Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a family of paired receptors that interact with ligands of the Nectin/Nectin-like (Necl) family has attracted great interest. Two of these ligands, Necl-5 (usually termed CD155 or PVR) and Nectin-2 (CD112), frequently expressed on different types of tumor cells, are recognized by a group of receptors expressed on T and NK cells that exert opposite functions after interacting with their ligands. These receptors include DNAM-1 (CD226), TIGIT, TACTILE (CD96) and the recently described PVRIG. Whereas activation through DNAM-1 after recognition of CD155 or CD112 enhances NK cell-mediated cytotoxicity against a wide range of tumor cells, TIGIT recognition of these ligands exerts an inhibitory effect on NK cells by diminishing IFN-γ production, as well as NK cell-mediated cytotoxicity. PVRIG has also been identified as an inhibitory receptor that recognizes CD112 but not CD155. However, little is known about the role of TACTILE as modulator of immune responses in humans. TACTILE control of tumor growth and metastases has been reported in murine models, and it has been suggested that it negatively regulates the anti-tumor functions mediated by DNAM-1. In NK cells from patients with solid cancer and leukemia, it has been observed a decreased expression of DNAM-1 that may shift the balance in favor to the inhibitory receptors TIGIT or PVRIG, further contributing to the diminished NK cell-mediated cytotoxic capacity observed in these patients. Analysis of DNAM-1, TIGIT, TACTILE and PVRIG on human NK cells from solid cancer or leukemia patients will clarify the role of these receptors in cancer surveillance. Overall, it can be speculated that in cancer patients the TIGIT/PVRIG pathways are upregulated and represent novel targets for checkpoint blockade immunotherapy.

CAR-T cell therapy has revolutionized cancer treatment. However, despite the achievements of this approach, there are still clinical challenges to address, such as antigen loss and the design of an optimal CAR structure. Multi-targeted CAR-T therapies, including tandem CAR-T cells, have emerged as a strategy to overcome some of these limitations and improve outcomes. Tandem CAR-T cells are currently being evaluated in preclinical and clinical studies for the treatment of hematological malignancies and solid tumors, showing promising results. These CARs have demonstrated efficacy, safety, and a relatively low relapse rate in these studies. Research suggests that TanCAR-T cells can enhance the outcomes and benefits of CAR-T cell therapy. However, challenges such as identifying the ideal CAR construct, selecting appropriate targets, and improving transduction efficiency remain unresolved, and further research is essential to address these limitations. This review highlights the potential of tandem CAR-T cells as a cancer treatment, summarizing preclinical and clinical studies with this innovative therapy and emphasizing the importance of continued research to overcome its limitations and improve its effectiveness.