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TNF-α Deficiency Underlies NK Cell Dysfunction in Colorectal Cancer

ABSTRACT: 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 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. These findings uncover TNF-α signaling 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305244 | GEO | 2026/03/04

REPOSITORIES: GEO

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Project description:Background: T cell-based immunotherapies including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells can induce durable responses in cancer patients. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of Natural Killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their Major Histocompatibility Complex class I (MHC I) expression due to acquired resistance mechanisms. However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy. Method: In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compound on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated utilizing compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types. Results: The screening approach led to the identification of a Cbl-b inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with TIGIT blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells. Conclusion: These findings underscore the relevance of Cbl-b inhibition in overcoming NK cells dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for cancer patients.

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TNF-α Deficiency Underlies NK Cell Dysfunction in Colorectal Cancer

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