Traditional cancer treatments often fail to eradicate solid tumors such as ovarian cancer, resulting in tumor relapse and metastasis. The immunosuppressive tumor microenvironment (TME) plays a key role in tumor recurrence, as resident immune cells become hypofunctional and lose their cancer surveillance abilities. Targeted drug delivery mediated by human immune cells offers a promising method of efficiently delivering small molecule drugs to the tumor site. We propose using the human natural killer cell line, NK92, engineered with chimeric antigen receptors (CAR-NK92), to deliver the immunomodulator SCH-58261 to the ovarian tumor site to combat the immunosuppressive TME. CARs are artificial receptors which allow the NK92 cells to recognize and attack cells expressing the desired antigen; in this case, we will target mesothelin, which is overexpressed on many ovarian cancers. SCH-58261 will be encapsulated in crosslinked multilamellar liposomal vesicles (cMLVs) which can be covalently attached to the NK92 cell surface via thiol-maleimide interactions. We hypothesize that CAR-NK92 cells will accumulate at mesothelin-overexpressing ovarian tumors, carrying their immunomodulatory drug payload, which will be released from the cMLVs in a controlled manner. Irradiated NK92 cells are an offthe-shelf therapy and have been extensively used in preclinical and clinical cancer studies to date. Thus far, our prior work has shown that 1) SCH-58261 can be encapsulated by cMLVs and stably conjugated to the CAR-NK92 cell surface, 2) anti-mesothelin CAR-NK92 cells are activated by and exert cytotoxic effects against mesothelin-expressing target cells in vitro, 3) SCH-58261 restores the functionality of TME-resident T cells when delivered by CAR-engineered T cells in vivo, and 4) conjugation to CAR-NK92 cells improves the delivery of cMLVs to the tumor site in vivo. We propose to expand upon this work by 1) exploring the drug release kinetics of SCH58261 in free and cell-conjugated cMLVs and ensuring that SCH-58261 does not adversely affect CAR-NK92 cell function, 2) testing the in vitro function of conjugated, irradiated CAR-NK92 cells, and 3) examining the effects of our therapy on tumor growth and on TME-resident T cells in an ovarian xenograft mouse model. The Wang lab from Viterbi School of Engineering and the Hu lab from Keck School of Medicine will team up for this novel, innovative project which combines nanomedicine with immunotherapy.