SUN-299 Targeting Cancer Cell Non-autonomous CAMKK2 Signaling for the Treatment of Advanced Prostate Cancer

Abstract Disclosure: F.E. Lujan: None. T.L. Pulliam: None. J.J. Han: None. D.E. Frigo: None. Currently, there is no cure for metastatic, castration-resistant prostate cancer (mCRPC). The lethality of this disease stage is thought to be driven in part by the immunosuppressive tumor microenvironment of mCRPC. Hence, mechanistically new treatments are desperately needed for this lethal disease stage which, to date, has been resistant to existing immunotherapies. Prior studies have established calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) as a promising new therapeutic target for the treatment of mCRPC through modulation of cancer cell metabolism. Emerging data indicate additional cancer cell-extrinsic roles for CAMKK2 in regulating the tumor immune microenvironment in other cancer types, specifically by regulating myeloid cell function. Here, we demonstrate that systemic ablation of Camkk2 enhances the efficacy of immune checkpoint therapy (ICT), impairs tumor growth, increases survival, and possibly promotes anti-cancer immune memory in syngeneic prostate cancer mouse models. In addition, we conditionally deleted Camkk2 in myeloid cells using a LysM-Cre driver and observed impaired syngeneic tumor growth, and thus improved survival, in LysM-CreTg/Tg;Camkk2fl/fl mice relative to matched LysM-CreTg/Tg control mice. These results suggest that targeting CAMKK2 in myeloid cells promotes an antitumoral immune response in prostate cancer. Further studies are needed to identify the immune cell populations involved in the anti-tumor immune response following Camkk2 deletion in myeloid cells that may contribute to the reduction in tumor progression. Moreover, the mechanisms by which CAMKK2 promotes immunosuppressive functions in myeloid cells remain unclear. Together with prior published work, our data indicate that CAMKK2 has dual cancer cell-autonomous and -non-autonomous oncogenic actions and thus, is an attractive, bifunctional therapeutic target for the treatment of advanced prostate cancer. Presentation: Sunday, July 13, 2025