Over the past decade, immunotherapy has led to major improvements in clinical oncology; however, resistance to therapy remains an obstacle. In this study, we interrogated the role of clusterin (CLU) in mechanisms of tumor resistance to therapies. Two main forms of CLU, nuclear (nCLU) and secreted (sCLU), are found ubiquitously expressed in tissues and body fluids, and overexpressed in aggressive cancers, such as colon and lung cancer. Functionally, sCLU has been shown to upregulate mesenchymal cell features in the context of TGF-beta signaling and mediate tumor resistance to apoptosis. Here, we evaluated sotevtamab, a clinical stage, humanized monoclonal anti-sCLU antibody, for its ability to improve immune-mediated anti-tumor activity. Our data demonstrate that pre-treatment of human colon and lung cancer cell lines with AB-16B5 increases their susceptibility to lysis mediated by natural killer (NK) cells and NK cells activated with the superagonist IL-15, nogapendekin-alfa inbakicept (NAI). The murine surrogate agent mAB-16B5 was evaluated in vivo against MC38 tumors, demonstrating enhanced anti-tumor activity when used in combination with immune checkpoint blockade (ICB). Currently, the mechanisms by which AB-16B5 increases immune-mediated tumor control are being investigated. These data provide rationale for further preclinical and potential clinical studies investigating blockade of sCLU to increase the outcome of immune-based therapies against advanced tumors.