PURPOSE

This study aimed to decipher the intricate interplay between the immune landscape and CRC pathogenesis, elucidating how distinct immunophenotypes causally influence disease susceptibility and stratify patient outcomes.

METHODS

We obtained the immunocyte phenotypes and CRC data from their respective genome-wide association studies. The primary analysis used the inverse variance weighting (IVW) method. We also simultaneously employed MR-Egger, weighted mode, simple mode, and weighted median approaches to strengthen the findings. Consensus clustering stratified 619 TCGA CRC patients by immunome expression. Functional assays examined the tumor suppressor GPD1L.

RESULTS

The IVW MR analysis identified 17 immunocyte phenotypes positively potentially associated with increased CRC risk (P < 0.05, OR > 1), and 18 phenotypes negatively potentially associated with decreased CRC risk (P < 0.05, OR < 1). These associations were not confounded by heterogeneity or horizontal pleiotropy (P > 0.05). Reverse MR analysis further revealed 4 additional immunocyte phenotypes positively potentially associated with CRC (P < 0.05, OR > 1). Clustering resolved prognostic C1/C2 subtypes dependent on coordinated immunophenotypic programs. GPD1L knockdown promoted CRC cell proliferation.

CONCLUSIONS

Genetic interrogation delineated causal immunome-CRC relationships at single-cell resolution. Immune-stratified CRC subtyping stratified patient outcomes. GPD1L exhibited tumor-suppressive functions. Our findings establish an integrated immunogenomic framework elucidating CRC pathogenesis with implications for precision immunotherapies.