Our study validated that only IL-12p70 and IL-7 levels demonstrated a strong causal relationship with colorectal cancer occurrence among 41 circulating cytokines used as instrumental variables, after accounting for sensitivity. While VEGF exhibited heterogeneity, its consistent p-value < 0.05 in both MR-Egger and weighted median method results led us to consider its causal relationship as well. However, for reliability, we excluded MCSF, IL-10 and IL-13 due to inconsistencies in sensitivity analysis results.
Our findings align with previous studies, offering more causative inference value. By utilizing MR, we accounted for confounding factors and reverse causation, evaluated assumptions, and examined the robustness and consistency of our results. Our research provides relevant evidence supporting the potential of IL-12p70, IL-7 and VEGF as cancer predictive biomarkers for subsequent research.
Our study partially overlaps with previous studies examining the correlation between circulating inflammatory factors and various cancer types[14]. Although our findings provide reliable evidence for developing immunotherapies targeting IL-12p70 and IL-7 in colorectal cancer, some limitations need addressing in future studies. First, we used colorectal cancer GWAS data primarily from one source, potentially limiting applicability to other races or populations. Second, the genetic variants employed as instrumental variables might not be optimal owing to factors such as gene-gene interactions or gene-environment interactions. Future studies should use a more diverse population and accurate instrumental variables to improve MR analysis's power and accuracy.
We reported two strongly correlated cytokines (IL-12p70 and IL-7) with colorectal cancer development and one factor with heterogeneity but still demonstrating causal relationships (VEGF). Additional validation is required to assess the potential of these cytokines as biomarkers for cancer prevention.
Continuing with our discussion, it is essential to highlight the clinical implications and potential applications of our findings. Understanding the causal relationships between specific circulating cytokines and colorectal cancer may help in devising targeted and personalized treatments, as well as early detection and prevention strategies[7, 15]. Liquid biopsies of circulating cytokines could offer a non-invasive alternative for cancer risk prediction, as opposed to conventional tissue biopsies[3].
Subsequent studies should concentrate on elucidating the precise molecular mechanisms and signaling pathways implicated in interactions between these cytokines and colorectal cancer development. Such insights could guide the development of innovative targeted therapies or augment the effectiveness of prevailing treatments, such as immunotherapies. Potential combination strategies involving existing VEGF-targeted drugs and new immunotherapies targeting IL-12p70 and IL-7 should also be explored[16–18].
Moreover, understanding the influence of circulating cytokines on colorectal cancer risk has broader implications for cancer research[7]. Identifying common biological pathways across different types of cancer can help develop therapies with broader applicability. Additionally, further examination of other circulating cytokines, apart from those included in our study, may unveil new and valuable relationships with various cancer types, paving the way for more therapeutic targets.
Lastly, it is crucial to ensure that future studies address the limitations such as sampling diverse populations and employing more accurate instrumental variables to enhance the power and accuracy of MR analysis. Expanding the scope of the research to other cancer types and studying the interplay between various cytokines, immune cells, and tumor microenvironment components can provide a comprehensive understanding required for the development of effective cancer interventions.
In conclusion, our MR analysis offers valuable insights into the causal relationships between specific circulating cytokines and colorectal cancer occurrence. The findings harbor considerable potential for developing innovative diagnostic, preventive, and therapeutic strategies, as well as guiding subsequent research examining the intricate associations between the immune system and cancer development across diverse cancer types.