TNFα-driven epigenetic upregulation of TIGIT creates a targetable vulnerability in tumors.

T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a key inhibitory receptor on cytotoxic lymphocytes, yet the mechanisms governing its context-dependent upregulation in tumors remain poorly defined. Here, we identify tumor necrosis factor-α (TNFα) signaling as an upstream driver of TIGIT expression. Integrated analyses of patient transcriptomic datasets revealed a consistent positive association between TNFα pathway activity and TIGIT expression across multiple cancer types, with strong concordance in melanoma and prognostic relevance in kidney renal clear cell carcinoma. Mechanistically, TNFα directly induced TIGIT expression in natural killer cells via TNFR2 signaling, increasing chromatin accessibility at distal TIGIT enhancers and promoting NF-κB and AP-1 recruitment together with BRD4 and P300. Functionally, combined anti-TNFα and anti-TIGIT treatment suppressed tumor growth and prolonged survival more effectively than either monotherapy in murine melanoma and colon cancer models. These findings define a TNFα-TNFR2-enhancer axis controlling TIGIT expression and provide a mechanistic rationale for dual TNFα and TIGIT targeting in inflamed tumors.