Spatial macrophage signatures and prognostic relevance of NFKB1 in colorectal cancer

BACKGROUNDTumor-associated macrophages (TAMs) exhibit substantial spatial and transcriptional heterogeneity in colorectal cancer (CRC).However, the prognostic relevance of spatial macrophage-associated transcriptional programs remains incompletely understood. AIMTo characterize spatial macrophage-associated transcriptional programs and evaluate the prognostic relevance of NFKB1 in CRC.stroma-enriched regions, whereas the activity of an M1-like macrophage-associated signature was higher at tumor-peripheral regions and in areas at tumor-normal interfaces.Higher M1-like scores were correlated with early tumor stage and better overall survival (OS).The assessed prognostic models showed moderate discrimination (the best mean cross-validated area under the curve was 0.650).NFKB1 was prioritized as a candidate gene associated with the M1-like signature.In selected external cohorts, higher NFKB1 expression was associated with improved OS and correlated with transcriptional features characteristic of immune-active states.Differences in predicted drug response values were observed between the NFKB1-high and NFKB1-low groups.CONCLUSION M1-and M2-like macrophage-associated transcriptional programs showed distinct spatial distributions in colorectal cancer.Higher M1-like signature activity was preferentially observed in tumor-peripheral regions and was associated with immuneactive features and more favorable survival.NFKB1 expression was also associated with the M1-like program and favorable outcomes in selected external cohorts.These findings support NFKB1 as a candidate bulk-transcriptomic biomarker.