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Immune checkpoint inhibitors have substantial advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients remain challenging. In this study, we explored the immunomodulatory function of contactin-4 (CNTN4). CNTN4 was highly expressed in tumor tissues, and expression impaired the antitumor function of T cells. CNTN4 bound to amyloid precursor protein (APP) on T cells, which attenuated conjugation between cancer cells and T cells, and diminished T cell receptor signaling cascades. We developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) that blocked the binding between CNTN4 and APP. Administration of either GENA-104A16 or 5A7 promoted antitumor T cell responses in a syngeneic mouse model and increased tumor-infiltrating lymphocytes in vivo. Furthermore, elevated CNTN4 levels were associated with poor prognosis and negatively correlated with various cytotoxic immune-related markers. These results suggest that CNTN4-APP is an inhibitory checkpoint in T cells and represents a promising therapeutic strategy for cancer immunotherapy. Editor's summary: Contactin-4 (CNTN4) is an adhesion molecule known to engage amyloid precursor protein (APP) in the brain, but the function of this axis in T cells and antitumor immunity is not known. Jeon et al. explored the immunomodulatory role of CNTN4-APP, finding that CNTN4 expressed on tumor cells prevents T cell activation by engaging APP on T cells. They developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) and found that blocking the CNTN4-APP interaction promoted tumor killing. Expression of APP on T cells negatively correlated with response to immune checkpoint inhibitors in patients with cancer. These findings indicate that CNTN4-APP functions as an inhibitory checkpoint in T cells. —Hannah Isles [ABSTRACT FROM AUTHOR]