Background: Microsatellite stable (MSS) colorectal cancer continues to have limited options for personalised therapeutic targets. The NFKB pathway is known to play an important role in inflammation-related carcinogenesis but has yet to be translated into therapies for the clinical patient. The aim of this study was to investigate the expression of cytoplasmic and punctate TAK1 (transforming growth factor β-activated protein kinase 1) in colorectal cancer and its relationship to immune checkpoint expression and prognosis. Methods: Patients undergoing primary colorectal cancer resection between 1997 and 2007 at Glasgow Royal Infirmary (UK) were studied for clinicopathological data and immunohistochemistry (IHC) performed on archival FFPE tissue from resected specimens. Antibodies for TAK1, PD-1, PD-L1, IKK alpha and other proteins were used for IHC, with digital analysis (QuPath) for quantification of cytoplasmic staining and punctate score for juxta-nuclear TAK1 assessment. Kaplan-Meier curves were created with log-rank test to determine survival. Cox-proportional hazards regression were used to determine multivariate hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 898 patients who underwent colorectal resection were identified. Higher TAK1 punctate expression was observed in left colon and rectal cancer, compared with right sided disease (p = 0.045). MMR proficient tumours had higher frequencies of high TAK1 punctate expression (p < 0.001). Both cytoplasmic and punctate TAK1 expression correlated with IKK expression (p < 0.050). High cytoplasmic TAK1 expression was associated with increased PD-1 and PD-L1 expression (p < 0.001). Punctate TAK1 expression was associated with worse survival (p = 0.037). These differences were accentuated in patients with MSS status (p = 0.016). On multivariate analysis, high punctate TAK1 expression remained a predictor of worse cancer-specific survival (HR 1.843, CI 1.129-2.956, p = 0.011). Conclusions: TAK1 expression was associated with MSI status, and higher TAK1 expression correlates with upregulated PD-1 and PD-L1 expression. High punctate TAK1 expression predicted cancer-specific survival. In subgroup analysis of MSS patients, high punctate TAK1 expression was associated with poor survival. Further interrogation into this pathway may identify inflammation-related therapeutic targets in MSS patients with colorectal cancer.