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

Abstract

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. The immune system naturally attacks cancer, but tumors often escape this defense by turning on or exploiting “brakes” on immune cells, known as immune checkpoints. TIGIT is one such checkpoint protein. Although drugs that block TIGIT have shown promising effects in laboratory studies and animal models, they have not yet provided consistent benefit for patients in clinical trials. Our study investigated the specific mechanisms responsible for elevated TIGIT expression on immune cells within the tumor microenvironment. By analyzing patient tumor datasets and performing experiments with human immune cells and mouse tumor models, we found that the inflammatory molecule TNFα, which is often elevated in tumors, directly increases TIGIT expression by changing how the TIGIT gene is regulated. In mouse models, blocking both TNFα and TIGIT suppressed tumor growth more effectively than either treatment alone. These findings suggest that combined targeting of TNFα and TIGIT may improve the effectiveness of cancer immunotherapy, especially for patients with highly inflamed tumors. These findings suggest that combined targeting of TNFα and TIGIT may improve, especially for patients with highly inflamed tumors.