TNF-α Deficiency Underlies NK Cell Dysfunction in Colorectal Cancer

We show that CRC patients exhibit early and pronounced alterations in peripheral blood NK cells, marked by a reduced frequency of total CD56⁺ cells, a shift toward CD56lowCD16⁺ subset, and impaired cytotoxic and cytokine responses. Notably, plasma from CRC patients, particularly those with advanced disease, induces similar dysfunction in healthy donor (HD) NK cells, suppressing mTORC1 signaling and effector activity.

Transcriptomic profiling of HD NK cells exposed to CRC plasma revealed downregulation of TNF-α signaling components, concordant with reduced systemic and intracellular TNF-α levels in patients. Additionally, CRC plasma suppressed the JAK-STAT pathway and upregulated SOCS family genes, further dampening NK cell responsiveness. Inhibition of TNF-α in HD NK cells recapitulated the CRC plasma–induced defects, while exogenous TNF-α partially restored NK cell function, including STAT5 and S6 phosphorylation.