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Introduction {#S1} ============ There are four NOTCH receptors (NOTCH1--4) in mammals, which are ubiquitously expressed. Activation of the NOTCH signaling occurs after engagement of a NOTCH receptor with one of its membrane bound Delta-like ligands 1,3,4 (DLL1, DLL3, DLL4) or Jagged ligands 1,2. In some contexts, NOTCH can become activated through ligand-independent mechanism(s) leading to a variety of human diseases ([@B1]). After ligand engagement NOTCH undergoes a series of proteolytic cleavages, resulting in an activated NOTCH intracellular domain (NICD), which translocates into the nucleus to activate gene transcription. Given that NOTCH signaling is critical in regulating cell fate decisions in many tissue types, it is not surprising that NOTCH activity is deregulated in several malignancies ([@B2]--[@B4]). The first evidence for the involvement of NOTCH signaling in cancer was discovered in T-cell acute lymphoblastic leukemia (T-ALL), where activating mutations were identified in NOTCH1 ([@B5]). Our laboratory showed that oncogenic NOTCH1 regulates MYC expression and leukemia-initiating cell activity and demonstrated the efficacy of NOTCH1 inhibitors in pre-clinical T-ALL models ([@B6]--[@B9]). Activating mutations in *NOTCH1* have also been identified in chronic lymphocytic leukemia, non-small cell lung carcinoma, and translocations involving NOTCH1/2 in patients with triple negative breast cancer ([@B10]--[@B13]). While mutations in NOTCH receptors are rare in other tumor types, NOTCH is aberrantly activated in several malignancies, including colorectal and pancreatic cancer, melanoma, adenocystic carcinoma, and medulloblastoma through a variety of mechanisms ([@B2], [@B4]). Conversely, loss of function mutations in *NOTCH1/2/3* have also been identified suggesting NOTCH can also function as a tumor suppressor ([@B2], [@B3]). While progress has been made in how NOTCH signaling contributes to malignant transformation, the role of NOTCH activity in anti-tumor immune responses is less clear. While several cell types contribute to anti-tumor responses, CD4 T-helper 1 (TH1) cells and CD8 cytotoxic T-lymphocytes (CTL), are critical in mediating anti-tumor immunity due to their ability to recognize tumor antigens and mediate tumor killing. Several studies have shown that NOTCH is required for activation and effector function of CD4 and CD8 T-cells ([@B14]). Tumor cells can dampen T-cell responses by producing immunosuppressive cytokines, expressing inhibitory ligands, and recruiting immunosuppressive myeloid and lymphoid cells into the tumor microenvironment ([@B15]). Given that NOTCH is required for T-cell activation and effector function it is reasonable to hypothesize that NOTCH contributes to T-cell anti-tumor responses and that tumor cells may evade T-cell mediated killing by suppressing NOTCH activation. Consistent with this hypothesis, new data suggest that NOTCH activation is suppressed in tumor-infiltrating T-cells and that NOTCH re-activation induces potent anti-tumor T-cell responses in mouse cancer models ([@B16]--[@B20]). Adoptive transplants of tumor antigen-specific T-cells is one immunotherapy used to overcome the limitations of endogenous T-cells and enhance anti-tumor responses. Tumor antigen-specific T-cells are either isolated from the tumor site or engineered with synthetic T-cell receptors (sTCRs) or chimeric antigen receptors (CARs) specific for tumor antigens ([@B21], [@B22]). Recently, NOTCH signaling has been utilized to improve the generation and efficacy of adoptive T-cell therapies (ACT) ([@B23], [@B24]). Furthermore, newly developed synthetic NOTCH receptors (synNOTCH) have been