Abstract 3221: Identification and characterization of FAK kinase as a novel regulator of PD-L1 stability and activity in cancer immune evasion

Abstract The PD-1/PD-L1 axis is an essential immune checkpoint that modulates T cell-mediated immune responses. Cancer cells exploit this checkpoint to inhibit anti-tumour immune activity, enabling immune evasion. Thus, blocking PD-1/PD-L1 using antibodies has become a cornerstone of cancer immunotherapies. However, despite promising results, these therapies show limited response rates in many cancer patients and often lead to adverse effects, impacting its overall efficacy. Therefore, understanding of the molecular mechanism underlying immunotherapy resistance is critical for successful cancer immunotherapy. Emerging research indicates that phosphorylation of PD-L1 by kinases significantly influence PD-L1 stability and functionality, thereby contributing to cancer cell immune evasion and influencing immunotherapy outcomes. However, although 560 kinases have been identified in the human kinome, there is no systematic screening of kinases regulating PD-L1 stability and its function in immune evasion. By using a PD-L1 NanoLuc luciferase biosensor, in this study, we performed a systematic kinome-wide screening and identified focal adhesion kinase (FAK) as a novel regulator of PD-L1 stability in cancer. Further investigation of FAK-mediated PD-L1 signalling and its role in immune evasion may provide a new therapeutic strategy for cancer treatment. Citation Format: Asia-lily Boyd, Prem Khanal, Yawei Hao, Xiaolong Yang. Identification and characterization of FAK kinase as a novel regulator of PD-L1 stability and activity in cancer immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3221.