TNF-α deficiency underlies NK cell dysfunction in colorectal cancer

Natural killer (NK) cells are central to innate antitumor immunity, yet their function is systemically compromised in colorectal cancer (CRC). 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 the CD56^lowCD16⁺ subset, and impaired cytotoxic and cytokine responses. Notably, plasma from CRC patients, particularly those with advanced disease, induces similar dysfunctions in healthy donor (HD) NK cells, suppressing mTORC1 signalling and effector activity. Transcriptomic profiling of HD NK cells exposed to CRC plasma revealed downregulation of TNF-<i>α</i> signalling components, concordant with reduced systemic and intracellular TNF-<i>α</i> levels in patients. Additionally, CRC plasma suppressed the JAK-STAT pathway and upregulated SOCS family genes, further dampening NK cell responsiveness. Inhibition of TNF-<i>α</i> in HD NK cells recapitulated the CRC plasma-induced defects, while exogenous TNF-<i>α</i> partially restored NK cell function, including STAT5 and S6 phosphorylation. These findings uncover TNF-<i>α</i> signalling deficiency as a systemic mechanism of NK cell suppression in CRC, linking impaired metabolism to immune evasion. Targeting this axis may offer a novel strategy to reinvigorate NK cell-mediated antitumor immunity in CRC.