Abstract
Immunotherapy has become a promising treatment for various cancers, including colorectal cancer (CRC). Despite significant progress, identifying immune cell-specific therapeutic targets remains challenging, especially for CD4(+) T cells, whose activation influences both anti-tumor and pro-tumor immune responses. This study aims to identify potential immunotherapy targets for CRC by exploring the causal relationships between CD4(+) T cell activation-associated genes and CRC through Mendelian randomization (MR) and single-cell RNA sequencing (scRNA-seq). We used transcriptome-wide MR, summary-based MR (SMR), and colocalization analysis, along with validation through multi-omics approaches, to identify 28 dynamic CD4(+) T cell-related genes as therapeutic targets. Notably, PARP14 and ORMDL3 emerged as key targets, with strong associations to immune therapy resistance and CRC. This research highlights the critical role of CD4(+) T cell activation in CRC progression and identifies novel potential targets for immunotherapy.