression was significantly associated with tumor metastasis, chemotherapy resistance, and poor prognosis of the patients. Drugs that can inhibit the oncogenic function of c-Myc currently have limited effects. Therefore, we screened for inhibitors that can sensitize c-Myc inhibitors. We found that SGC2085, a CARM1 inhibitor, enhanced the efficacy of MYCi975, a c-Myc inhibitor. This combination disrupts the transcriptional c-Myc-p300-CARM1 (CPC) complex by R371 with R372 in c-Myc and E75 with Y153 in CARM1. Additionally, the combination promotes the accumulation of arachidonic acid, which in turn induces ferroptosis. Furthermore, the combination of SGC2085 and MYCi975 significantly increased B cells, CD8(+)T cells infiltration and decreased the level of CD8(+) T cell exhaustion, neutrophils, and MDSC. These findings revealed that SGC2085 and MYCi975 could disrupt the transcriptional complex CPC, affect metabolic pathways, and reprogram the immune microenvironment. This study provides a potential therapeutic strategy for ESCC patients.