Tumor-Promoting vs. Protective Immune Phenotypes in Stage III Colorectal Cancer: A Mendelian Randomization Study on Chemotherapy Outcomes

Background Colorectal cancer (CRC) prognosis remains challenging despite advancements in chemotherapy, necessitating reliable prognostic biomarkers. Plasma immune cells play two different roles in the advancement of tumors, but their causal relationship with post-chemotherapy CRC outcomes is poorly understood. This research utilized Mendelian randomization (MR) to examine the causal relationships between plasma immune cell levels and the prognosis of stage III CRC following oxaliplatin-based chemotherapy and to investigate the fundamental genetic mechanisms. Methods Using genome-wide association study (GWAS) data from 3,757 Europeans, 731 plasma immune cell traits were analyzed as exposures. Outcomes included overall survival (OS) and progression-free survival (PFS) of 3,647 stage III CRC patients from the NCCTG N0147 trial and DACHS cohort. Inverse variance-weighted (IVW), MR-Egger, constrained maximum likelihood (cML-MA), and Bayesian MR analyses were conducted. Sensitivity tests (Cochran’s Q, Steiger directionality) validated this robustness. Multi-marker Analysis of GenoMic Annotation (MAGMA) and Summary-data-based Mendelian Randomization (SMR) identified candidate genes using cis-eQTL data. Results MR analyses identified six immune phenotypes with stable causal associations: three tumor-promoting traits (elevated HLA-DR on CD33⁻ HLA-DR⁺ cells [OS: HR = 2.57, P = 0.0038; PFS: HR = 2.52, P = 0.0021], CD28⁻ CD4⁻CD8⁻ T cell count [OS: HR = 3.11, P = 0.0073; PFS: HR = 3.17, P = 0.0031], and SSC-A on CD14⁺ monocytes [OS: HR = 2.64, P = 0.036; PFS: HR = 3.17, P = 0.0064]) and three protective traits (CD14 on CD33⁺ HLA-DR⁺ CD14dim cells [OS: HR = 0.35, P = 0.0118; PFS: HR = 0.33, P = 0.0034], FSC-A on NK cells [OS: HR = 0.22, P = 0.0046; PFS: HR = 0.29, P = 0.0234], and CD28⁺ CD45RA⁺ CD8⁺ T cell count [OS: HR = 0.30, P = 0.0325; PFS: HR = 0.34, P = 0.0331]). Genetic analyses revealed associations with LEMD2 (OS: p SMR = 0.0367), MPVL17L2 (PFS: p SMR = 0.0314), and BAK1 (PFS: p SMR = 0.0232), highlighting their roles in CRC prognosis. Conclusion This MR study identifies plasma immune cell subsets and genetic regulators as critical determinants of CRC prognosis post-chemotherapy. Tumor-promoting and protective immune phenotypes reflect the complexity of CRC’s immune microenvironment. The novel roles of LEMD2, MPVL17L2, and BAK1 provide mechanistic insights for targeted therapies. These findings advance personalized immunotherapy strategies and underscore the potential of immune biomarkers in clinical decision-making.