Abstract
The inhibitor of DNA binding protein ID3 has been associated with the progression of colorectal cancer (CRC). Despite its significance, its specific role in the immune evasion strategies utilized by CRC remains unclear. RNA-seq analysis revealed that ID3 was positively associated with the PD-L1 immune checkpoint. We further demonstrated that tumor cell-expressed ID3 enhanced PD-L1 expression, suppressed the infiltration and activation of CD8(+) T cells, and facilitated the immune evasion of CRC cells. Additionally, we found that knockdown of ID3 significantly enhanced the effectiveness of PD-L1 antibody blockade treatment in combating CRC, reduced the upregulation of PD-L1 induced by the antibody, and altered the immune microenvironment within CRC. Mechanistically, ID3 interacted with the transcription factor MYC and reconstructed the four-dimensional structure of MYC, thereby enhancing its binding affinity to the PD-L1 promoter and augmenting PD-L1 transcriptional activity. By integrating analysis of ChIP-seq, RNA-seq, and ImmPort gene sets, we found that ID3's DNA-assisted binding function was widespread and could either enhance or suppress gene transcription, not only affecting tumor immune escape through immune checkpoints but also regulating various cytokines and immune cells involved in tumor immunity. In conclusion, our study uncovers a mechanism by which ID3 promotes immune evasion in CRC and implicates that targeting ID3 may improve the efficacy of anti-PD-1/PD-L1 immunotherapy.